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1704 Current Organic Chemistry, 2013, 17, 1704-1709

Conceptual Challenges for Contemporary Theories of the Origin(s) of Life

Carol E. Cleland*

Department of Philosophy, Center for Astrobiology, University of Colorado, Boulder, CO 80309-0232, USA

Abstract: Contemporary theories of the origin of life divide along the same conceptual lines as contemporary accounts of the nature of
life, with small molecule theories (e.g., Wächtershäuser’s iron pyrite world) corresponding to metabolic theories/definitions of life and
genes-first theories (currently dominated by the RNA world) corresponding to evolutionary (e.g., chemical Darwinian) theo-
ries/definitions of life. I discuss some difficulties faced by this general approach: First, it isn’t at all obvious that a successful theory of
the origin of life will divide along the same lines as a theory of the nature of life. Second, in both cases there is the worry that signs of life
are being mistakenly treated as essential to life. Third, most theories of the origin of life tend to minimize or even side step the transition
from nonliving ensembles of molecules to the first proto-organisms. I close with a suggestion for dealing with some of these difficult
problems.

Keywords: Origin of life, Prebiotic chemistry, RNA world, Small molecule theories, Containment theories, Biological natural selection,
Molecular natural selection.

INTRODUCTION
Two general approaches to understanding the origin of life have
dominated scientific thought since the early twentieth century: the
genes-first school, currently represented by the RNA World, and
the metabolism-first school, currently represented by what Robert
Shapiro has dubbed the “small molecule theory” [1]. The first part
of this essay traces the division between genes-first and metabo-
lism-first accounts of the origin of life back to the writings of the
ancient Greek philosopher Aristotle on the nature of life. As I dis-
cuss, it isn’t obvious that a successful scientific theory of the nature
of life will divide along the same lines as a successful scientific
theory of the origin of life; as an analogy, one can understand the
nature of the mineral quartz (SiO2) without knowing how it is pro-
duced by natural processes. Furthermore, with respect to both the
nature and origin of life there is the worry that signs of life are mis-
takenly being elevated as essential to life. By analogy, the triple
point of water can be used to recognize which chemical substances
are water but it does not reveal the underlying nature of water (be-
ing composed of H2O). Indeed, it wasn’t until the work of Lavoisier
in the late eighteenth century that chemists began breaking with the
old Aristotelian concept of chemical substance, paving the way for
an empirically compelling, molecular account of the nature of
chemical substances. One cannot help but wonder whether scien-
tific progress in understanding the origin of life is being impeded by
tacit acceptance of what amounts to an old Aristotelian theoretical
framework for understanding the nature of life.
The second half of this essay focuses on some central but un-
derappreciated conceptual difficulties facing the small molecule
theory and the RNA World. First, the small molecule theory is very
vague about the identity of the molecules and processes involved in
the development of the earliest primitive metabolic cycles, which
makes it seem less well developed as a model of the origin of life
than the RNA World. But as will become apparent, the RNA World
is not as well fleshed out as commonly supposed and, like the small
molecule theory, the proverbial devil is in the details. In addition,
*Address correspondence to this author at the Department of Philosophy, Center for
Astrobiology, University of Colorado, Boulder, CO 80309-0232, USA;
Tel: 303-492-7619; E-mail: Carol.Cleland@Colorado.edu
both the small molecule theory and the RNA World tend to mini-
mize or even side step the most difficult problem facing a scientifi-
cally compelling theory of the origins of life: the abiotic transition
from a nonliving ensemble of molecules to a primitive living
chemical system.
There are two critical stages involved in this transition: (1) the
abiotic synthesis of primordial biopolymers and chemical reaction
networks capable of jumpstarting the RNA World or small mole-
cule theory from basic molecular building blocks (e.g., amino acids,
lipids, and nucleobases), and (2) the development of the complex
cooperative arrangement (mediated by ribosomes in contemporary
organisms) between proteins and nucleic acids required for Darwin-
ian evolution. That we have an inadequate understanding of the
former in the case of the RNA World is flagged by the frequent use
of the vague term “spontaneous” to characterize the abiotic synthe-
sis of the first RNA oligomer(s) under natural conditions. Analo-
gously, advocates of the small molecule theory use the obscure
concept of emergence to gloss over the transition from an ensemble
of small organic molecules to a collectively autocatalytic, chemical
reaction system. The focus of both theories is primarily on what
happens after the formation of the pertinent simple biopolymers and
chemically heterogeneous and unorganized reaction systems in
which they participate. Furthermore, both theories partition living
systems into a genetic part and a metabolic part and position them-
selves as rivals with respect to this division, with the RNA World
privileging the former and the small molecule theory privileging the
latter. This tends to marginalize the issue of how these two subunits
became integrated.
THE LEGACY OF ARISTOTLE
Two characteristics are commonly advanced as essential to life:
(O) the capacity to self-organize and maintain self-organization for
an extended period of time against both internal and external per-
turbations and (R) the capacity to reproduce and (since the advent
of Darwin’s theory of evolution by natural selection) transmit to
progeny adaptive characteristics. As stated, characteristics O and R
are abstract and functional: no reference is made to the material
composition and physical architecture of systems realizing them.
Indeed, they could be implemented on digital computers as purely

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Conceptual Challenges for Contemporary Theories of the Origin(s) of Life
informational (input-output) structures, which explains much of the
impetus behind hard and soft artificial life (aka Alife) research;
synthetic biology is also sometimes classified as Alife but because
it is restricted to organic matter is different in kind from robotic and
software based artificial life. This raises the issue of the degree to
which life is truly independent of its material composition and
physical structure. For most chemico-physical systems there is a
point at which the process of abstraction must stop or one loses
information critical to understanding the unity of the system as a
certain sort of thing. As an illustration, all physical entities are
made of mass, but this is not enough to explain how rock salt dif-
fers from ammonium salt or water from nitric acid.
The idea that O and R are essential to life is very old. They are
found in rudimentary form in the writings of Aristotle, who charac-
terized life in terms of the capacities for “self-nutrition” and “self-
reproduction” [2]. Writing more than two thousand years before
Darwin, Aristotle believed that biological species were fixed and
eternal; he did not entertain the idea of biological evolution. On the
other hand, he did recognize that living things have the peculiar
property of being “self-caused.”
Aristotle debated whether nutrition or reproduction is more
fundamental to life. In some of his writings, he seems to opt for
reproduction over nutrition and literally “define” life in terms of
reproduction [3]. Most contemporary scientific accounts of the
nature of life, which are commonly formulated as definitions†, fol-
low Aristotle in treating one of these characteristics as logically or
theoretically more fundamental than the other. Metabolic-
biochemical (e.g., Oparin [5]), thermodynamic (e.g., Kauffman [6]),
and more abstract autopoietic (e.g., Verela et al. [7]) definitions of
life reflect the view that O is more fundamental than R, whereas
Darwinian (e.g., Dawkins [8]), genetic-biochemical (e.g., Joyce
[9]), and more inclusive evolutionary (e.g., Bedau [10]) definitions
of life reflect the view that R is more fundamental. Nevertheless
there is little scientific support for the claim that one is more fun-
damental than the other. Life as we know it on Earth today (with
the possible exception of viruses, whose status as living entities is
unclear) exhibit both O and R. As a consequence both characteris-
tics are equally in need of explanation in terms of natural processes.
We cannot rule out the possibility that O and R are independent,
equally essential characteristics of life. If this is the case, the bifur-
cation of contemporary definitions of life along the lines of O or R
is fundamentally mistaken.
This isn’t the only worry associated with dividing theories of
the nature and origins of life along the lines of O and R. While all
cellular life thus far encountered on Earth exhibits O and R, we
cannot rule out the possibility that the most fundamental character-
istics of life have yet to be discovered. It is possible that O and R
represent potentially unreliable symptoms of more fundamental but
as yet unknown properties. This has happened before in science.
Lacking recourse to molecular theory, the alchemists chose sol-
vency as the essential property of water, and as a consequence iden-
tified chemical substances, e.g., nitric acid, that we now know are
not water as water [11]; it is not an accident that they called nitric
acid ‘aqua fortis’. Similarly, prior to the germ theory of disease,
most diseases were identified by means of symptoms, which some-
times resulted in what we now recognize as the same disease (qua
underlying infectious agent) being classified as distinct diseases and
† licate and undergo evolution by natural selection (R), and metabo-
(I have argued elsewhere that it is a mistake to try to define life, and that theories and
definitions are very different sorts of things [4]. But this point is not important for
purposes of this paper)
Current Organic Chemistry, 2013, Vol. 17, No. 16 1705
different diseases being classified as the same disease. Tuberculo-
sis, for example, doesn’t produce the tell tale ‘consumptive cough’
when it infects the lymph glands, as opposed to lungs. Biologists
may someday discover that O and R are, like solvency and a con-
sumptive cough, unreliable symptoms of more fundamental under-
lying properties.
The problem is exacerbated in the case of life because molecu-
lar biologists have ascertained that familiar life on Earth descends
from a last universal common ancestor (LUCA) and biochemists
have identified some modest ways in which life might have been
different at the molecular and biochemical level. These discoveries
suggest that we are dealing with a single, possibly unrepresentative,
sample of life. One cannot generalize to all life, wherever and
whenever it may be found, from a single sample of life. To do so
would be a bit like trying to come up with a theory of mammals
when one can observe only zebras. It is unlikely that someone faced
with this task would focus on their mammary glands because they
are characteristic only of female zebras. A more likely candidate
would be their stripes, which are common to all zebras. Yet the
mammary glands of female zebras are far more relevant to their
nature as mammals than their ubiquitous stripes. The moral is that,
from a logical point of view, one cannot safely ground a generaliza-
tion about all of life on characteristics universal to familiar Earth
life.
In this context, the history of Aristotle’s once dominant concept
of chemical substance should be sobering. Following earlier Greek
thought, Aristotle contended that all earthly material substances are
constructed from four basic elements: earth, water, air, and fire
[12]. By the seventeenth century most alchemists excluded fire as
an element but remained committed to the other three [13]. From a
modern perspective, one of the striking features of this neo-
Aristotelian account of material substance is that it cuts along the
same lines as the three phases of matter, namely, solid (earth), liq-
uid (water), and gas (air). The neo-Aristotelian account of material
substance only began to fall out of favor in the late eighteenth cen-
tury with work such as Antoine Lavoisier’s seminal paper “On the
nature of water and on experiments that appear to prove that this
substance is not properly speaking an element, but can be decom-
posed and recombined” [14]. The development of modern chemis-
try critically hinged upon the development of a phase independent
concept of chemical substance by Josiah Gibbs and others in the
nineteenth century. In short, the rejection of the old Aristotelian
theoretical framework for understanding matter was crucial to the
development of modern chemistry. One cannot help but wonder
whether contemporary scientific thought about the nature of life is
being held hostage to ancient Aristotelian ideas about life. While it
may be difficult for us to imagine how something other than O and
R could be essential to life it is important to keep in mind that, in
the absence of molecular theory, a seventeenth century scientist
would have been similarly challenged in imagining how the essence
of water could consist of something other than a sensible property
such as being a good solvent.
THE NATURE VS. ORIGIN QUESTION
Theories of the origin of life tend to bifurcate along the same
lines as definitions of life. With a few exceptions – e.g., Freeman
Dyson’s ([15]) “double-origin” theory – genes-first theories of the
origin of life (e.g., the RNA World) emphasize the capacity to rep-
lism-first theories (e.g., the small molecule theory) emphasize the
capacity to self-organize and maintain self-organization (O). As
1706 Current Organic Chemistry, 2013, Vol. 17, No. 16
discussed in the next section, the rubrics ‘RNA World’ and ‘small
molecule theory’ each encompass a diversity of theories differing in
important chemico-physical details. Alexander Oparin was the first
to explicitly champion the belief that there is an intimate connection
between a theory of the nature of life and a theory of the origins of
life [5]. But even supposing, for the sake of argument, that we had a
satisfactory theory of the nature of life there is little reason to be-
lieve that one could extract from it (what amounts to) a causal rec-
ipe for life.
Consider the mineral quartz. One cannot infer how quartz is
made under natural conditions (via magmatic processes) from either
its unique macro-mineralogical properties (hardness, chemical in-
ertness vis-à-vis most substances, heat resistance, crystal habit, etc.)
or its molecular composition (SiO2). These properties (especially
the latter) supply scientifically compelling answers to queries about
the nature of quartz and they are used to discriminate quartz from
other minerals, but they don’t reveal the geological processes that
actually produce it. To bring this point closer home, biochemists
have a good understanding of the molecular composition, structure,
and biological function of nucleic acids. Indeed, they are even able
to synthesize them in artificial, laboratory settings. But they still
struggle to understand how these enormous, highly complex,
chemically fragile and versatile biomolecules could have been pro-
duced on the early Earth under plausible natural, geochemical con-
ditions [16]. In a nutshell, it is not in general true that one can infer
how something is made from an understanding of its nature.
Darwin’s theory of evolution by natural selection is sometimes
cited as establishing that life is special in this regard. Yet despite
Darwin’s often cited speculations in an 1870 letter to Joseph
Hooker about life originating in a “warm little pond,” his theory has
little to say about how the first living things on Earth emerged from
nonliving matter. The scope of Darwin’s theory is the history and
diversity of life on Earth. It provides a unified, naturalistic account
of phenotypic similarities and differences (geographical and geo-
temporal) among what we now know is a single kind of life—
organisms descended from a last universal common ancestor. That
is to say, Darwin’s theory presupposes the existence of a certain
kind of life—familiar Earth life. With regard to the general possi-
bilities for life or the natural mechanisms responsible for its emer-
gence from nonliving chemicals on Earth or elsewhere Darwin’s
theory is silent.
Some researchers nevertheless contend that natural selection,
the core mechanism of Darwinian evolution, characterizes all life,
wherever and whenever it may be found in the universe. Richard
Dawkins [8] famously argues that natural selection is the funda-
mental principle of life. But even supposing that Dawkins was cor-
rect about the nature of life it wouldn’t follow that natural selection
can explain how living systems emerge from nonliving ensembles
of molecules. Darwin’s concept of natural selection presupposes a
strong biological concept of heredity: heritable variation and differ-
ential heritable fitness in a population of self-replicating entities.
Because they lack hereditary systems of this sort, nonliving entities
cannot undergo evolution in Darwin’s sense. One of the central
challenges facing a theory of the origin of life is to explain how a
chemical system could develop the kind of sophisticated hereditary
properties required for Darwinian natural selection.
This problem is sometimes overlooked by defenders of the
RNA World theory of the origin of life, which draws much of its
motivation from Manfred Eigen [17], who defended a principle of
molecular (also known as chemical) natural selection to explain the
development of the earliest living molecular systems from
Carol E. Cleland
nonliving chemicals. But as discussed in the following section, the
concept of heredity invoked by defenders of the RNA World is so
attenuated from a biological perspective that it isn’t clear that it can
do the work required of it. Some physical scientists advocate gener-
alizing the concept of natural selection even further. Theoretical
physicist Lee Smolin [18], for instance, contends that the historical
development of the universe can be explained in terms of a princi-
ple of cosmological natural selection, which doesn’t involve a rec-
ognizable concept of heredity. The more removed from biology a
principle of selection—however natural it may seem—the less ob-
vious that it could shed light on the origins or, for that matter, na-
ture of life.
CONTEMPORARY THEORIES OF THE ORIGIN OF LIFE
Contemporary models of the origin of life are sometimes
treated as if they fall into three general categories: (1) containment
theories, (2) the small molecule theory (henceforth: SM World),
and (3) the RNA World. Containment theories focus on the selec-
tion, concentration, and protection of molecular precursors to bio-
molecules. There are formidable energetic and chemical obstacles
to the abiotic synthesis of small biopolymers, whether peptides or
RNA oligomers (or monomeric nucleotides, for that matter), under
natural conditions. Basic molecular building blocks (such as amino
acids, or ribose and nucleobases) must be present in sufficient quan-
tities and brought into close enough proximity to chemically react
while minimizing the possibility of interfering chemical reactions.
The resultant short peptides or RNA oligomers are chemically frag-
ile and require protection from degrading chemical and physical
processes if they are to develop the length and complexity required
for biological functionality. Vesicles of various sorts—e.g., coacer-
vates [5], proteinoid microspheres ([19]), amphiphilic vesicles (e.g.,
[20-23]), and atmospheric aerosols [24]—as well as mineral sur-
faces (e.g., [25-27]) and voids in porous rocks [e.g., 28] have been
advanced as mechanisms for achieving containment.
Most containment theories are prebiotic in the sense that they
are primarily concerned with the development of molecular precur-
sors to compounds having enough complexity and sophistication to
realize biological functions such as metabolism, reproduction, and
Darwinian evolution, e.g., ([20], [22], [27]). But a few researchers
(e.g., Morowitz) identify the transition from nonliving ensembles of
molecules to a minimal living chemical system with the develop-
ment of certain kinds of vesicles (those enclosed by amphiphlic
bilayers [21]); I will have more to say about this shortly.
The SM World and the RNA World, on the other hand, are con-
cerned with more advanced stages in the genesis of life. According
to the SM World, the “emergence” of collectively autocatalytic
networks of chemical reactions involving small molecules marks
the transition to life from nonlife. The SM World focuses on the
development of increasingly complex levels of chemical organiza-
tion, culminating in a proto-metabolism; see, e.g., [1], [6], and [23].
There are a number of problems with the SM World, however.
First, as the appellation suggests, the identity of the small molecules
involved is fairly open. Although most versions focus on small
organic molecules such as amino acids, small peptides, and cofac-
tors, Robert Shapiro doesn’t rule out the development of metabo-
lisms based upon small inorganic molecules [1]. Either way, how-
ever, it seems likely that the chemical-reaction networks involved
have to cope with a variety of small environmental molecules, not
all of which are advantageous and some of which have the potential
to inhibit or disrupt its development.
Conceptual Challenges for Contemporary Theories of the Origin(s) of Life
In addition, the SM World faces the problem of jumpstarting
the kind of dynamical organization required for proto-metabolic
cycles. As the frequent use of the term “emergence” by its propo-
nents indicates the physico-chemical processes that achieve this are
not well understood. Indeed, Stuart Kauffmann conjectures that a
new law of thermodynamics for open systems that are far from
equilibrium is required [6]. Unfortunately, he doesn’t provide a
precisely formulated statement of this mysterious law, which
amounts to a concession that we currently have no idea how a col-
lection of small molecules could self-organize into proto-metabolic
cycles capable of further development. The plausibility of the SM
World rests upon fleshing out the nebulous concept of emergence in
an empirically testable way rather than simply using it to cover up a
yawning gap in our understanding.
The RNA World, in contrast, is predicated on the “spontane-
ous” formation of a small RNA oligomer capable of catalyzing its
own replication. The focus is on “evolving” longer and more com-
plex RNA polymers with increasingly efficient catalytic capacities,
providing a molecular foundation for a genetic system; see, e.g.,
[22], [27], and [29]. Despite what some of its advocates claim, the
RNA World faces problems strikingly analogous to those con-
fronted by the SM World.
The term “spontaneous” marks just as serious a lacuna in the
RNA World model as does “emergence” in the SM World. The
assembly of RNA from precursor monomers (nucleotides) and the
synthesis of the latter from basic molecular building blocks (ribose,
phosphate, and nitrogenous bases) under plausible natural condi-
tions on the early Earth faces major chemical and physical hurdles,
and even supposing that these difficulties could be overcome the
resultant simple RNA oligomers are extremely fragile. The difficul-
ties are so serious—as Christian De Duve [30] and others (e.g.,
Dyson [15] and Shapiro [1]) have argued, much more challenging
than the abiotic synthesis of peptides from amino acids under natu-
ral conditions—that some advocates of the RNA World mean by
“spontaneous” an extremely improbable (one-off) event. Such an
occurrence, however, would amount to a scientific miracle uncom-
fortably akin to a divine act of creation [31]. Extremely improbable
events cannot be explained scientifically; science can only sanction
the claim that they are not physically impossible.
Because the prebiotic synthesis of an RNA polymer under natu-
ral conditions seems so improbable, some advocates of the RNA
World postulate a pre-RNA World involving an analogue of nucleic
acids that was later replaced by RNA. None of the candidates (e.g.,
PNA, TNA, or GNA) thus far suggested, however, are much of an
improvement over RNA [32]. If it is to provide a scientifically
compelling account of the origin of life, the RNA World needs to
replace “spontaneous” with a combination of chemical-reaction
sequences under which the assembly of RNA oligomers from some
combination of their basic molecular building blocks under plausi-
ble natural conditions on the early Earth turns out to be highly
probable.
Although the focus on a specific variety of nucleic acid sug-
gests that it is better fleshed out than SM World, the RNA World is
not well defined; this is acknowledged by some of its proponents
[22]. Some versions emphasize a community of fairly homogenous,
self-catalytic RNA oligomers “evolving” into more complex and
catalytically efficient polymers through a process of molecular
natural selection [33], whereas others focus on a co-evolving com-
munity of diverse but mutually catalytic RNA oligomers (e.g.,
[22]), and still others are open to small organic molecules such as
amino acids and short peptides playing supporting catalytic roles in
Current Organic Chemistry, 2013, Vol. 17, No. 16 1707
the development of increasingly complex and catalytically efficient
RNA polymers (e.g., [34]). Many advocates of the RNA World,
however, are not very specific about which version they have in
mind, which lends an illusion of greater unity to the RNA world
than it actually possesses.
The division of contemporary models of the origin of life into
containment theories, the SM World, and the RNA World blurs
some important distinctions. First, these models are not incompati-
ble. They are pitched at different levels of theoretical analysis. Most
containment theories are concerned with chemical and physical
conditions required for the abiotic synthesis and protection of small
biopolymers, and hence fall primarily within the purview of prebi-
otic chemistry. For this reason most researchers in the SM and
RNA Worlds treat containment as necessary but not sufficient for
the emergence of life [e.g., 1,20,22,23,27,29]. The SM World and
the RNA World, on the other hand, are not prebiotic and represent
rival theories of the origin of life. Both presuppose the synthesis of
small, primordial biopolymers (peptides and RNA oligomers) and,
privileging one type of biofunctionality over another, focus on the
development of increasingly complex, quasi-metabolic, reaction
networks (SM World) or longer and catalytically more efficient
RNA oligomers (RNA World). And this brings us back to issues
discussed in the first half of this paper. A metabolism-first theory
might be true for the origin of life despite the fact that characteristic
R (in essence, a genetic system) is more fundamental to the nature
of life than characteristic O (metabolism) or a genes-first theory
might be true for the origin of life despite the fact that characteristic
O is more fundamental to the nature of life than R. Moreover, under
very different chemical and physical conditions (e.g., Earth vs.
Titan) there might be quite different causal pathways for achieving
characteristics O and R, some producing the building blocks for
metabolism first and others producing the building blocks for genes
first, or alternatively, the physico-chemical underpinnings of O and
R might have developed concurrently from basic building blocks.
Finally, there is the unsettling and seemingly far fetched possibility
that neither O nor R are fundamental to life but rather represent
high-level properties (aka symptoms) of familiar Earth life, in
which case it is a mistake to use them as criteria for determining the
stage at which a nonliving ensemble of molecules transitions to a
primitive living chemical system. Containment theories of the ori-
gin of life, on the other hand, are neutral as to whether O or R is
more fundamental to life. Indeed, a requirement for some sort of
“container,” whether vesicle or absorbent mineral surface, is often
explicitly included in the SM World and the RNA World because
the chemical reactions are energetically up hill and the precursor
biomolecules easily degraded.
Some researchers seem cognizant of the importance of distin-
guishing a theory of the origins of life from that of the nature of
life. Harold Morowitz, for instance, explicitly defends a vesicles-
first theory of the origin of life on the grounds that enclosure by
amphiphilic bilayer membranes is required for the development of
chemical-reaction networks having sufficient complexity and so-
phistication to qualify as proto-metabolic [21]. Similarly, Leslie
Orgel, an advocate of the RNA World, contends that a genetic
polymer is required to achieve the level of organization of chemi-
cal-reaction sequences required for a primitive metabolism [35]. In
both cases, metabolism is being held up as more essential to life
than containment or a genetic system even though it is not being
endorsed as the crucial step in the transition to life from nonliving
chemicals. The view that metabolism is the most fundamental char-
acteristic of life is also expressed in the writings of Erwin
1708 Current Organic Chemistry, 2013, Vol. 17, No. 16
Schrödinger, who somewhat ironically is associated with a nucleic
acid (qua “large aperiodic solid”) account of the nature of life: In
his words, “What is the characteristic feature of life? When is a
piece of matter said to be alive? When it goes on “doing some-
thing”, moving, exchanging material with its environment, and so
forth, and that for a much longer period than we would expect an
inanimate piece of matter to “keep going” under similar circum-
stances” [36].
Not all defenders of theories of the origin of life are as clear
about their views on the nature of life as Morowitz, Orgel, and
Schrödinger, and this can lead to ambiguities. An advocate the
RNA world who endorses a metabolic account of the nature of life
is chiefly concerned with the critical role played by a genetic sys-
tem in orchestrating a sufficiently complex network of autocatalytic
chemical-reaction sequences to count as proto-metabolic. For the
latter represents the pivotal step in the actual genesis of life; the role
of the RNA World is prebiotic. One would anticipate such a re-
searcher to be sympathetic to an RNA world consisting of a greater
diversity of small organic molecules (amino acids, short peptides,
and cofactor, as well as RNA oligomers and their precursors) than a
defender of the RNA World who embraced a genetic account of the
nature of life. Not all defenders of the RNA World are, like Orgel,
committed to a metabolic account of the nature of life. A good illus-
tration is Jerald Joyce who (at least at one time) explicitly endorsed
a “chemical-Darwinian definition of life” [8]. It is not surprising
that Joyce’s discussions of the RNA World frequently portrays it as
consisting almost exclusively of (a diverse set of) RNA oligomers
and their precursors [e.g., [22]) since, on his view, a sufficiently
sophisticated RNA World can make the transition to life (produce
“ribo-organisms,” [37]) all on its own, independently of peptides
and proteins.
Some defenders of the SM World also seem tacitly committed
to a genetic account of the nature of life. Anyone defending the SM
World on the grounds that the assembly of RNA oligomers, as well
as some of their precursors, require chemical-reaction networks
complex enough to qualify as primitively metabolic is tacitly privi-
leging a genetic system. The same goes for someone compelled to
include a “compositional genome” (in which genetic information is
represented by the identity and concentration of molecular constitu-
ents, as opposed to being “stored” indirectly in a list) that is later
replaced by a molecular genome as a critical component of the SM
World [23]. It is of course possible that an advocate of the SM
World who privileges a genetic system believes that both metabo-
lism and a genetic system are essential to life. Unfortunately, how-
ever, many are unclear about their commitments vis-à-vis the nature
of life and may be unnecessarily augmenting their account of the
SM World with an additional level of potentially problematic com-
plexity; if one holds a metabolic account of the nature of life and
believes that proto-metabolic networks sufficient for primitive life
don’t require a genetic system, there is no need to introduce one at
such an early stage. The point is lack of clarity about one’s com-
mitments on the nature of life can lead to theoretical ambiguities
and confusions over what needs to be included in a theory of the
origins of life. Indeed, the lines between the SM World and the
RNA World begin to blur when one carefully distinguishes a theory
of the origins of life from a theory of the nature of life, and hybrid
models, combining aspects of both the RNA World and the SM
World, become increasingly attractive.
Neither the SM World nor the RNA World directly address one
of the most difficult problems concerning the origin of familiar
Earth life, namely, the development of the complex, cooperative
Carol E. Cleland
arrangement between proteins and nucleic acids; even viruses re-
quire this arrangement insofar as they have to harness the metabolic
machinery of a cell in order to propagate themselves. This is hardly
surprising when one considers that both theories accept the neo-
Aristotelian bifurcation of life into a metabolic part and a genetic
part, and position themselves as rivals. The integration of these
parts into a single, unified, living system so-to-speak falls through
the crack. Appeals to a compositional genome by some advocates
of the SM World do not illuminate how a nucleic acid polymer able
to encode a protein-based, metabolic (and structural) system ever
got off the ground. Similarly, postulating a community of RNA
polymers developing increasingly complex self or mutually cata-
lytic capacities does not reveal how RNA molecules acquired the
ability to encode and orchestrate a protein-based, metabolic-
structural system.
It is sometimes argued that the RNA World provides a unified
account of the metabolic and genetic aspects of life in virtue of the
dual ability of RNA molecules to store hereditary information and
catalyze chemical reactions, including their own replication. It is a
stretch, however, to characterize an RNA polymer from the RNA
world as “encoding” hereditary information in a biological sense.
An encoding device converts information from one form to another.
Nothing of this sort happens in the RNA World. There isn’t a
physical distinction between the molecule that does the encoding
and the molecule being encoded; under the simplest and purest
versions of the RNA World [33], they are literally the same. At
best, an RNA polymer or ensemble of RNA polymers might be said
to encode itself in virtue of its ability to propagate its chemical
identity through a process of self or mutual catalysis. Because the
copying process is not perfect RNA polymers of varying catalytic
efficiencies will be produced, and those that are more efficient and
physico-chemically robust will generate more of themselves than
those that are not.
From a superficial standpoint the process described above
sounds a bit like biological natural selection. There are critical dif-
ferences, however. In Darwinian evolution the distinction between
the phenotype (metabolic, structural, and behavioral characteristics)
and the genotype of an organism is central to the selection process.
The fitness of an organism depends upon its phenotype, which is
determined by the catalytic and structural properties of proteins.
The role of the genetic system is to propagate the phenotypic prod-
ucts of natural selection to future generations in virtue of the fact
that the pertinent proteins are already encoded on the nucleic acids
of the survivors. Changes occurring directly (unmediated by inter-
actions of the phenotype with the environment) to the nucleic acid-
based genome of an organism are not the product of biological
natural selection but mutation, often due to molecular level interac-
tions with the physico-chemical environment (chemicals, radiation,
etc.). Viewed from this perspective, what goes on in the RNA
World seems more like Lamarckian evolution—the direct transmis-
sion of acquired molecular characteristics (mutations) to future
“generations”—than Darwinian evolution. One may of course de-
liberately extend the concept of natural selection to encompass
molecular selection of the sort hypothesized to occur in the RNA
World, but only at the risk of climbing to a level of analysis that is
too abstract to make good scientific sense of biological natural se-
lection. Molecular natural selection and biological natural selection
do not appear to lie on opposite ends of a physico-chemical contin-
uum. The actual mechanisms involved seem quite different, which
brings us back to the problem of making good sense of the complex
Conceptual Challenges for Contemporary Theories of the Origin(s) of Life
cooperative arrangement between the protein-based, metabolic
subsystem of familiar Earth life and its nucleic acid-based, genetic
subsystem.
So how did the dual protein-nucleic acid system characterizing
contemporary life today arise under natural conditions? As the dis-
cussion above underscores, this is not a peripheral issue with re-
spect to the issue of how life as we know it today originated on
Earth. Many of the most distinctive characteristics of familiar life,
including Darwinian evolution, presuppose it, which is not of
course to claim that all life, wherever it may be found in the uni-
verse, requires it. The bifurcation of scientific thought about the
origin of life into rival RNA World and SM World camps makes
solving this problem more difficult than it would otherwise be. For
it is always more difficult to explain how two subsystems are inte-
grated if one begins by thinking of them as wholly separate. Per-
haps the integration of proteins and nucleic acids began very early
on in a hybrid molecular “world” consisting of a variety of small
molecules, including amino acids, small peptides, metal ions, phos-
phates, ribose, and nitrogenous bases, participating in increasingly
complex and sophisticated chemical-reaction networks, and the
functional division of contemporary life into a dual molecular sys-
tem emerged at a later stage. Freeman Dyson’s double origin theory
takes this possibility serious [15], as do some recent hybrid theories
of the origin of life (e.g., [38]). If the dual molecular character of the
basic functional units of highly evolved familiar life emerged gradu-
ally, through a process of chemical differentiation, research con-
ducted solely within the paradigm of the RNA World or alternatively
the SM World will tend to be self-defeating. Each paradigm will
guide scientific thinking and focus experimental research along dif-
ferent but equally unproductive lines. Viewed in this light, a more
promising approach is not to abandon the RNA World or the SM
World but to soften their sharp edges and be willing to consider hy-
brid theories combining aspects of both.
The concepts of the RNA World and the SM World provide
much needed places to stand—fulcrums from which to initiate sci-
entifically promising investigations of the physico-chemical genesis
of life—but it is premature to conclude that either holds the ultimate
answer to the question of how life originates here on Earth or else-
where in the universe. Indeed, historical precedents are not hard to
find. Before the 19th century and again at the turn of the 20th cen-
tury physicists were bitterly divided into rival camps over whether
light is composed of particles or waves. As is now known, neither
of these theories is correct. But it took the development of a radical
new theory, quantum mechanics, in the early 20th century for physi-
cists to finally understand the dual wave-particle character of light.
We cannot rule out the possibility that we are facing an analogous
dilemma in our attempts to understand the nature of life.
CONFLICT OF INTEREST
The authors confirm that this article content has no conflicts of
interest.
ACKNOWLEDGEMENTS
Declared none.
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Revised: May 07, 2013 Accepted: May 12, 2013