Studies in History and Philosophy of Biological and Biomedical Sciences 43 (2012) 741750

Contents lists available at SciVerse ScienceDirect

Studies in History and Philosophy of Biological and

Biomedical Sciences
journal homepage: www.elsevier.com/locate/shpsc

How the discovery of ribozymes cast RNA in the roles of both chicken
and egg in origin-of-life theories
Neeraja Sankaran
History of Science, Technology & Medicine Underwood International College, Yonsei University, 50 Yonsei-Ro, Seodaemun-Gu, Seoul 120-749, Republic of Korea

a r t i c l e i n f o a b s t r a c t

Article history: Scientic theories about the origin-of-life theories have historically been characterized by the chicken-
Received 18 February 2012 and-egg problem of which essential aspect of life was the rst to appear, replication or self-sustenance.
Received in revised form 10 June 2012 By the 1950s the question was cast in molecular terms and DNA and proteins had come to represent the
Available online 9 August 2012
carriers of the two functions. Meanwhile, RNA, the other nucleic acid, had played a capricious role in ori-
gin theories. Because it contained building blocks very similar to DNA, biologists recognized early that
Keywords: RNA could store information in its linear sequences. With the discovery in the 1980s that RNA molecules
Origins of life
were capable of biological catalysis, a function hitherto ascribed to proteins alone, RNA took on the role of
Ribozymes
RNA
the single entity that could act as both chicken and egg. Within a few years of the discovery of these cat-
RNA World alytic RNAs (ribozymes) scientists had formulated an RNA World hypothesis that posited an early phase
in the evolution of life where all key functions were performed by RNA molecules. This paper traces the
history the role of RNA in origin-of-life theories with a focus on how the discovery of ribozymes inu-
enced the discourse.
2012 Elsevier Ltd. All rights reserved.

When citing this paper, please use the full journal title Studies in History and Philosophy of Biological and Biomedical Sciences

1. Introduction Guerrier-Takada et al., 1983)brought RNA from a place of relative

One of the prevalent ideas regarding the origins and evolution
of life on earth to have taken hold within the scientic community
has been that of the RNA World. First proposed in 1986 by Wal-
ter Gilbert (1986) this model suggests that in the early years of
evolution, living systems, prior to the development of their current
biochemical makeup based on an interacting system of DNA and
proteins, consisted entirely of RNA molecules that alone performed
both major life functions of information storage and metabolism.
Though not without opposition, this idea of an RNA World has en-
dured in the decades since it was rst proposed and continues to
provide fertile ground for research and debate within the commu-
nities of scholars and researchers engaged in the issue of how life
might have rst originated on earth (Dworkin et al., 2003; Copley
et al., 2007; Branciamore et al., 2009; Fisher, 2010). This paper
aims to show how the discoveries of hitherto unknown functions
of RNA molecules in contemporary living systems in the early
1980snamely enzymatic action or catalysis (Kruger et al., 1982;
anonymity as one in a large crowd of possibilities to center stage as
an important player in scenarios of the origin of life on earth.
2. Historical and historiographic overview
2.1. The contemporary guises of a classic conundrum
A 1971 paper by the Nobel-winning physical chemist Manfred
Eigen begins with the following snapshot of the status of origins-
of-life research at the time:
The question about the origin of life often appears as a question
about cause and effect [. . .] As a consequence of the exciting
discoveries of molecular biology a common version of the
above question is: Which came rst, the protein or the nucleic
acid?a modern variant of the old chicken-and-the-egg prob-
lem. The term rst is usually meant to dene a causal rather
than a temporal relationship, and the words protein and

E-mail address: sankanet@gmail.com

1369-8486/$ - see front matter 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.shpsc.2012.06.002
742 N. Sankaran / Studies in History and Philosophy of Biological and Biomedical Sciences 43 (2012) 741750
nucleic acid may be substituted by function and informa-
tion. The question in this form, when applied to the interplay
of nucleic acids and proteins as presently encountered in the
living cell, leads ad absurdum, because function cannot occur
in an organized manner unless information is present and this
information only acquires its meaning via the function for
which it is coding (Eigen, 1971, p. 465).
Eigens summary best encapsulates the chicken-and-egg situa-
tion that had beset origins of life research for some decades before
the discovery of catalytic RNAs, which forms the pivotal moment in
the history described in this paper. But the problem Eigen de-
scribed was just the latest iteration of the classic conundrum that
had plagued students of the nature and origins of life for centu-
ries (Kamminga, 1980, p. 347). Quite literally the chicken-and-
egg question is a question about origins of life that has it roots in
classical times. Although often associated with Aristotle, possibly
because of his known experimental work on chicken embryology
(Harr, 1983, pp. 2532) and his book On the Generation of Animals
(Aristotle, 2004), the question is directly attributable to the rst
century Roman philosopher and public intellectual Plutarch
(Table-talk II 3.1-3, 635 e638 a). As a metaphor, the chicken-
or-egg conundrum encapsulates the problems confounding various
scientic theories about life and its origins for a long stretch of
time from the late nineteenth century until the mid 1980s.
Following in the wake of Darwins ideas about biological evolu-
tion, late 19th-century advances in the newly developing sub-elds
of the life sciences such as microbiology, cell biology, and biochem-
istry added much fuel to the debates concerning both issues of
what life was and how it might have originated on earth. By the
early decades of the twentieth century, these different lines of
investigation had given rise two distinct camps of thought about
the issues (in a precursor to the chicken-and-egg situation de-
scribed by Eigen). On one side were those that emphasized the
importance of the cells nucleus to life, and hence the functions
of information and replication. On the opposite camp were those
who gave primacy to the cytoplasm, and consequently, catalytic
and metabolic activities (Kamminga, 1980, pp. 308330; Podolsky,
1996, p. 80). This dichotomy made its rst formal appearance in
the scientic community at a session on the origins of life at the
1912 British Association for the Advancement of Science meeting
at Dundee (Podolsky, 1996, p. 81), where E.A. Minchin, a zoologist
from Oxford University, opened the discussion with an argument
favoring the nucleocentric view:
By most biologists the cytoplasm has been considered to repre-
sent the true living substance. [. . .] There are, however, many
reasons for believing that the chromatin-substance, invariably
present in the nucleus, or occurring as grains, chromidia, scat-
tered in the cytoplasm, represents the primary and essential liv-
ing matter. [. . .] I regard the chromatin as the primitive living
substance, and hold the view that the earliest forms of life were
very minute particles of chromatin, round which in the course
of evolution achromatinic substances were formed. Within the
cytoplasmic envelopes thus produced the chromatin-grains
increased in number. Organisms of the degree of structural
complexity of a true cell arose nally by concentration of the
chromatin-grains (chromidiae) into a compact organized mass,
the nucleus proper (Minchin, 1912, pp. 510511).
Although his argument is articulated in terms of cellular com-
ponentschromatin (and hence nucleus) and cytoplasmMinchin
was clearly according primacy to chromatin because of its per-
ceived functions since virtually nothing was known about the
material of chromatin at the time. His main reasons for adhering
1
Felix dHerelle (1873-1949). French-Canadian microbiologist and one of the discoverers of bacteriophages (1917).
to a nucleocentric view of life included rst, the observation that
chromatin was an essential component of all known living beings,
none of which had been known to survive without it, and second,
the relationship between the material of chromatin and life-pro-
cesses such as fertilization and heredity (Minchin, 1912, p. 510).
Minchins views were challenged by H. E. Armstrong, then pres-
ident of the chemistry section (B) of the Royal Society, during the
discussion session immediately following the address:
I can not think of a naked mass of protoplasm, call it chromatin
(stainable substance) or what you will, playing the part of an
organism; At most I imagine it would function as yeast zymase
functions. If it is to grow and be reproduced, the nuclear mate-
rial must be shut up along with the appropriate food materials
and such constructive appliances as are required to bring about
the association of the various elements entering into the struc-
ture of the organism. (Armstrong, 1913, pp. 539540).
The perception of life as the dichotomy that is evident in this
early exchange persisted throughout the early twentieth century.
The geneticist H. J. Muller, for instance, was so rmly persuaded
that the basis of life was the gene that, at a 1926 symposium of
the International Congress of Plant Sciences on the gene, the title
of his address was The gene as the basis of life, (Muller 1929).
Although he acknowledged the fundamental importance of metab-
olism to lifeI think that most biologists will agree that we cannot
speak of matter as living unless it has the property of growth, at
least during a part of its career, (Muller, 1929, p. 914)he
argued that such growth was meaningless outside the context of
the gene:
In the evolution of living matter, there was probably not a form
of protoplasm, ancestral to our present protoplasm, which
already had the power of growth (or specic autocatalysis)
without containing genes (that is, without that exceptional
form of specic autocatalyst which is able to mutate and still
retain its specic autocatalytic function, as we know a chromo-
somal gene can). If this is true, it means that life did not occur
before the gene (Muller, 1929, p. 916, emphasis added).
Representing the opposing viewpoint around the same time
was the Russian biochemist Alexander Oparin who accorded
metabolism a clear priority in lifes functions (1924; 1938). Mean-
while, J.B.S. Haldanewho along with Oparin is widely regarded as
one of the founding-fathers of the twentieth century schools of
thought on chemical evolution and the origin of lifeclearly recog-
nized the dichotomy as reected in the way that he articulated the
problem of the denition of life at the time:
Clearly we are in doubt as to the proper criterion for life.
DHerelle1 says that the bacteriophage is alive, because, like the
ea or the tiger, it can multiply indenitely at the cost of living
beings. His opponents say that it can multiply only as long as
its food is alive, whereas the tiger certainly, and the ea probably,
can live on dead products of life. They suggest that the bacterio-
phage is like a book or a work of art, which is constantly being
copied by living beings, and therefore only metaphorically alive,
its real life being in its copiers. (Haldane, 1967 [1929], p. 249).
A decade later, in a commentary on the subject of the nature
and evolution of life, Jerome Alexander also identied the two nec-
essary and fundamental properties for all living organisms: Self-
duplication and the ability to direct chemical change by catalysis
(Alexander, 1942, p. 252), though he did not necessarily accord any
one function priority over the other. By the early 1950s the dichot-
omy in considering origins of life, though still very much in exis-
 N. Sankaran / Studies in History and Philosophy of Biological and Biomedical Sciences 43 (2012) 741750
tence, had transformed to reect the biological knowledge of the
times. As specic functions became explicitly mapped to specic
types of moleculesinformation (genetic information) to DNA
and metabolism and catalysis to proteins, respectivelythe chick-
en-and-egg question shifted correspondingly and settled into the
form summarized by Eigen as quoted earlier. As observed by Laz-
cano (2010, p.9), Attempts to understand the origin of life have
been shaped by our burgeoning knowledge of DNA replication
and protein biosynthesis. Whereas those who dened life as an
active metabolizing system favored a protein-rst viewpoint
and believed that the earliest living beings were aggregates of pro-
tein enzymes capable of self-regulation (Podolsky, 1996, p. 80),
investigators who saw the basic function of life as an ability to
duplicate subscribed to the notion of primordial organisms consist-
ing of genes or nucleic acids only (Ravin, 1977). The impasse would
remained rmly in place, until the unexpected discovery of the
RNA catalysis.
2.2. Reprise: Origins-of-life research in the 20th century
According to the historian Harmke Kamminga, who published
what was perhaps the rst, comprehensive account of the history
of origins of life research, the earliest attempts toward scientic
inquiries on this topic can be dated to the 1860s when the discov-
eries and ideas of such gures as Charles Darwin and Louis Pas-
teuron evolution from common descent and spontaneous
generation respectivelybegan to spread among their peers (Kam-
minga, 1980; 1988). At rst, the work of these two men seems to
have paradoxical implications for various theories of lifes origins.
On the one hand, Darwins theory of evolution by natural selection
suggested the existence, in the very distant past, of a common
ancestor for all extant life forms on earth. In contrast, Pasteurs
experiments, disproving the possibility of spontaneous generation,
indicated a like-begets-like situation whereby no organism could
come intro being without parents that it resembled to a large de-
gree in gross appearance and behaviour. The conicting implica-
tions of these ideas, Kamminga has argued (1980, pp. 79), led
different people to formulate theories about the origins of life dur-
ing the late nineteenth century, which were not grounded as much
in scientic investigations as in their creators conceptions about
the nature of life. In fact, she claims, questions and ideas about
the nature of life dominated the eld to such an extent that it
was only after the 1950s, with new experimental techniques and
information from different disciplines, that the question of the ori-
gins of life shifted from an area of speculation to an active area of
experimental investigations (1981, p. 2).
Kammingas treatment drew a clear and persuasive distinction
between the investigations on the chemical and biochemical ori-
gins of life on early earth and those on spontaneous generation
(1981, p. 11), which other noted historians including John Farley
(1972, 1974, 1977) and James Strick (1999) have often tackled un-
der the same umbrella. One of the main reasons that Kamminga of-
fered for making this distinction was that the validity of Pasteurs
ideas under the present conditions on earth did not contradict the
idea that a gradual transformation of carbon compounds into very
simple living systems must have taken place on primitive earth,
which would have had very different, albeit unknown, conditions
in comparison to the present (1981, p. 9). As the main focus of this
present paper lies in events after 1980, nearly a century after Pas-
teur and the heat of the spontaneous generation debates, and
which, moreover, have no antecedents in that controversy, this pa-
per will also adopt Kammingas demarcation of research in the
eld and not discuss the history of spontaneous generation any
further.
John Keosian, an investigator engaged in origins research, ob-
served that the earliest schools of thought about the origins of life
743
on primitive earth were divided on the fundamental issue of
whether life appeared on earth quite suddenly from nonliving mat-
ter or emerged gradually through stages from non-living matter. At
the heart of this debate, he went on to argue, lay the signicance
ascribed by the two groups to dening life itself. Whereas this def-
inition was of central importance to those who believe life arose
suddenly, Keosian posited that for those who thought of lifes
emergence as gradual, the drawing of a line between the inanimate
and living systems was less pressing (Keosian, 1974, p. 285). His
argument is in accord with Kammingas account which shows
the earliest theories on the origins of life by such biologists and
thinkers as T.H. Huxley, Herbert Spencer, and Ernst Haeckel going
directly to the issue of how living matterdubbed as protoplasm
(Huxley, 1870, pp. 1924)may have evolved from non-living
matter rather than dwelling on the question of the differences be-
tween non-living and living beings (Kamminga, 1980, pp. 5284;
1988, pp. 57).
Kammingas dissertation (1980, pp. 222328) analyzed in con-
siderable detail the dominant role of Oparin in origin-of-life theo-
rizing during the 1920s and 1930s, which naturally weighted her
analysis on the side of cytoplasmic or biochemical approach to
the problem. But although she provided a thoughtful and valuable
analysis of the contributions of a seminal gure in origins-of-life
theorizing, the historian Podolsky, who investigated the topic a
decade later, made the valid observation that her focus resulted
in a neglect of the importance of viruses, which were important
players for those on the opposing, nucleocentric side of the origins
debates (Podolsky, 1996, p. 83). Since the beginning of the 20th
century, viruses have posed a conundrum to life scientists regard-
ing their precise status in the living kingdom because of their abil-
ity to exist as both non-living chemicals and living infectious
organisms, albeit as the latter only in the context of living hosts.
As Podolsky pointed out, their properties simultaneously rendered
the viruses as a conceptual shorthand for the denition of life, an
operational model, for the development of life, and nally, a con-
ceivable primordial precursor to all later life forms (1996, pp.
8384).
With his paper Podolsky not only lled the lacuna he had iden-
tied in terms of the role of viruses in origins-of-life theorizing, but
also illuminated the roles of other key gures among Oparins con-
temporaries in this history, including those of Felix dHerelle, Jer-
ome Alexander, and J. B. S. Haldane. The paper also carried the
history of origins theorizing beyond the period covered by Kam-
minga and into the near-contemporary era. In fact, Podolskys pa-
per seems to have heralded a Cambrian explosion of writings
on the subject of the origins of life as identied in a 2000 review
of the state of the eld by Strick. But whereas origins research
had experienced a dizzying growth, since the 1960s when NASA
became a large-scale patron of the eld, at the time he was writ-
ing, Strick hastened to point out that there were still very few ex-
tant works dealing with the subject in a substantially historical
way (Strick, 2000, pp. 371372). Although he concluded his essay
with the hope that the books he was reviewing represented a very
exciting beginning to what we may hope will become a more
developed area of study in history and philosophy of biology (p.
384), bibliographic searches on the topic more than a decade later
still bear out his charge. Whereas the origins of life was then and
continues to grow as a hot topic of research and discussion within
various disciplines of science and even philosophy, scholarship on
the history of research in the eld remains relatively sparse.
In surveying the eld to choose the books to review, for instance,
Strick mentioned nding only two (Dick, 1998; Fry, 2000) by
authors who treated the subject in a substantially historical
way in his assessment (2000, p.371), and even these works left
large gaps in the history of the subject. Dicks book deals with the
history of the search for extraterrestrial life, which, although a fas-
744 N. Sankaran / Studies in History and Philosophy of Biological and Biomedical Sciences 43 (2012) 741750
cinating subject in its own right, merely displaces the question of
lifes origins rather than actually grappling with the issue. Although
more relevant in terms of subject, Frys book was, by her own
admission, intended for readers interested in science (Fry, 2000,
p.2), rather than for historians and, consequently, did not go too
deeply into the historiography and historical analysis of debates.
Meanwhile, Podolskys contribution, as important as it proved
in illuminating the role of viruses in origins theorizing, was incom-
plete in that it did not deal with other important playersboth hu-
man and otherwisethat were also omitted by Kamminga. One
player of particular signicance, which is the focus of this paper,
is the macromolecule RNA, which was mentioned by Podolsky,
but conned to the conclusion of his account (1996, pp. 122
126), mostly to provide a context for the viral role in origins re-
search. Fry similarly touched on RNA relatively briey towards
the end of her book (Fry, 2000, Chapter 11), which ends around
the period during which RNA was just becoming prominent.
3. RNA
Of all the molecules of modern molecular biology, RNA has
undoubtedly occupied the most capricious position in the history
of the subject, waxing and waning in its perceived importance
throughout the twentieth century as a player in lifes basic activi-
ties in comparison to DNA and proteins. Many working scientists
will admit that through the late 1940s and 1950s, when they were
working out the biochemical details of lifes basic processes, they
did not consider RNA to be as important in the system. As various
laboratories uncovered more information about the fundamental
importance of RNA over the next decade, however, they were com-
pelled to reexamine their earlier assessment and acknowledge the
centrality of RNA in biology (Sharp, 2009). For example, looking
back on the shifting landscapes of molecular biology, biologist and
science-writer Maura Flannery noted that,
While it is impossible to do science, or anything else without
making some basic assumptions, still, suppositions do at times
come back to haunt scientists. Assuming that DNA was a dumb
molecule is one of the most famous, but right up there is the
idea that RNA plays second ddle to DNA. Repeatedly in the his-
tory of molecular biology assumptions about RNA have been
proven wrong as slowly the versatility of RNA has become more
and more evident (Flannery, 2003, p. 216).
Structurally, RNA molecules are made of linked building blocks
called nucleotides, similar, but not identical, to those that make up
DNA molecules. In both types of nucleic acids, the basic nucleotide
building block consists of a sugar molecule, a phosphate group and
one of four nitrogenous bases known as the purines and pyrimi-
dines. Alternating sugar and phosphate molecules form the back-
bone of the polynucleotide strand and the bases protrude from
this backbone The main differences between the two types of nu-
cleic acids lie in the sugar molecules that make up their backbones.
Whereas RNA contains a sugar called ribose in its backbone, DNA
contains a deoxyribose sugar, which differs from ribose in that it
lacks a hydroxyl group on its third carbon. This seemingly small
difference contributes signicantly to the nal form of the nucleic
acid, as it provides the basis of the capacity of the sugars to form
chemical bonds with other components of the nucleic acid chain
(Saenger, 1984, p. 556). Another difference between the two nu-
cleic acids is that RNA molecules contain a uracil (U) base instead
of the T or thymine base in DNA. The differences in the composi-
tion results in, among other features, a single-stranded form for
most RNA molecules, in comparison to the famed double helix of
DNA, which is the result of the formation of chemical bonds be-
tween complementary bases (A with T and G with C) in its two
strands. This single-stranded conguration of RNA renders them
more exible than the rigid DNA helix, and this uidity, combined
with the greater ability of ribose over deoxyribose to form internal
bonds, allows RNA greater freedom to fold up and assume various
kinds of secondary structure (Saenger, 1984, p. 556; Pace and
Marsh, 1985, pp. 112113).
Both DNA and RNA store information in the form of the linear
sequences of their purine and pyrimidine bases, the two strands
of DNA carrying complementary rather than identical bases. Mean-
while, other functions, particularly those of the different functional
types of RNA, depend on the three-dimensional congurations of
the molecules. In this respect RNA molecules are more akin to pro-
tein molecules, the catalytic functions of which had long been rec-
ognized to lie in their three dimensional shapes, determined by the
way in which the molecule is folded.
From the vantage position of hindsight, it is easy to understand
how RNA, with its free hydroxyl group on the ribose and ability to
fold and form tertiary structures similar to proteins, can form cat-
alytic sites, which the rigid DNA cannot pull off with equal ease
(Saenger, 1984, p. 556). But as molecular biologists Norman Pace
and Terry Marsh recalled a little over two years after the discovery
of the ribozymes, It had long been presumed that only proteins
could provide catalytic functions, although there was no reason
for this presumption beyond the time-honored observation that
enzyme activities, when puried had always proven to be pro-
teins (1985, p. 97). This observation had led scientists to solidify
their vision of a perceived division of labourespecially once they
had gured out what DNA looked like and how it worked (Keyes,
1999, p. 2)of lifes functions, and further emphasized the dichot-
omy between the two camps of the origins debates. DNA was held
to be the carrier of all informationencoded into the sequence of
its baseswhile proteins constituted the workforce of life, execut-
ing their metabolic functions through catalysis. The greater com-
plexity and variety in protein structure seemed to corroborate
their ability to handle the more complex metabolic activities in
comparison to those of the nucleic acids.
So entrenched among the molecular biologists was the idea of
the division of labour in biology, that the discovery of catalytic
activity by RNA molecules in the early 1980s was completely
unexpected, according to Pace and Marsh (1985, p. 97). Neither
their team, which was headed by Sydney Altman at Yale Univer-
sity, nor Thomas Cech and his team at the University of Colorado,
were even looking for such RNA-based enzymatic activity when
they stumbled upon it. Cechs group was studying various aspects
of the expression such as the transcription, splicing and further
processing of ribosomal RNA genes in a protozoan organism called
Tetrahymena thermophila. They noticed that the RNA precursor of
the ribosomal RNA grew smaller in size without losing its function,
which indicated that it was undergoing degradation in the absence
of any protein enzymes. Through a series of experiments they
found that an intron sequence in the RNA molecule was responsi-
ble for catalyzing its own excision (Kruger at al., 1982; Atkins et al.,
2000, p. 6). The group dubbed the catalytic RNA as ribozymes to re-
ect both their chemistry and enzymatic activity, i.e.ribonucleic
enzymes (Kruger et al., 1982, p. 154) and the name stuck. Mean-
while, Altmans team at Yale University, had been investigating
the processing of transfer RNA (tRNA) molecules in bacteria, using
Escherichia coli and Bacillus subtilis as models for their experi-
ments. As early as 1977 Altmans laboratory had reported that
the RNA component of Ribonuclease P was essential for the en-
zyme to function (Stark et al.), and in 1983 they conrmed that
it was this essential RNA moiety and not protein that carried the
catalytic properties of the enzyme (Guerrier-Takada et al., 1983).
In both cases the laboratories worked under the assumption
that only proteins were capable of catalysis. Cechs laboratory,
for instance, noted in their paper that the investigators specically
 N. Sankaran / Studies in History and Philosophy of Biological and Biomedical Sciences 43 (2012) 741750
went looking for proteins in the system they were studying (Kruger
et al., 1982, p. 147) and Altman stated quite explicitly thatthe
RNA moiety alone [. . .] was not believed to be capable of perform-
ing catalytic functionk (Guerrier-Takada et al., 1983, p. 849). It
wasnt until their experiments denitively showed the retention
of enzymatic activity upon destroying the protein component of
the molecule and the loss of enzymatic activity with the destruc-
tion of RNA that they were persuaded of the catalytic abilities of
RNA (Atkins et al., 2000, p. 6). In both laboratories, however, the
evidence from the experiments was quite clear. The enzymatic
processes under scrutiny were very denitely being catalyzed by
RNA and not proteins.
Once they accepted the evidence, Altmans group were quick to
make the following observation:
Except for a trivial reason, novelty, should we be surprised that
an RNA molecule is an enzyme? There are relatively few chem-
ical constraints on the macromolecular nature of catalytic sur-
faces. Proteins are enzymes; carbohydrates can be altered to
be catalytic agents (Breslow, 1982); RNA can have catalytic
capabilities, Guerrier-Takada et al., 1983, p. 855).
Regardless of the nal aims of the Cech and Altmans groups
respective projects, the implications of the existence of these mol-
ecules in contemporary living systems for understanding life in an
earlier era were compelling enough merit mention by both groups
in the discussion sections of their papers. The nding of self-splic-
ing RNA adds a new dimension to discussions about possible roles
for RNA early in evolution. In a primordial organism, with a very
limited genome and few enzymes, self-arranging RNA might have
allowed the creation of a diversity of sequences from a single
RNA molecule, proposed the Colorado group (Kruger et al., 1982,
p. 155), speculating on the course of early evolution and the devel-
opment of genetic variation.
The conjectures from Altmans group made an even stronger,
more explicit case for RNA as a player in early life:
If proteins were relative latecomers in the evolution of macro-
molecules, then primeval manipulations of nucleic acids may
have been carried out entirely or predominantly by catalytic
nucleic acids themselves. The remnants of these early, impor-
tant, biological events may be apparent in the reaction of RNA-
ase P, in the processing of some rRNAs, in ribosomes [. . .] and
undoubtedly in other reactions catalyzed by RNA that remain
to be identied, (Guerrier-Takada et al., 1983, p. 855).
The implications of the discovery of catalytic RNA elicited an
immediate response from the wider scientic community and revi-
talized the origins of life discourse. Virtually overnight it seems,
RNAs image underwent a dramatic change, from something of a
country cousin in the world of molecular biology to the entity that
could have been the start of it all (Lewin, 1986, p. 545). The dem-
onstration that RNA could act as an enzyme simplied the assump-
tions required of a rudimentary, self-replicating entity (Pace and
Marsh, 1985, p. 97). True, the intial evidence from both laboratories
furnished proof for what was essentially a single type of catalytic
activity for RNAnamely the breaking of a specic type of chemical
bond, called a phosphodiester bond, between successive units in a
nucleic acid chainbut the very fact of catalysis in one instance
raised the possibility of the existence of more ribozymes, both in
number and in variety. Others will undoutedly emerge, predicted
Pace and Marsh (1985, p. 111), who even proposed a scheme for a
possible self-replicating RNA (1985, pp. 113115).
In less than a year their prophesy came to pass, as scientists be-
gan to furnish data indicating other types of enzymatic acitivity for
RNA, such as the formation of RNA chains from its basic nucleotide
building blocks (Cech, 1986). The existense of such enzymes gave
745
more credence to idea of a period in the early biosphere when
both the information needed for life and the enzymatic activity
of living organisms were contained in RNA molecules (Dworkin
et al., 2003, p. 125). A scant three years after the rst descriptions
of RNA catalysis had appeared in print, Walter Gilbert coined the
phrase RNA World, to describe a phase in the evolution of life
which, he proposed, existed before the evolution of living systems
into their modern protein-DNA forms (Gilbert, 1986).
4. RNA in prebiotic earthantecedents and early ideas
Although discovery of ribozymes in the 1980s (Kruger et al.,
1982; Guerrier-Takada et al., 1983) undoubtedly had a profound
impact on the shaping of various origin-of-life theories that came
after, the molecules were, in a manner of speaking, the physical ba-
sis for a putative entity that had been proposed many decades ear-
lier by Leonard Troland (Kamminga, 1986, pp. 45; Keosian, 1974,
pp. 285286). A professor of psychology from Harvard University,
who also sustained a productive career in theoretical and applied
physics, Troland published articles on philosophical issues which
came from a denite philosophical position, a form of psychical
monism tempered by acceptance of physico-chemical explanations
at the scientic level, (Beebe-Center, 1932, p. 817). These philo-
sophical ideas are manifest in the sequence of papers on lifes ori-
gins in which he laid out his ideas for the necessary criteria for life
to have originated, (Troland, 1914; Troland, 1916; Troland, 1917).
Trolands conception of the essential unit for life was that of a ge-
netic enzyme, a molecule that had the ability to regulate various
life activities by catalysis and possess the ability to catalyze its
own duplication (i.e. autocatalysis) thereby regulating the activi-
ties of the next generation as well. As he explained:
It has for some years been my conviction that the conception of
enzyme action or of specic catalysis, provides a denite, gen-
eral solution for all of the fundamental biological enigmas:
the mysteries of origin of living matter, of the source of varia-
tions, of the mechanism of heredity and ontogeny, and of gen-
eral organic regulation. .. Catalysis is essentially a
determinative relationship, and the enzyme theory of life, as a
general biological hypothesis, would claim that all intra-vital
or hereditary determination, is in the last analysis, catalytic
(1917, p. 327).
At rst glance this explanation might seem to present the basis
for a cytoplasmic, protein-rst rather than nucleic acid (and thus,
RNA) rst view of the origin of life because at the time Troland pro-
posed these ideas, catalysis, and indeed all biological functions
were assumed to reside in proteins. But he explicitly sided with
the nucleocentric view of the origin of life, stressing the impor-
tance of an autocatalytic molecule or a genetic enzyme for the
creation of the rst primitive cell-like system that was capable of
both reproduction and metabolism:
Let us suppose that there suddenly appears at some point in the
ocean body one molecule of a catalytic substance [that] has a
further specic catalytic effect upon the reaction which was
responsible for its own initial production. [. . .] Such an agent,
doubly specic, may be called a genetic enzyme and for this pri-
meval exemplar of the species we may employ the name
protase.
The result of the production of one molecule of protase in the
ocean waters can easily be seen. [. . .] further molecules will be
formed about the original oneat a constantly increasing rate.
But, simultaneously, there will also be formed an envelope
[. . .]. This is the picture afforded by the theory of enzymes of
the genesis of the rst and most primitive living cell. The gen-
eral plan of the cell is that of all cells, the mass of protase
746 N. Sankaran / Studies in History and Philosophy of Biological and Biomedical Sciences 43 (2012) 741750

constituting the nucleus and the surrounding catalyzed sub- led to the rst cellular life forms on our planet, (1994, p. xiii)
stance, the cytoplasm (Troland, 1916, p. 380). did not include this paper.
One reason for this odd omission could be that by the 1960s
It seems clear from his language that for Troland, the primary
when this conference was held, the famously versatile and poly-
dening criterion for life was the function of catalysis rather than
math Haldane was no longer active in biochemistry and molecular
the molecules that carried out the task. Indeed, in his detailed
biology, his primary interests having shifted to population genetics
explanation he never mentioned chemical entities such as proteins
and statistics. Haldanes main research contributions to the ques-
or DNA, and relied entirely on function and the cellular location of
tion of the origins of life dated to the 1920s and 1930s (Kamminga,
the early molecules. His notion of a dual function residing in a single
1980, pp. 246250), which contribution was certainly included as
entity that was given esh with the discovery of autocatalytic ribo-
noted. Consequently, it seems that in the 1960s Haldanes ideas
zymes (Gilbert, 1986). Cechwhom Podolsky sees as the modern-
were not disseminated beyond the immediate environs of the con-
day successor to Troland, (Podolsky, 1996, p. 126)recounted the
ference. An otherwise prolic writer for different audience levels,
following incident soon after his laboratorys discovery,
Haldane himself does not seem to have made any efforts to publi-
I was invited to speak at an Origins of Life Club at UCLA; the cize or expand his ideas through further writings. His proposal for
audience was very excited by our work and very polite, but it RNA as the primordial molecule was challenged immediately at the
became clear that I did not know much about the chicken- very same meeting, as indicated in the conference proceedings
and-egg problem of origins. That experience was an incredible (Haldane, 1965, p. 16). For instance, the German virologist Gerhard
stimulus to become knowledgeable. Only then did I understand Schramm argued that there was no need for differentiating be-
that a lot of scientists had been more-or-less waiting for the tween DNA and RNA and that the earliest life forms had a more
discovery of ribozymes! (Cech, 2012). primitive type of nucleic-acid. Although he readily accepted Sch-
ramms argument, Haldane pointed out that his speculations in-
Trolands emphasis on the importance of autocatalysis for life
cluded not only the origin of life in the past, but also the
was echoed in Mullers gene theory of life (1929). As Muller saw
specications for the rst synthetic organism in the future, and
it, growth, which he deemed as an essential property of life in-
that RNA was the most likely candidate for the latter (Haldane,
volves autocatalysis, inasmuch as the substances that grow must
1965, p. 16). Yet another reason for the lack of attention to Hal-
so affect some of the surrounding materials that the latter are
danes paper may be that the later theories that do consider RNA
transformed into end-products some of which are identical in com-
as a possibility do not stem from his line of argument and seem
position with the former substances (Muller, 1929, p. 914). But
to be rooted instead in ideas that carry echoes of Trolands concep-
although he postulated that the rst autocatalyst must have been
tions of life in terms of catalysis.
a gene (1929, p. 916) Muller did not in this 1929 paper discuss
In his review article about RNA evolution and the origins of life,
or even speculate about the material basis of the gene at that time.
Gerald Joyce (1989, p. 217), a noted researcher and commentator
As he would explain later although believing in the importance
on contemporary research on the topic, cited the work of a physi-
and multiplicity of specic enzymes in protoplasmic reactions,
cian-turned-theoretical-biologist Henry Quastler, in the lineage of
and the dependence of their presence on genes, I believed it illegit-
propositions for early life being composed entirely of RNA. Quas-
imate to identify genes with enzymes, and too early to decide in
tler, an Austrian radiobiologist who emigrated to the United States
what then known category of chemical substances (if any) genes
sometime during the 1940s and worked at the University of Illinois
belonged, (Muller, 1966, p. 497).
Laboratory of Control Systems and Argonne National Laboratory,
Autocatalysis, however, seems to have taken a back seat with the
was especially interested in applying mathematics in the guise of
discovery of DNA as the material basis for genes (Avery, MacLeod, &
information science toward understanding living systems (Kay,
McCarty, 1944). With the growing understanding of its chemical
1998, p. 509). He cast the origins-of-life question primarily as a
structure over the next decadeculminating in the proposal of the
problem of the emergence of order or organization, as is evident
famed double helix model for its structurethere was as discussed
from the title of his book on the subject, The emergence of biolog-
earlier, a consolidation of the separation of functions of replicative
ical organization (Quastler, 1964). Published posthumously, this
information and catalysis to DNA and proteins respectively. It was
book was a revision of his lecture notes for a course on the appli-
also during this time that status of RNA in molecular biology under-
cation of theoretical and mathematical approaches to the study
went dramatic changes with many peaks and valleys; poised at one
of biology, and looked at the question from a probabilistic perspec-
time as the most likely candidate for the gene, it had by the 1950s
tive. Staking his territory for discussion at the outset of the book,
been relegated to the position, as Flannery (1991, p. 438) observed,
Quastler conceded that of the many possible propositions for
a mere middle-man between DNA and protein, even as information
explaining lifes origins from its nonliving precursors, not all were
about its structure, forms and function continued to be produced.
subject to scientic inquiry. Of those that are, the most attractive
The rst person to explicitly propose a role for RNA in originat-
is the proposition that nonliving components have assumed a con-
ing life was J. B. S. Haldane, during a 1963 conference on the origins
guration compatible with life through some lucky accident
of life (Haldane, 1965). His conception of the rst living organism
(Quastler, 1964, p. 1).
was that of the rst system capable of reproduction, and his
Like other theorizers, Quastler prefaced his discussion of origins
main reason for considering RNA appears to have been one of ef-
theories with a working denition of life. To be compatible with
ciency or simplicity. According to him, the greater complexity of
life, a conguration must combine metabolic activity with stability,
DNAa double helix in contrast to RNAs single strandsuggested
even adaptability, and it must be able to reproduce itself from avail-
that it was an adaptation to increase the complexity of the system
able components (1964, p. 1). Whereas his denition of life gives
[i.e. primordial living being] rather than part of the primitive sys-
due deference to the dichotomy of lifes functions in origins theoriz-
tem itself (Haldane, 1965, p. 15). What is puzzling however, is
ing noted by Kamminga, and even conforms to the division of la-
the fact noted by Kamminga in her analysis (1980, p. 250), that de-
bourof metabolism to proteins and reproduction/replication to
spite Haldanes being inuential and well-known gure in origins-
nucleic acidshis theory for the emergence of life does not trans-
of-life research, his 1965 paper on the role of RNA has been largely
pose this dichotomy to the problem of lifes origins as other theories
overlooked in the of the later literature on this subject. Even Dea-
did. Indeed, Quastler engaged with the chicken-and-egg problem of
mer and Fleischakers comprehensive compilation of more that
origins research only in molecular terms, while treating the func-
forty papers focussing on the physico-chemical processes that
tional dichotomy that earlier researchers had struggled with as a
 N. Sankaran / Studies in History and Philosophy of Biological and Biomedical Sciences 43 (2012) 741750
non-issue. In his view, information was a later arrival than function,
a result of a process that he described as an accidental choice
remembered, (Quastler, 1964, p. 16). For the working of the pre-
biological polynucleotide system, almost all base sequences are
equally effective (1964, p.15) he claimed. Information or meaning
did not emerge until the accident of a particular single strand
becoming the ancestor of the system, i.e. through the stability prop-
erties of the system descended from that particular single strand,
(1964, p. 16), in much the same manner that information was cre-
ated during the setting of a combination for a new number lock:
It does not matter how the combination was originally selected.
[. . .] What matters is that before the combination is set into the
lock, every number sequence is exactly as good as every other
one (namely, no good!), and after it has been set, one sequence
is useful and all others are useless. Thus the choice of a sequence
and the subsequent implementation of the choice by setting the
lock have created information (Quastler, 1964, pp. 1617).
On the molecular front, Quastler considered the origins ques-
tion in terms of the mathematical probabilities of the appearance
of the macromolecules responsible for these functions of life. His
hypothesis for the emergence of a living system from the rich
hot salty sea of building blocks on early Earth began, like the ideas
of others, with a consideration of the transition from organic mol-
ecules to organized cellular structure in several steps, the rst of
which was likely the formation of macromolecules similar to
those found in living things (Quastler, 1964, p. 7). Although he
conceded that proteins, or rather amino acids, could indeed be
formed, and in turn themselves form simple polypeptides under
conditions presumed to resemble those on early Earth, he never-
theless discounted them as the primary candidates for being lifes
earliest molecules becausenobody has yet envisaged a mecha-
nism by which proteins formed by accident could be replicated
(Quastler, 1964, p. 7). Since a known mechanism of replication ex-
ists for polynucleotides, he added, it is more plausible to consider
the possibility that the formation of polynucleotides constituted
the rst step in the emergence of life. The specic candidate that
he postulated in this scenario was a single-stranded polynucleo-
tide (1964, p. 8), which, in the mid-1960s, simply translated as
RNA. As Quastler went on to explain in further detail:
It does seem likely that nucleic acid systems would have arisen
in the primeval soup of building blocks, and that their emer-
gence would rapidly transform the ambient into the habitat of
well-dened and stable molecular systems which compete with
each other and exhibit mutability and rudimentary adaptability
(Quastler, 1964, p. 14).
Joyces reference to Quastler and RNA notwithstanding, a quick
glance at the citation history2 of Quastlers theories (which would
constitute a fascinating study in their own right) reveals them to
have not excited as much comment from his contemporaries en-
gaged in origins-of-life research as from those interested in the
applications of information theory to biology. Although nearly 100
sources that have cited Quastler, very few researchers before Joyce
cited him in the context of origins research, and even then, not nec-
essarily in connection with RNA (Salisbury, 1971 and Chernavskii &
Chernavskaya, 1975). A recent resurgence of interest in the implica-
tions of Quastlers theories seems evident in a sudden appearances in
the past decade of references to his work (Chernavskii, 2000; Carrier,
2004), although again, these papers are not primarily engaged with
the RNA aspect of his arguments.
2
Analysis on Google Scholar conducted by author and last accessed Feb. 18, 2012.
3
On the occasion of Orgels seventieth birthday, a former colleague James Ferris remarked that I have always felt that this paper had a major tongue-in-cheek component,
(1997, p. 433). That Ferris may not have been off the mark is suggested in a quip by Crick in a letter to the British biologist Peter Medawar, Nice of you to think of Panspermia for
Vogue (curiously enough,we did originally consider Playboy), (1977a).
747
Meanwhile, RNA seems to have appeared next as an explicit and
serious contender in origin scenarios in the publications from two
independent sources working on similar problems: one in a book
by the biophysicist Carl Woese (1967, pp. 179195), and the other
in a pair of papers by Francis Crick (1968) and Leslie Orgel (1968).
These scientists were looking into origins of the genetic codethat
special relationship between proteins and nucleic acids that
equates specic triplet combinations of nucleotides (called codons)
with specic amino acids and thus enables genes to be expressed
and replicatedand the translation apparatus. As Woese expli-
cated the problem:
In the past a good deal of attention centered about the contro-
versy of whether proteins or genes came rst. This, I think, is
missing the main point. A gene without any gene expression
is meaningless. And proteins without enzymatic function are a
far cry from the proteins of the cell of today. Obviously the exis-
tence of both genes and true enzymes require the existence of a
translation apparatus. Thus the question of which came rst,
gene or protein, is not the important one. It is how the gene-
protein relationship, that is, translation, arose (Woese, 1967,
p. 189).
Speculating about how this association between codons and
amino acids might have evolved in the absence of any obvious
cast-and-mold relationship between the two, Woese, Crick and Or-
gel homed in on the chicken-and-egg problem posed by the con-
temporary nucleic acid-protein systems. Orgel and Crick
recounted later (1993, p. 238) that already in 1968 they had sug-
gested that the priority problem could be solved if, early in evolu-
tion, polynucleotides had acted as catalysts (Crick, 1968, p. 372).
Woese speculated that, at these early stages polynucleotide catal-
ysis could even have been as important as any catalytic activity
manifested by the other major biopolymer, polypeptides, (1967,
p.186). These scientists also speculated briey that RNA might
have arisen before DNA because this simplied the process of
translation by eliminating the transcription step of modern sys-
tems (Crick, 1968, pp. 37137). Unable to nd a way out of the
absolute requirement for RNA in the process of translation (Pace
and Marsh, 1985, p. 97), these early speculators about lifes origins
on Earth saw RNA replication as a central requirement for process-
ing genetic information (Orgel and Crick, 1993).
Perhaps in the face of the lack of physical or experimental evi-
denceabetted in part by the assumption that RNA catalysts did
not exist in contemporary living organisms (Robertson and Joyce,
2012, p. 1) as well as the idea that the question of which nucleotide
came rst was perhaps not that important (Orgel, 1968, p. 382)or
their own involvement in other, more pressing research problems,
none of these scientists published their ideas about nucleotide-dri-
ven catalysis further. Nor did their papers provide immediate
inspiration for others. Altman (2012), for instance, recalls that I
know I read the Crick and Orgel papers when they were originally
published but they had little effect on me at that time.
Meanwhile, Crick and Orgel never entirely gave up speculating
on the topic of lifes origins. In 1973, for instance, they published
an article discussing their ideas about directed panspermia, the
idea that earths rst living organisms were deliberately transmit-
ted to the earth by intelligent brings on another planet, (Crick and
Orgel, 1973, p. 341). Outlandish as the idea may seem3- and the
authors do admit to signicant hurdles to testing their hypotheses
and ideasthe paper offers a valid counterargument to the claim
that panspermia merely displaces the problem of origins without
748 N. Sankaran / Studies in History and Philosophy of Biological and Biomedical Sciences 43 (2012) 741750
really addressing it, and also shows the authors continued emphasis
on the importance of catalysis, for origins scenarios:
For all we know there may be other types of planet on which
the origin of life ab initio is greatly more probable than on
our own. For example, such a planet may possess a mineral,
or compound, of crucial catalytic importance, which is rare on
Earth, (Crick and Orgel, 1973, p. 341342, emphasis added).
Thus, while Crick and Orgel maintained their interest in the
eld and held on the idea of the importance of catalysisRNA
was no more or less a contender for the spotlight than any of the
numerous other candidates and theories put forward at the time.
That proteins still held the pride of place as biological catalysts is
evident from Cricks explanation in a personal letter of the possi-
bility that the rst enzymes consisted of a folded RNA molecule to
which a small peptide (e.g. a tripeptide) had adsorbed, the peptide
doing the chemistry of the catalysis, (Crick, 1978). As they
acknowledged in their 25-year retrospective on past speculations
about RNA and the origins of life:
How clearly did we anticipate the exciting experimental discov-
eries of the last decade? We must confess that we did not antic-
ipate them at all! We discussed a number of hypothetical
schemes for the origins of our genetic system and touched on
each of the major features of the RNA world hypothesis. How-
ever, we did not ourselves search for, nor did we encourage oth-
ers to search for, relics of the RNA world in contemporary
organisms. We took it for granted that RNA-based catalysis
was necessarily less efcient than protein-based catalysis, and
consequently that RNA catalysts had been superseded by pro-
tein enzymes in every case. The same assumption led us to
underestimate the potential complexity of an RNA world (Orgel
and Crick, 1993, p. 238).
RNA, thus, receded to the wings for a time, and did not come un-
der the spotlight again as a prominent player in origins scenarios
until after the discovery of ribozymes.
5. Conclusion: Origins in the wake of the RNA World
Evidence for the existence and even the centrality of RNA-based
catalysis in modern life forms continued to mount since the
announcement of the rst ribozymes (Joyce, 1989; Noller et al.,
1992; McGinness and Joyce, 2003; Ma and Yu, 2006), providing
support for the notion of the RNA World hypothesis and keeping
it alive and well, in origins of life debates (Meyers et al., 2008).
The primary evidence for an RNA world comes from the roles of
RNA in modern cells; these are considered relics or molecular
fossils from an earlier living system, according to one example
(Jeffares et al., 1998, p. 18) from the growing body of literature
on the subject (Lahav, 1993; Gordon, 1995; Schwartz, 1995; Hor-
gan, 1996; Di Giulio, 1997; Wattis and Coveney, 1999; Forterre,
2005; Spirin, 2005; Gesteland et al., 2006; Bielski and Tencer,
2007; Chen et al., 2007; Copley et al., 2007; Lucrezia et al., 2007;
Yarus, 2011). Naturally the model is not without its share of holes,
and the RNA World hypothesis has its share of detractors and nay-
sayers (Waldrop, 1989; Gibson, 1993; James and Ellington, 1995;
Andras and Andras, 2005; Vlassov et al., 2005; Lupi et al., 2006;
Monnard, 2007; Vasas et al., 2010). Rather than making the issue
vanish however, these arguments and the responses to them have
only served to reinforce the dynamism of the hypothesis and the
RNA World has proven more robust than many earlier and contem-
poraneous origin theories. The ribozymes in the ribosomes, the
sites for translation of the genetic code into the amino acid chains
of protein in all known cellular life forms on earth, have played
their role in fueling the RNA World discussions. Although scientists
had long known about the abundance of RNA in ribosomes, until
the 1990s they had assumed that the RNA was present merely to
provide the scaffolding on which the protein enzymes conducted
their duties of catalyzing the formation of peptide bonds between
successive amino acids in the growing chain. However, in 1992 re-
sults from the laboratory of Harry Noller indicated that the RNA
component played a much more integral role in catalyzing pep-
tide-bond formation than had been understood earlier (Noller
et al., 1992), eventually leading Cech (2000) to title one of his arti-
cles The ribosome is a ribozyme.
With additional evidence from elds such as structural and syn-
thetic biology it became clear that ribozymes are not mere relics of
lifes distant past, but continue to function as key players in its fun-
damental processes even today. In this respect RNA molecules now
function as a focal point for origins theorizing by RNA world pro-
ponents in much the same way that Podolsky (1996, pp. 8384)
showed viruses to have done for the nucleocentrists earlier. Just
as viruses were used variously by different theorizers, as meta-
phors for life, as operational and ahistorical models for originating
life de novo and as primordial precursors of modern living beings,
RNA in the post-ribozyme era has taken on multple meanings in
different contexts.
The obvious metaphorical use of RNA as chicken-and-egg aside,
different examples suggesting operational and phylogenetic roles
for RNA abound in the scientic literature. Chela-Floris (1994), a
theoretical physicist and more recently, Fisher (2010), a biologist
have proposed that viroids (RNA-containing virus-like obligate
parasites of plants) and RNA viruses that can be found today may
be relics or vestiges of an ancient RNA world. Their speculations re-
vive a place for viruses in the origins theories, albeit in quite the
opposite capacity than that of maintaining the dichotomy in the
eld as they had in the early-to-mid twentieth century (Podolsky,
1996, p.125). Another idea is that the modern metabolic setup of
living cells might be a palimpsest overwritten on an ancestor
originally made of RNA (Benner et al., 1989). In their paper, Benner
et al. (1989, p. 7054) also offer a model for the breakthrough
organism, or the last putative ancestor to use only RNA for both
catalysis and information, thereby showing both phylogenetic
and operational roles for RNA in origins scenarios. Elsewhere syn-
thetic biologists have synthesized RNA molecules that its creators
suggest may be used for designing hypothetical RNA-based living
systems in the so-called RNA world, (Saito and Inoue, 2009, p.
398), providing a type of operational or analogical system for con-
temporary origins theorizers that Podolskys nucleocentrists might
have only dreamed of in the 1920s and 1930s.
To what purpose are such advances? The recent achievements
in synthetic biology cant help bring to mind Haldanes long-ago
suggestion that even if we were able to create an RNA-based living
system de novo from non-living precursors, we would not have ob-
tained any real proof for what happened billions of years ago, only
what might have happened (Haldane, 1965, p. 16). Well, Haldanes
hypothetical situation has more or less come to pass and we are, as
predicted, no closer to knowing how life originated, which raises or
rather revives, the question of Why, should the problem of ori-
gins of life be even approached by scientists. While there is no con-
crete answer, the fact remains that the question of origins is one
that has never failed to engage the mind at a deep philosophical le-
vel (Ruse, 1997). Scientists persist in their search for possibile
explanations for how life might have begun, justied purely, it
might seem, in terms of the intellectual challenge and philosophi-
cal satisfaction grappling with such problems provide. Crick, for in-
stance, once confessed in a letter to his philosopher friend Georg
Kreisel that, In fact the origin of life may be one of those scientic
problems which may take a very long time to yield a satisfactory
answer and indeed may never do so, (1977b). That the discovery
of ribozymes drew him back to the eld despite his views on the
 N. Sankaran / Studies in History and Philosophy of Biological and Biomedical Sciences 43 (2012) 741750
intractable nature of the problem offers but one reason as to why
the RNA world has endured in the capricious, confusing and oft-
contentious world of origin of life theorizing.
Acknowledgments
This paper has been some dozen years in the making, beginning
as a topic for a methods paper in graduate school. Thanks then,
must rst be offered to Yale University professors John Harley
Warner who taught the course and Bill Summers who suggested
that the paper was worth attempting to publish (in a much revised
form naturally). A heartfelt thanks is also due to Dr. Prof. Heiner
Fangerau of the University of Ulm for hosting me in his laboratory
during the summer of 2010 while I conducted library research with
partial support from the American University in Cairo postodoctp-
ral research fellowship. A version of the paper was presented at the
2011 annual meeting of the British Society of the History of Sci-
ence, travel to which was partially supported by funds from Yonsei
University. The paper was developed further and presented at the
Indian Institute of Science, Bangalore, India in Jan 2012 as part of
the Universitys Spectrum Lecture series and I would especially like
to thank Dr. Nanjundiah and graduate students at the Institute for
the rousing discussion that followed and which greatly enhanced
subsequent iterations of the paper. Colleagues and friends at large,
notably Pierre-Olivier Method and Luis Campos offered invaluable
criticisms and advice and Tim Warren lent his discerning editorial
eye at different stages of the writing process. Finally I would like to
express my appreciation to the anonymous reviewer, whose per-
spective and comments vastly improved the nal paper. Only I
am responsible for any and all errors that have persisted.
References
Alexander, J. (1942). Theories as to the origin and nature of life. Science, 96,
252253.
Altman, S. (2012). Personal communication via e-mail, June 2, 2012.
Andras, P., & Andras, C. (2005). The origins of lifethe protein interaction world
hypothesis: protein interactions were the rst form of self-reproducing life and
nucleic acids evolved later as memory molecules. Medical Hypotheses, 64(4),
678688.
Aristotle. (2004). On the Generation of Animals. (A. Platt, Trans.). Kessinger
Publishing.
Armstrong, H. E. (1913). The origin of life: A chemists fantasy. Annual Report of the
Board of Regents of The Smithsonian Institution, 1912, 527541.
Atkins, J. F., Ellington, A., Friedman, B. E., Gesteland, R. F., Noller, H. F., Pasquale, S.
M., Storey, R. D., Uhlenbeck, O. C., & Weiner, A. M. (2000). Bringing RNA into
view: RNA and its roles in biology. Colorado Springs, CO: Biological Sciences
Curriculum Study.
Avery, O. T., MacLeod, C. M., & McCarty, M. (1944). Studies on the chemical nature of
the substance inducing transformation of pneumococcal types. The Journal of
experimental medicine, 79(2), 137158.
Beebe-Center, J. G. (1932). Leonard Thompson Troland: 18891932. The American
Journal of Psychology, 44(4), 817820.
Benner, S. A., Ellington, A. D., & Tauer, A. (1989). Modern metabolism as a
palimpsest of the RNA world. Proceedings of the National Academy of Sciences,
USA, 86, 7054.
Bielski, R., & Tencer, M. (2007). A possible path to the RNA world: enantioselective
and diastereoselective purication of ribose. Origins of Life and Evolution of
Biospheres, 37(2), 167175.
Branciamore, S., Gallori, E., Szathmry, E., & Czrn, T. (2009). The origin of life:
Chemical evolution of a metabolic system in a mineral honeycomb? Journal of
Molecular Evolution, 69, 458469.
Breslow, R. (1982). Articial enzymes. Science, 218, 532537.
Carrier, R. C. (2004). The argument from biogenesis: Probabilities against a natural
origin of life. Biology and Philosophy, 19(5), 739764.
Cech, T. (1986). A model for the RNA-catalyzed replication of RNA. Proceedings of the
National Academy of Science, USA, 83, 43604363.
Cech, T. R. (2000). The ribosome is a ribozyme. Science, 289, 878879.
Cech, T. R. (2012). Personal communication via e-mail, June 8, 2012.
Chela-Flores, J. (1994). Are viroids molecular fossils of the RNA world? Journal of
Theoretical Biology, 166(2), 163166.
Chen, X., Li, N., & Ellington, A. D. (2007). Ribozyme catalysis of metabolism in the
RNA world. Chemistry & Biodiversity, 4(4), 633655.
Chernavskii, D. S. (2000). The origin of life and thinking from the viewpoint of
modern physics. Physics-Uspekhi, 43(2), 151176.
749
Chernavskii, D. S., & Chernavskaya, N. M. (1975). Some theoretical aspects of the
problem of life origin. Journal of Theoretical Biology, 50(1), 1323.
Copley, S. D., Smith, E., & Morowitz, H. (2007). The origin of the RNA world: co-
evolution of genes and metabolism. Bioorganic Chemistry, 35, 430443.
Crick, F. (1968). The origin of the genetic code. Journal of Molecular Biology, 38,
367379.
Crick, Francis. Letter from Francis Crick to Peter Medawar (April 21, 1977). <http://
proles.nlm.nih.gov/ps/retrieve/ResourceMetadata/SCBBVG>; 1977a.
Crick, F. Letter from Francis Crick to Georg Kreisel (December 2, 1977). Retrieved from
<http://proles.nlm.nih.gov/SC/B/B/R/D/>; 1977b.
Crick, Francis H.C. Letter from Francis Crick to Georg Kreisel (March 17, 1978). <http://
proles.nlm.nih.gov/ps/retrieve/ResourceMetadata/SCBBRC>; 1978.
Crick, F. H. C., & Orgel, Leslie. E. (1973). Directed panspermia. Icarus, 19, 341346.
Deamer, D. W., & Fleischaker, G. R. (Eds.). (1994). Origins of life: The central concepts.
Boston, MA: Jones and Bartlett Publishers.
Dick, S. J. (1998). Life on other worlds: The 20th century extraterrestrial life debate.
Cambridge: Cambridge University Press.
Di Giulio, M. (1997). On the RNA world: evidence in favor of an early
ribonucleopeptide world. Journal of Molecular Evolution, 45(6), 571578.
Dworkin, J. P., Lazcano, A., & Miller, S. (2003). The roads to and from the RNA world.
Journal of Theoretical Biology, 222, 127134.
Eigen, M. (1971). Selforganization of matter and evolution of biological
macromolecules. Die Naturwissenschaften, 58, 465523.
Farley, J. (1972). The spontaneous generation controversy (18591880): British and
German reactions to the problem of abiogenesis. Journal of the History of Biology,
5, 285319.
Farley, J. (1974). The initial reactions of French biologists to Darwins Origin of
Species. Journal of the History of Biology, 7, 275370.
Farley, J. (1977). The spontaneous generation controversy from descartes to oparin.
Baltimore: Johns Hopkins University Press.
Ferris, J. P. (1997). The prebiotic Leslie Orgel: Some of his contributions to our
understanding of the origins of life. Origins of Life and Evolution of Biospheres,
27(5), 431435.
Fisher, S. (2010). Are RNA viruses vestiges of an RNA world? Journal for General
Philosophy of Science, 41, 121141.
Flannery, M. C. (1991). Respect for RNA. The American Biology Teacher, 53(7),
438441.
Flannery, M. C. (2003). Never assume: the Lesson of RNA. The American Biology
Teacher, 65(3), 216221.
Forterre, P. (2005). The two ages of the RNA world, and the transition to the DNA
world: a story of viruses and cells. Biochimie, 87(910), 793803.
Fry, I. (2000). The emergence of life on Earth: A historical and scientic overview. New
Brunswick, NJ: Rutgers University Press.
Gesteland, R. F., Cech, T., & Atkins, J. F. (2006). The RNA world: the nature of modern
RNA suggests a prebiotic RNA world. CSHL Press.
Gibson, L. J. (1993). Did Life Begin in an RNA World. Origins, 20, 4552.
Gilbert, W. (1986). The RNA World. Nature, 319, 618.
Gordon, K. H. J. (1995). Were RNA replication and translation directly coupled in the
RNA (+protein?) world? Journal of Theoretical Biology, 173(2), 179193.
Guerrier-Takada, C., Gardiner, K., Marsh, T., Pace, N., & Altman, S. (1983). The RNA
moiety of Ribonuclease P is the catalytic subunit of the enzyme. Cell, 35,
849857.
Haldane, J. B. S. (1965). Data needed for the blueprint of the rst organism. In The
Origins of prebiological systems and of their molecular matrices: Proceedings of a
conference conducted at Walkulla Springs, Florida on 27-30 October 1963
(pp. 1118). New York: Academic Press.
Haldane, J. B. S. (1929). The origin of life. in J. D. Bernal (1967), The origin of life,
Oxford University Press, London, pp. 242249. London: Weidenfeld and
Nicolson (Reprinted from The Rationalist Annual, 3, 310, 1929).
Harr, R. (1983). Great scientic experiments: Twenty experiments that changed our
view of the world. Oxford, New York: Oxford University Press.
Horgan, J. (1996). The world according to RNA. Experiments lend support to the
leading theory of lifes origin. Scientic American, 274(1), 2730.
Huxley, Thomas H. (1870). On the physical basis of life, 2nd American ed. (New
Haven: Charles C. Chateld).
James, K. D., & Ellington, A. D. (1995). The search for missing links between self-
replicating nucleic acids and the RNA world. Origins of Life and Evolution of
Biospheres, 25(6), 515530.
Jeffares, D. C., Poole, A. M., & Penny, D. (1998). Relics from the RNA world. Journal of
Molecular Evolution, 46(1), 1836.
Joyce, G. F. (1989). RNA evolution and the origins of life. Nature, 338, 217224.
Kamminga, H. (1980). History of theories of the origin of life, PhD thesis, London
Univ., (Chelsea College).
Kamminga, H. (1986). The protoplasm and the gene. In G. Caims-Smith & H.
Hartman (Eds.), Clay Minerals and the Origins of Life (pp. 110). Cambridge:
Cambridge University Press.
Kamminga, H. (1988). Historical perspective: The problem of the origin of life in the
context of developments in biology. Origins of Life and Evolution of the Biosphere,
18, 111.
Kay, L. E. (1998). A book of life? How the genome became an information system
and DNA a language. Perspectives in biology and medicine, 41(4), 504528.
Keosian, J. (1974). Lifes beginnings Origin or evolution? Origins of Life and
Evolution of the Biosphere, 5, 285293.
Keyes, M. E. (1999). The prion challenge to the Central Dogma of molecular
biology, 19651991: Part I: Prelude to prions. Studies in History and Philosophy
of Biological and Biomedical Sciences, 30, 119.
750 N. Sankaran / Studies in History and Philosophy of Biological and Biomedical Sciences 43 (2012) 741750
Kruger, K., Grabowski, P. J., Zaug, A., Sands, J., Gottschling, D. E., & Cech, T. (1982).
Self-splicing RNA: Autoexcision and autocyclization of the ribosomal RNA
intervening sequence of Tetrahymena. Cell, 31, 147157.
Lahav, N. (1993). The RNA-world and co-evolution hypotheses and the origin of life:
implications, research strategies and perspectives. Origins of Life and Evolution of
the Biosphere: The Journal of the International Society for the Study of the Origin of
Life, 23(56), 329344.
Lazcano, A. (2010). Historical development of origins research. Cold Spring Harbor
Perspectives in Biology, 2(11), 16.
Lewin, R. (1986). RNA catalysis gives fresh perspective on the origin of life. Science,
231, 545546.
Lucrezia, D., Anella, F., & Chiarabelli, C. (2007). Question 5: On the chemical reality
of the RNA world. Origins of Life and Evolution of Biospheres, 37(45), 379385.
Lupi, O., Dadalti, P., Cruz, E., Sanberg, P. R., et al. (2006). Are prions related to the
emergence of early life? Medical hypotheses, 67(5), 10271033.
Ma, W., & Yu, C. (2006). Intramolecular RNA replicase: Possibly the rst self-
replicating molecule in the RNA world. Origins of Life and Evolution of Biospheres,
36(4), 413420.
McGinness, K. E., & Joyce, G. F. (2003). In search of an RNA replicase ribozyme.
Chemistry & biology, 10(1), 514.
Meyers, B. C., Matzke, M., & Sundaresan, V. (2008). The RNA world is alive and well.
Trends in Plant Science, 13(7), 311313.
Minchin, E. A. (1912). Joint discussion with section K on the origin of life. Report of
the Eighty-Second Meeting of the British Association for the Advancement of
Science, 510511.
Monnard, P. A. (2007). Question 5: Does the RNA-world still retain its appeal after
40 years of research? Origins of Life and Evolution of Biospheres, 37(4), 387390.
Muller, H. J. (1929). The gene as the basis of life. Proceedings of the International
Congress of Plant Sciences, 1, 897921.
Muller, H. (1966). The gene material as the initiator and the organizing basis of life.
American Naturalist, 100, 493517.
Noller, H., Hoffarth, V., & Zimniak, L. (1992). Unusual resistance of peptidyl
transferase to protein extraction procedures. Science, 256, 14161419.
Oparin, A. I. (1924). The origin of life, transl. A. Synge, In J. D. Bernal (1967), The
origin of life, Oxford University Press, London, pp. 199234. London:
Weidenfeld and Nicolson.
Oparin, A. I. (1938). The origin of life. New York: MacMillan.
Orgel, L. E. (1968). Evolution of the genetic apparatus. Journal of Molecular Biology,
38, 381393.
Orgel, L. E., & Crick, F. (1993). Anticipating an RNA World, some past speculations on
the origin of life: Where are they today? FASEB Journal, 7, 238239.
Pace, N., & Marsh, T. (1985). RNA catalysis and the origin of life. Origins of Life and
Evolution of the Biosphere, 16, 97116.
Plutarch. (circa 1st century A.D.). Whether the hen or the egg came rst? (Table-talk
II 3.1-3, 635 e638 a). In P.A. Clement, & H.B. Hofeit, (Eds.), (1969). Plutarchs
Moralia VIII, (Loeb Classical Library series) (pp. 144157). London: Harvard
University Press.
Podolsky, S. (1996). The role of the virus in origin-of-life theorizing. Journal of the
History of Biology, 29, 79126.
Quastler, H. (1964). The emergence of biological organization. New Haven: Yale
University Press.
Ravin, Arnold. V. (1977). The gene as catalyst; the gene as organism. Studies in the
History of Biology, 1, 145.
Robertson, M. P., & Joyce, G. F. (2012). The origins of the RNA world. Cold Spring
Harbor Perspectives in Biology, 4(5), 22.
Ruse, M. (1997). The origin of life: Philosophical perspectives. Journal of Theoretical
Biology, 187, 473482.
Saenger, W. (1984). Principles of nucleic acid structure. Springer-Verlag.
Saito, H., & Inoue, T. (2009). Synthetic biology with RNA motifs. The International
Journal of Biochemistry & Cell Biology, 41(2), 398404.
Salisbury, F. B. (1971). Doubts about the modern synthetic theory of evolution. The
American Biology Teacher, 33(6), 335354.
Schwartz, A. W. (1995). The RNA world and its origins. Planetary and Space Science,
43(12), 161165.
Sharp, P. A. (2009). The centrality of RNA. Cell, 136(4), 577580.
Strick, J. (1999). Darwinism and the origin of life: The role of H. C. Bastian in the
British spontaneous generation debates, 18681873. Journal of the History of
Biology, 32, 5192.
Strick, J. (2000). Essay review: The Cambrian explosion (Of books on the origin of
life). Journal of the History of Biology, 33, 371384.
Spirin, A. S. (2005). The RNA world and its evolution. Molecular Biology, 39(4),
466472.
Stark, B. C., Kole, R., Bowman, E. J., & Altman, S. (1977). Ribonuclease P: An enzyme
with an essential RNA component. Proceedings of the National Academy of
Sciences, USA, 75, 37193721.
Troland, L. T. (1914). The chemical origin and regulation of life. Monist, 24, 92133.
Troland, L. T. (1916). The enzyme theory of life. Cleveland Medical Journal, 15,
377385.
Troland, L. T. (1917). Biological enigmas and the theory of enzyme action. American
Naturalist, 51, 321350.
Vasas, V., Szathmry, E., & Santos, M. (2010). Lack of evolvability in self-sustaining
autocatalytic networks constraints metabolism-rst scenarios for the origin of
life. Proceedings of the National Academy of Sciences USA, 107(4), 1470.
Vlassov, A. V., Kazakov, S. A., Johnston, B. H., & Landweber, L. F. (2005). The RNA
world on ice. A new scenario for the emergence of RNA information. Journal of
Molecular Evolution, 61(2), 264273.
Waldrop, M. M. (1989). Did life really start out in an RNA world? Science, 246(4935),
1248.
Wattis, J. A. D., & Coveney, P. V. (1999). The origin of the RNA world: A kinetic
model. The Journal of Physical Chemistry B, 103(21), 42314250.
Woese, C. R. (1967). The genetic code: the molecular basis for genetic expression. New
York: Harper & Row.
Yarus, M. (2011). Getting past the RNA world: The initial Darwinian ancestor. Cold
Spring Harbor Perspectives in Biology, 3(4).