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[Appeared in Biology and Philosophy 2004, 19, 205-222]
Title:
The arbitrariness of the genetic code
Author:
Ulrich E. Stegmann
Affiliation:
Philosophy Department, University of Bielefeld, Germany
Philosophy Department, King’s College London
Address for correspondence: Philosophy Department
King’s College London
Strand, London WC2R 2LS
United Kingdom
E-mail:
[email protected]
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Abstract. The genetic code has been regarded as arbitrary in the sense that the codonamino acid assignments could be different than they actually are. This general idea has
been spelled out differently by previous, often rather implicit accounts of arbitrariness.
They have drawn on the frozen accident theory, on evolutionary contingency, on
alternative causal pathways, and on the absence of direct stereochemical interactions
between codons and amino acids. It has also been suggested that the arbitrariness of the
genetic code justifies attributing semantic information to macromolecules, notably to
DNA. I argue that these accounts of arbitrariness are unsatisfactory. I propose that the code
is arbitrary in the sense of Jacques Monod’s concept of chemical arbitrariness: the genetic
code is arbitrary in that any codon requires certain chemical and structural properties to
specify a particular amino acid, but these properties are not required in virtue of a principle
of chemistry. This notion of arbitrariness is compatible with several recent hypotheses
about code evolution. I maintain that the code’s chemical arbitrariness is neither sufficient
nor necessary for attributing semantic information to nucleic acids.
Key words: arbitrariness, genetic code, complementarity, competitive inhibition, allosteric
effectors, principles of chemistry, frozen accident theory, evolutionary contingency,
genetic information.
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The genetic code summarises which codons specify which amino acids during protein
synthesis. Many biologists and philosophers suggest that it is arbitrary that a particular
codon specifies one particular amino acid rather than a different one (e.g., Monod 1971;
Maynard Smith 2000a; Godfrey-Smith 2000a; Sarkar 2000; Sterelny 2000). The only
generally accepted sense of ‘arbitrary’ seems to be that the assignments could be different
than they actually are. Of course, this does not say much about the sense in which they
could be different. A more substantial claim is, for example, that the genetic code could be
different because an early version of the code became established by chance events rather
than by selection or stereochemical factors (Francis Crick’s ‘frozen accident theory’,
1968). Ironically, though, the code is probably not arbitrary in this sense because empirical
research tends to disconfirm Crick’s hypothesis. Other attempts to unpack ‘arbitrariness’
face similar difficulties. As Godfrey-Smith put it, arbitrariness has proven a “useful if
elusive concept in biology” (2000a: 205). Despite these difficulties, I maintain that there is
an important sense in which the genetic code is arbitrary. My aim is to specify this sense
and to explore some of its implications.
Perhaps the most important implication concerns the notion of genetic information. Despite
its vagueness, arbitrariness is thought to be useful in establishing how molecules like DNA
might convey semantic genetic information1 (Godfrey-Smith 2000a, b; Maynard Smith
2000a, b; Sarkar 2000; Sterelny 2000). The argument has not been worked out, but it
seems to be based on an analogy between chemical and linguistic arbitrariness. Linguistic
arbitrariness expresses the fact that the linguistic properties of a word are usually not
naturally related to its meaning. The phonetic form of ‘dog’ does not reflect a property of
dogs. In Peircean terms, the relation between a word and its meaning is symbolic.
Similarly, the genetic code’s arbitrariness is understood as the absence of a natural
connection between codons and amino acids. Chemical arbitrariness arguably establishes a
language-like symbolic relation between codons and amino acids. It is then thought
legitimate to attribute meaning and semantic information to genes or its components.
I first outline and evaluate rather implicit ideas about the nature of the code’s arbitrariness.
They are based on the ‘frozen accident hypothesis’, on evolutionary contingency, and on
the indirectness of interactions. Sarkar’s account of arbitrariness is also discussed (section
1). I then explicate Jacques Monod’s concept of chemical arbitrariness (section 2). In the
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next section I apply it to the genetic code arguing that the genetic code is arbitrary in this
sense. I return to three of the previous suggestions regarding arbitrariness (indirectness of
interactions, frozen accident theory, and evolutionary contingency) in order to evaluate
them further in the light of Monod’s ‘chemical arbitrariness’ (section 3). The last section
(4) explores what this concept contributes to the debate about genetic information. My
conclusion will be that chemical arbitrariness does not imply that molecules carry semantic
genetic information. Also, provided there are semantic molecules, arbitrariness is not
required for having meaning.
1. Accounts of arbitrariness
1.1 The frozen accident theory
The arbitrariness of the genetic code has been associated with Crick’s (1968) frozen
accident theory (e.g., Godfrey-Smith 2000b: footnote p. 33; Monod 1971: p. 135; Jacob
1974: p. 306; Sarkar 2000: p. 210). According to this theory, the first stage in the evolution
of the code was the establishment or fixation of a primitive code in the common ancestor
of extant organisms. Assignments were established in the population when they were
shared by all its members. Thereafter, new amino acids were added to the code until the
costs of further expansion outweighed its benefits. At this stage, the code became frozen
and the detrimental effects of alterations prevented the code from evolving any further. For
Crick, the code’s establishment during the first stage of code evolution was essentially the
result of “chance” and “happy accidents”:
To account for [the code] being the same in all organisms one must assume that all
life evolved from a single organism (more strictly, from a single closely inbreeding
population). In its extreme from, the [‘frozen accident’] theory implies that the
allocation of codons to amino acids at this point was entirely a matter of “chance”
(Crick 1968, p. 370).
Accidental “allocation” of codons to amino acids refers to the establishment of
assignments in the ancestor population rather than to their generation. For it is
uncontroversial that variation is generated by chance events like mutations. The
controversial proposal was that fixation at an early stage was not caused by selection and
was not predetermined by stereochemical* constraints (*-marked terms are explained in
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the glossary). Against the stereochemical theory (e.g., Woese 1967), Crick proposed that
codon and amino acids did not interact directly with each other even during earliest code
evolution2. Without the specificity* of direct interactions, the chemical properties of
codons or amino acids did not restrict or determine the set of assignments which then could
become fixed.
Although Crick (1968) did not explicitly exclude selection as the main cause of early
fixation, the hypothesis that “allocation” was driven by accidents implies that selection was
not essential. However, he thought selection did play a role in the later stages of code
evolution. According to the frozen accident theory, there was a net benefit to the addition
of new amino acids and, therefore, the code gradually expanded due to selection. The
benefit was the production of less “crude” proteins. Crick rejected the hypothesis that the
main benefit was selection for minimising the effect of mutations (p. 376). He thought this
kind of selection had occurred, but only to limit the disruptive effects of adding new amino
acids.
Consequently, explaining the arbitrariness of the genetic code in terms of the frozen
accident theory amounts to claiming that the code is arbitrary insofar its early stages
became fixed by chance events rather than by selection or stereochemistry. An initial
worry with this idea is that, on this account, the genetic code may not be arbitrary after all.
For many aspects of the frozen accident theory have been challenged (reviewed in
Maynard Smith and Szathmáry 1995; Knight et al. 1999, 2001). Indeed, it seems that
current research tends to support various selective, historical, and stereochemical
hypotheses of code evolution. At least some of these hypotheses suggest that fixation of
the early code was not a matter of chance. This is true for stereochemical theories (a recent
proposal is by Seligmann and Amzallag 2002). In general, in vitro selection experiments
are regarded as supporting the view that direct chemical affinities between codons and
amino acids determined assignments during early stages of code evolution (e.g.,
Illangasekare and Yarus 2002; Knight 1999; but see Ellington et al. 2000).
1.2 Evolutionary contingency
Instead of emphasising fixation by chance events one might focus on the claim that the
code was and perhaps still is changed by evolution, irrespective of whether evolution is
driven by chance or by selective mechanisms. Arbitrariness can be seen as arising from the
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fact that tRNAs and assignment enzymes were altered in the course of evolution and that
the outcome could have been different (Maynard Smith 2000a: p. 183). This idea can be
refined in terms of Beatty‘s (1995) evolutionary contingency hypothesis. It could be
argued that arbitrariness expresses the claim that a code with a different set of assignments
would have been functionally equivalent to the ‘canonical’ code. Since functional
equivalence is seen as a source of strong evolutionary contingency (p. 58), the code would
be arbitrary in the sense of being highly contingent. On this account, however, other
biochemical or biological regularities are as arbitrary as the genetic code. For Beatty seems
to regard all biological generalisations regarding such regularities as being highly
contingent (p. 57).
1.3 Sarkar’s proposal
A similar challenge faces Sarkar’s (2000) proposal. He defines arbitrariness in terms of the
presence of alternative causal paths for a particular effect: If a theory about how s produces
σ does not rule out that a different s’ could produce σ, then s may be regarded a sign for σ
(p. 210). On this account nearly all biochemical relation would be arbitrary. For
biochemical theories are about particular reactions and not about their evolutionary
alternatives and, therefore, the theories do not exclude those alternatives. Sarkar is ready to
embrace such a consequence (p. 211).
1.4 Indirect interactions between codons and amino acids
Arbitrariness has also been viewed as resulting from the fact that codons do not specify
amino acids by direct stereochemical interactions but rather indirectly. A similar
indirectness is found between gene regulators (e.g., transcription factors) and the gene
product whose synthesis they regulate:
In the terminology of semiotics, there is no necessary connection between [the
regulating factors‘] form (chemical composition) and meaning (genes switched on
or off). Other features of molecular biology are symbolic in this sense: for example,
CAC codes for histidine but there is no chemical reason why it should not code for
glycine (Maynard Smith 2000a: p. 185).
Since codons do not interact directly with amino acids, the set of amino acids they could
(in principle) specify is not limited by stereochemical affinities between codons and amino
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acids3. Maynard Smith observes that such an idea was first entertained by Jacques Monod.
As Monod put it:
... there exists no direct steric relationship between the coding triplet and the coded
amino acid. This leads to a most important conclusion: this code ... seems to be
chemically arbitrary, inasmuch the transfer of information could just as well take
place according to some other convention (Monod 1971: p. 106)4.
Explaining arbitrariness in terms of a convention perhaps begs the question. The more
substantial claim is that the arbitrariness of the genetic code results from the indirectness of
codon amino acid interactions. This may seem to imply that indirectness is all that is
needed for arbitrariness. However, this conclusion is problematic because any remote
chemical effect of a cause would then be related arbitrarily to its cause. Thus, arbitrariness
would not denote a set of causal processes different in kind from non-arbitrary processes
(Godfrey-Smith 2000a: p. 203). Moreover, as I will argue in the following, indirectness of
interaction does not imply chemical arbitrariness in Monod’s sense.
2 Monod’s concept of arbitrariness
2.1 Chemical necessity
Monod applied the concept of chemical arbitrariness to the genetic code in his 1970 book
Le hasard et la necessité, but he developed it in the early 1960’s and in an entirely
different context. At the time, it described the peculiarity of allosteric enzymes*. Monod
first used this concept in a conference report (Monod and Jacob 1961) and referred to it, in
a seminal paper on enzyme function, as “arbitrariness, chemically speaking” (Monod et al.
1963).
Monod never gave a definition or abstract characterisation of the notion of chemical
arbitrariness. This will be my aim here. However, he drew a close connection between
arbitrariness and the absence of ‘chemical necessity’. For example, when describing the
regulation of a particular allosteric enzyme (ß-galactosidase), Monod wrote:
There is no chemically necessary relationship between the fact that β-galactosidase
hydrolyses β-galactosides, and the fact that its biosynthesis is induced by the same
compounds. Physiologically useful or ‘rational’, this relationship is chemically
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arbitrary - ‘gratuitous’, one may say. This fundamental concept of gratuity - i.e., the
independence, chemically speaking, between the function itself and the nature of
the chemical signal controlling it - applies to allosteric proteins. (Monod 1971: p.
78)
According to Monod, chemical arbitrariness is similar or even equivalent to the absence of
chemical necessity. So I start by exploring ‘chemical necessity’ and then ask what its
absence amounts to.
Chemical necessity applies to certain interactions between molecules. An essential feature
of chemical necessity is that these interactions only occur if certain requirements are
satisfied. Take, for instance, the interaction between a particular substrate molecule and its
enzyme. The substrate binds specifically (to just one kind of enzyme) only if the substrate
fits into the enzyme’s active site*, i.e., if the substrate has chemical and spatial properties
complementary* to the binding site (Monod 1971: p. 60). The necessary condition for the
formation of enzyme-substrate complexes is complementarity, both spatial and chemical,
between a substrate and its enzyme’s active site5.
In addition to the presence of certain necessary conditions, Monod’s concept of chemical
necessity involves an appeal to chemical principles. According to Monod, the formation of
noncovalent* associations between macromolecules requires complementary surface areas
as a matter of chemical principle. This is the content of his “fundamental principle of
associative stereospecifity” (Monod 1971: p. 104). Since enzyme-substrate complexes are
a kind of noncovalent associations between two macromolecules, they require
complementarity in virtue this principle.
This double aspect of Monod’s ‘chemical necessity’ can also be inferred from his
discussion of competitive inhibition (Jacob and Monod 1963: p. 310; Monod et al. 1963: p.
33). In competitive inhibition, a substrate’s chemical transformation is slowed down by the
presence of small molecules other than the substrate. These ‘competitive inhibitors’ bind to
the enzymes’ active sites and so sterically* hinder substrate molecules from binding to the
same sites. In order to bind to these sites, the chemical and structural properties of
competitive inhibitors must be very similar to the substrate’s properties needed for binding
to the enzyme. Hence the term ‘substrate analogue’ for competitive inhibitors. In Monod’s
words, competitive inhibitors “must bear” the structural relation of “chemical analogy”
with the substrate; and chemical analogy between substrate and competitive inhibitors is
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“inherent” and “obligatory” (Monod et al. 1963: p. 307). In short, the necessary condition
for competitive inhibition is a high degree of stereochemical similarity between substrate
and inhibitor. Furthermore, Monod and Jacob (1961: p. 391) hypothesised a general
“principle of steric analogy” according to which competitive inhibitors must be structurally
similar (i.e., ‘isosteric’) to their substrates in order to inhibit them6.
I conclude from these examples that Monod’s ‘chemical necessity’ involves both necessary
conditions and, in some sense, chemical principles. I suggest reconstructing Monod’s
concept of chemical necessity thus:
Chemical necessity. A relation R between two molecules is chemically necessary
with respect to R’, if and only if (i) R is a necessary condition for another relation
R’ to hold between them, and (ii) the R is a necessary condition for R’-relation
holds in virtue of a chemical principle.
This explication applies to the two examples as follows. To say ‘It is chemically necessary
that a substrate is complementary to its enzyme’ is to claim that there is a principle of
chemistry to the effect that complementarity (R) is required for forming stable associations
by noncovalent bonds (R’). Similarly, the proposition ‘It is chemically necessary that a
competitive inhibitor is isosteric to its substrate’ states that there is a biochemical principle
to the effect that two molecules must be isosteric (R) for one to competitively inhibit the
other (R’).
It may be confusing to find chemical necessity being predicated both of the relation R (e.g.
of complementarity) and the relation between R and R’ (e.g., of complementarity being the
requirement for the formation of enzyme-substrate complexes). However, either way the
same claim is made: complementarity is required for enzyme-substrate complexes as a
matter of chemical principle.
2.2 Chemical principles
Monod’s ‘chemical necessity’ relies on chemical principles. A tentative characterisation of
chemical principles would highlight that they typically generalise across different kinds of
molecules (or other chemical entities). A regularity concerning specifically one particular
enzyme and its substrate would hardly count as a chemical principle. However, there is
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more to chemical principles than general scope. If evolution had eliminated all proteins
which are composed of more than two subunits, then it would not be a chemical principle
that proteins are composed of not more than two subunits. Intuitively, this is because
proteins could have more than two subunits.
A principle of chemistry is about what ‘must’ be the case for chemical reasons. In practical
terms at least, this idea is often associated with macroscopic consequences arising from the
basic properties of molecules or their constituents. For example, Monod’s principle of
associative stereospecificity bases the requirement for complementarity on the general
nature of noncovalent chemical bonds (Monod 1971: p. 60): individual noncovalent bonds
are weak; in order for noncovalent bonds to hold two molecules together, many
noncovalent bonds are required and the atoms of the two molecules must have the optimal
distance between them. The required number of noncovalent bonds of optimal distance can
only be formed if the two molecules share spatially and chemically complementary surface
areas. As a consequence, molecules must be complementary to each other in order to be
held together by noncovalent bonds.
Thus, to say that complementarity is required in virtue of a chemical principle implies that
this requirement results from basic properties shared not only by the particular chemical
entities in question. This characterisation can be used to distinguish between necessary
conditions which hold in virtue of chemical principles and those that do not. Of course, it
does not replace a substantial analysis of the concept of chemical principle.
Monod’s ‘principle of associative stereospecificity’ has the features of typical ‘laws’ or
principles in chemistry. They express our knowledge of how the world works and they are
often inexact (Christie and Christie 2000). The ‘principle of associative stereospecificity’ is
inexact because it does not specify which degree of complementarity is required to form
noncovalent associations. Another feature of chemical principles is that they have
exceptions (Christie and Christie 2000). However, the exceptions to the ‘principle of steric
analogy’ seem numerous enough to have led to the abandonment of this principle.
The next step towards clarifying ‘chemical arbitrariness’ will be to explore what the
absence of chemical necessity amounts to. Two alternatives suggest themselves. The lack
of chemical necessity amounts to either (i) the absence of a chemical principle; in this case,
the relation R would still be a necessary condition for another relation R’, albeit not in
virtue of a chemical principle; or (ii) the absence of the necessary condition itself. In order
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to discriminate between these alternatives, I now examine how Monod and his co-workers
developed and used the concept of chemical arbitrariness in their enzyme studies.
2.3 Allosteric interactions
The concept of chemical arbitrariness was put forward by Monod as a description of the
action of allosteric proteins (Monod and Jacob 1961; Monod et al. 1963; Monod 1971).
According to their structural model, an allosteric protein has at least two spatially separated
binding sites, one specific to the substrate molecule and the other specific to an effector
molecule*. Binding of an effector induces a conformational change in the structure of the
protein that causes a change in the properties of the catalytic site. This, in turn, stimulates
or inhibits an enzyme’s catalytic activity.
According to Monod, two related features in this model of allosteric interaction result in
the lack of chemical necessity: effectors and substrate molecules bind to separate sites of
the allosteric protein and the effector is not a reactant of the catalysed reaction.
An absolutely essential, albeit negative, assumption implicit in this description is
that an allosteric effector, since it binds at a site altogether distinct from the active
site and since it does not participate at any stage in the reaction activated by the
protein, need not bear any particular chemical or metabolic relation of any sort with
the substrate itself. (Monod et al. 1963: p. 307)
How does the binding to two spatially separated sites result in a lack of chemical
necessity? Consider first the consequences on what Monod calls the ‘chemical relations’
between effector and substrate, e.g., complementarity. First, substrate and effector do not
interact chemically with one another, for instance, they do not form noncovalent bonds.
Therefore, the effector need not be complementary or reactive towards the substrate in
order to have a regulating effect on it. Second, substrate and effector need to be
complementary to the two separate binding sites and the sites can (and usually do) differ
from one another in their stereochemical properties. Consequently, the substrate need not
be isosteric to the effector. Third, the properties of one binding site does not influence or
determine the properties of the other.
The paragraph cited above also suggests that effector and substrate need not stand in a
particular metabolic relation with each other (Monod et al. 1963: 307). A metabolic
relation marks the relative positions of effector and substrate within the web of metabolic
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pathways. Consider the case of feedback inhibition where an enzyme catalysing the first
step in a metabolic pathway is inhibited by the ultimate product (the effector) of the same
pathway. For example, the ultimate product of a pathway which starts with the substrate
threonine is isoleucine. Isoleucine inhibits the catalytic activity of the enzyme threoninedeaminase which catalyses the chemical transformation of threonine (p. 308). In addition
to the regulatory relation of inhibition between isoleucine and threonine, they stand in a
particular metabolic relation: the effector is the ultimate product of the metabolic pathway
starting with its substrate. To deny the need for a particular metabolic relation means, in
this case, that the effector does not need to be the ultimate product of a pathway in order to
inhibit the first substrate of that pathway. It could be, for instance, an intermediate product
or the ultimate product of a different pathway:
... since again there is no obligatory correlation between specific substrates and inhibitors
of allosteric enzymes, the effect need not be restricted to “endproduct” inhibition...
(Monod and Jacob 1961:p. 391).
2.4 Chemical arbitrariness
The discussion of allosteric interactions shows that, at some point, Monod seems to equate
the lack of chemical necessity with the absence of a necessary condition. For instance,
effectors must not be complementary to their substrates in order to inhibit (or stimulate) the
substrate’s chemical transformation. On the other hand, there are necessary conditions. For
example, certain stereochemical properties of a particular effector are required in order to
bind to the regulatory site of its enzyme and to have a regulatory effect on a particular
substrate.
The apparent contradiction arises because Monod argues with respect to molecular classes
like substrates, enzymes and effectors, but not with respect to members of such classes like
threonine. At the level of molecular classes, there is no particular structural or metabolic
relation which is required for an effector to regulate a substrate. Not all effectors need to be
isosteric to their substrates and not all effectors need to be endproducts. In other words,
there is no relation which is common to all members of the effector- and substrate-classes
and which is required for another relation to hold between them. However, at the level of
particular kinds of effectors and substrates, a certain metabolic or structural relation is
usually required for enzymatic modulation. For example, the effector of the substrate
threonine must be the endproduct of the threonine pathway. For only this endproduct
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happens to have the chemical properties required for binding to the enzyme threoninedeaminase so as to inhibit the chemical transformation of threonine.
The important thing to notice is that, irrespective of the level at issue, there is no
biochemical principle in virtue of which a requirement for a certain structural or metabolic
relation obtains. At the level of particular substrates, there is no such principle because the
requirement arises (in part) from the composition of the relevant enzyme. There is no
regularity to the effect that the stereochemistry of an enzyme’s regulatory site depends on
the stereochemistry of its catalytic site. At the level of molecular classes there is no
biochemical principle because there is no general requirement for inhibition (or activation)
in the first place. Even if there was a general requirement, this would not imply a
corresponding biochemical principle. Suppose evolution had eliminated all species whose
inhibitory effectors were not endproducts, then all substrates in all remaining taxa were
inhibited by the their endproducts. It would be a general requirement that allosteric
inhibitors are endproducts. Nevertheless, there still would be no biochemical principle to
this effect.
For a more precise formulation of the concept of chemical arbitrariness, let M1 and M2
stand for different (particular or classes of) molecules. Further, let R denote one relation
between different molecules - regulatory, structural or metabolic. Additional relations of
this kind among the same pair of molecules are indexed as R’. Hence, the reconstruction of
Monod’s concept of chemical arbitrariness:
Chemical arbitrariness. The relation R between molecules M1 and M2 is
chemically arbitrary with respect to R’, if and only if either (i) R is not required for
R’ or (ii) if R is required for R’, then it is not a chemical principle that R is required
for R’.
The relation between isoleucine and threonine is an example for the latter case, because
being the endproduct of a substrate pathway (R) is required for inhibiting this substrate
(R’), but not in virtue of a chemical principle. Another example for the latter case is the
previous thought experiment in which being the endproduct (R) is universally required for
inhibition (R’) in all effector-substrate pairs, but in which there is no principle for this
requirement. A case in which R is not required for R’ in the first place is provided by the
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actual relation between the classes of effectors and substrates: Not all effectors must be, for
example, endproducts in order to inhibit enzyme activity. Hence, R is not required for R’ at
the class-level. Since there is no (universal) requirement, there is also no chemical
principle governing it.
As with chemical necessity, chemical arbitrariness may be predicated of both R and the
second-order relation R is required for R’. For example, we might say “It is chemically
arbitrary that the effector isoleucine is the endproduct of the threonine pathway” (R), but
also “It is chemically arbitrary that isoleucine needs to be the endproduct of the threonine
pathway in order to regulate this pathway” (R is required for R’). Despite appearance both
expressions amount to the same claim: there is no chemical principle to the effect that
isoleucine must to be the endproduct of the threonine pathway in order to (help) regulate
the chemical transformation of threonine.
3. The genetic code
3.1 The chemical arbitrariness of the genetic code
What does it mean to say that a codon’s chemical properties are arbitrary with respect to
the amino acid it specifies? Consider a codon CAC (M1) and its amino acid histidine (M2)
as the two ‘molecules’. Some properties of CAC and histidine are required for
specification of histidine, for example, CAC must be complementary to the anticodon
GUG in order to specify histidine. Also, histidine has to have some properties in virtue of
which it is specifically recognised by the enzyme which attaches it to the proper tRNA.
These properties constitute a structural relation (R) between CAC and histidine. Instead of
listing the required properties, we can refer to this relation and say that the structural
relation R between CAC and histidine is a necessary condition for CAC to specify histidine
(R’).
Amino acids are linked to their tRNAs by specific enzymes, the aminoacyl-tRNAsynthetases. The binding sites for amino acids and for tRNAs are spatially separated within
an aminoacyl-tRNA-synthetase molecule. Similarly, many tRNAs have several spatially
separated interaction sites for their enzyme. At these sites, the amino acid-enzyme and
tRNA-enzyme interactions are specific and ultimately determine which amino acid is
linked to which tRNA. Importantly, one binding site of an enzyme does not determine the
properties of this enzyme’s other binding site (similarly for the binding sites of tRNAs).
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There is no chemical principle stating a dependence between the binding sites within
molecules. Thus, to say that there is no chemical reason why CAC codes for histidine but
not for glycine is to claim the following: there are chemical properties of CAC (and
histidine) which are required for CAC to specify histidine, but they are not required in
virtue of a chemical principle; and, therefore, it is chemically possible that CAC could
specify for glycine or any other amino acid.
When speaking at the level of the ‘molecule’ classes of codons and amino acids in general,
arbitrariness can be expressed using the second formulation of the definition of
arbitrariness. The two ‘molecules’ at issue are the class of codons (M1) and the class of
amino acids (M2). For all we know, there is no chemical principle according to which all
codons require one particular structural relation (R) in order to specify their respective
amino acids (R’). Hence, at the general level, there is no structural relation R which is
required for specification (R’).
In short, I argue that the genetic code is arbitrary and that Monod’s concept of chemical
arbitrariness captures most adequately the sense in which it is arbitrary. The following
summarises this account:
Arbitrariness of the genetic code. The structural relation (R) between codons (M1)
and amino acids (M2) is chemically arbitrary with respect to the specification of
amino acids by codons (R’), in that either (i) R is not required for R’ or (ii) if R is
required for R’, then it is not a chemical principle that R is required for R’.
3.2 Comparison with previous accounts of arbitrariness
Initial worries with previous accounts of the arbitrariness of the genetic code have been
discussed above. The question now is how they relate to my explication of Monod’s
account. More specifically, can Monod’s account be replaced by an appeal to indirect
determination, to an evolutionary origin from chance events or to evolvability?
1. One suggestion was that arbitrariness results from the fact that codons interact indirectly
with their amino acids. The indirectness of interaction would free them from chemical
constraints. However, arbitrariness does not result from indirectness in the sense that
indirectness is sufficient for arbitrariness. Suppose there was a chemical principle to the
effect that the stereochemical properties of binding sites within molecules like tRNAs and
aminoacyl-tRNA-synthetases depend on each other. Then, codons would still interact
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indirectly with amino acids but, since both codons and amino acids would need to fit to the
binding sites, the principle relating intramolecular binding sites would eventually
determine the kind of structure a codon must have in order to specify a particular amino
acid. Therefore, the structural relation between codons and amino acids would be
chemically necessary.
This consideration shows that the indirectness of interactions (or the lack of direct
stereospecific interactions) is not, by itself, sufficient for arbitrariness. The idea that it is
may have arisen from an ambiguity of the term ‘separate’ as applied to the binding sites of
an enzyme. The binding sites are spatially separate, but they are also separate in the sense
of being structurally and functionally independent. This independence is simply another
way of claiming that there is no chemical principle connecting the properties of the two
sites. It is this absence which gives rise to the arbitrariness of the genetic code.
2. Some have associated the genetic code’s arbitrariness with the role chance events played
in establishing its first assignments. As discussed above, Crick’s frozen accident
hypothesis might be false on empirical grounds so that the code would not be arbitrary in
this sense. However, even if the hypothesis was true and the code had evolved through
random processes, this would neither be sufficient nor necessary for the code’s chemical
arbitrariness. If the code’s assignments had become fixed by selection, then there would
not have been a chemical principle making the binding sites of tRNAs depend on each
other (this also applies to Crick’s hypothetical, primitive tRNAs). The structural relations
between codons and amino acids would still be chemically arbitrary with respect to the
codons’ ability to specify amino acids.
An enzyme’s stereochemistry provides another example. The enzyme’s chemical
properties determine which metabolites become connected through an enzyme and, as
Monod emphasises, they result from selection for regulatory efficiency. More beneficial
metabolic relations will be favoured by selection:
In other words, any physiologically useful regulatory connection, between any two
or more pathways, might become established by adequate selective construction of
the interaction sites on an allosteric enzyme... Since the allosteric effect is not
inherently related to any particular structural feature common to substrate and
inhibitor, the enzymes subject to this effect must be considered as pure products of
selection for efficient regulatory devices (Monod and Jacob 1961: p. 391).
16
According to Monod, the structural or metabolic relations between effectors and substrates
are chemically arbitrary, yet determined by selection. Chance events are, therefore, not
required for establishing chemically arbitrary metabolic relations.
Evolutionary chance events are not sufficient for chemical arbitrariness either, because
they may establish chemically necessary relations. Take the relation between competitive
inhibitors and substrate. For the sake of argument I grant Monod’s “principle of steric
analogy” such that the inhibitor is related in a chemically necessary way to the substrate. I
suppose that a plant species inhibits substrate S by the isosteric inhibitor A1 and, further,
that a subpopulation gets genetically isolated. Within the subpopulation, an enzyme
appears which is modified in that it is inhibited by the different, but isosteric, inhibitor A2
(different inhibitors may differ from the substrate in different respects). The modified
enzyme spreads though the entire subpopulation by random genetic drift. As a result, even
though chance events determined the kind of inhibitor that inhibits S (via the modified
enzyme) in the subpopulation, the relation between A2 and S would not be chemically
arbitrary.
3. The initial objection against equating arbitrariness with evolutionary contingency was
that, since all biochemical processes are evolutionary contingent in Beatty’s (1995) sense,
all would be chemically arbitrary. Apart from this worry I think chemical arbitrariness
cannot be identified with evolutionary contingency, because contingency is insufficient for
arbitrariness.
Evolutionary contingency does not imply arbitrariness because evolutionary contingent
relations (in the strong sense) can be chemically necessary. For example, it is evolutionary
contingent that threonine-deaminase catalyses the reaction of threonine instead of a
different substrate, because catalysing a different reaction might have been as beneficial.
At the same time, their chemical structures are chemically necessary in the sense that the
two molecules need to be complementary in virtue of a chemical principle. Similarly, the
complementarity of nucleotide bases in DNA is a chemically necessary relation in the
sense that it follows from a chemical principle that they need to be complementary in order
to form pairs by noncovalent (hydrogen) bonds. However, the fact that thymine but not
uracil occurs in DNA is thought to be the result of natural selection for avoiding the
negative effects of point mutations (Nelson and Cox 2000: pp. 348, 953)7. Perhaps a base
other than thymine would have been functionally equivalent to thymine. Although the
17
pairing of thymine with adenine is evolutionary contingent, it is also chemically necessary.
Hence, evolutionary contingency is not sufficient for chemical arbitrariness.
There is a weak sense in which evolutionary contingency is necessary for chemical
arbitrariness: if all evolutionary outcomes are contingent (which may be doubted), arbitrary
relations could not have arisen without evolutionary contingency. However, if all outcomes
are evolutionary contingent, chemically necessary relations could not have evolved without
contingency either, because they are evolutionary outcomes as well. Thus, even if
necessary for arbitrariness in this sense, evolutionary contingency does not distinguish
arbitrariness from chemical necessity.
4. Symbolic relations
As noted in the introduction, the arbitrariness of the genetic code is considered by many
authors as a major source for justifying semantic claims in molecular biology (GodfreySmith 2000b: p. 33; Maynard-Smith 2000a: p. 183; Sarkar 2000: pp. 210-211; Sterelny
2000: p. 197). Words and letters are conventionally related to their meanings or to signs
from other alphabets like the Morse signs. It is this conventional relation which makes
letters and Morse signs symbolic. The thought seems to be that arbitrariness between
molecular entities establishes a similar, symbolic kind of relation between them.
There is a way to assess such a claim even before the idea has been worked out further. For
as long as arbitrariness is, in some way, essential for molecules to have meaning, we
should expect that all molecules conveying meaning should be chemically arbitrary. They
should be related arbitrarily to what is considered to be their meaning and to other
molecules that are regarded as standing for them. However, we cannot determine
straightforwardly whether all informational molecules exhibit such chemically arbitrary
relations, because it is controversial whether there are any such molecules. Fortunately,
there is no controversy over which are the primary candidates: DNA and RNA are the
molecules that are supposed to contain genetic information. As stated in the “central
dogma” of molecular biology (Crick 1970), the information is passed on to other cells and
to the next generation through the process of replication, and it is transferred to RNA and
proteins through the processes of transcription and translation, respectively. Therefore, if
one accepts that DNA and RNA contain information and that arbitrariness is essential for
18
having information, one is committed to claim that at least they bear the relevant
chemically arbitrary relations8.
Since codons are chemically arbitrarily related to amino acids, a given mRNA is arbitrarily
related to the proteins it specifies. This is what the arbitrariness of the genetic code is all
about. However, no such arbitrary relation is found in the other two supposedly
informational processes. Both in transcription and replication, the nucleic acid bases pair
up noncovalently with each other and this requires them to be complementary. For
example, the base cytosine needs to be complementary to the base guanine in order to bind
noncovalently to it. Importantly, the requirement for complementarity follows from a
general biochemical principle (Monod’s “principle of associative stereospecificity”). Thus,
when pairing up during transcription or replication, the nucleotide bases are related in a
chemically necessary way to each other. If we accept that semantic information is
transferred during replication and transcription, we find that the nucleotide base symbols
do not need to be chemically arbitrarily related to transfer this information.
One response is to deny that transcription and replication are informational. After all, the
result of a closer investigation was open. However, this move would have to explain how
mRNAs can contain genetic information when no information has been passed on to them
during their transcription. It also would be difficult to see where the genetic information in
the offspring’s mRNA comes from when no information has been passed on the
offspring’s DNA during replication.
In conclusion, some of the processes expected to involve semantic information are
certainly not chemically arbitrary and, therefore, chemical arbitrariness is not a necessary
condition for a semantic relation. However, it is also implausible to suggest that
arbitrariness is sufficient for having meaning. For many biochemical relations which are
chemically arbitrary are not regarded as being symbolic. Consider, for example, the
binding of oxygen to haemoglobin (e.g., Nelson and Cox 2000). Like many enzymes,
haemoglobin is an allosteric protein. Each of its four subunits contains a heme group to
which one oxygen molecule can bind. Binding to a heme results in a conformational
change of the subunits such that other oxygen molecules can bind more easily to the
remaining three heme groups. The relation between two oxygen molecules bound to
haemoglobin is chemically arbitrary in the following sense: an oxygen molecule requires
certain structural and chemical properties in order to induce the binding of another oxygen
19
molecule, but this requirement does not hold in virtue of a chemical principle. For the
stereochemistry of one protein (or heme group) binding site does not depend on the
stereochemistry of the other as a matter of chemical principle. Although chemically
arbitrary, the whole process does not involve any symbolic relation. Oxygen molecules are
not regarded as signals to bind other oxygen molecules. Many other allosteric proteins, like
myosin and some heat shock proteins (Hsp 70), also establish chemically arbitrary but nonsymbolic relations between their ligands.
These considerations show that the chemical arbitrariness of the genetic code is neither
necessary nor sufficient for nucleic acids to possess meaning. Monod’s concept of
chemical arbitrariness does not support the idea of semantic molecules.
Acknowledgements
I thank Matteo Mameli, David Papineau, and Marcel Weber for their comments on several
versions of the manuscript. I am also indebted to Kim Sterelny, two anonymous referees,
and Shirley Hong for their suggestions and comments. The paper was written while at the
Philosophy Department at King’s College London. Research was supported by the
Deutsche Akademie der Naturforscher Leopoldina through funds from the German
Ministry of Education and Research (BMBF-LPD 9901/8-83).
Glossary
Stereochemistry is a characteristic of many biomolecules: their function depends not only
on their covalent bonds and functional groups (groups of atoms with specific properties),
but also an their three-dimensional structure. Specificity is the ability of enzymes and other
proteins to distinguish between two competing ligands. Also used more generally for
interactions involving the recognition of particular molecules. Strictly speaking,
stereospecificity is the ability to distinguish between stereoisomeres, i.e., molecules which
have the same substituent groups of atoms (e.g., -H, -OH) bound to carbon atoms, but
which differ in their spatial arrangement. Also used more loosely as the ability of proteins
to distinguish between molecules based on their stereochemical properties. Steric refers to
the spatial properties of a molecule.
In biochemistry, complementarity expresses the idea that two molecules fit to each other
like lock and key in terms of both their spatial and chemical properties.
20
Allosteric enzymes have two spatially separated sites for noncovalent binding of small
molecules (ligands). The substrate binds to the catalytic or active site. A specific
metabolite, the effector, can bind to the regulatory site, thereby modulating the enzyme‘s
catalytic activity. Allosteric stands for having a different, isosteric for having a similar
structure.
Noncovalent bonds are weak attractive interactions between two atoms, e.g., hydrogen,
ionic, and van der Waals bonds. In contrast to covalent bonds, they do not consist in
sharing pairs of electrons but in electrostatic interactions between atoms.
References
Beatty, J. 1995: The Evolutionary Contingency Thesis. In Concepts, Theories and
Rationality in the Biological Sciences (eds. G. Wolters & J. G. Lennox), pp. 45-81.
Pittsburgh: University of Pittsburgh Press.
Crick, F. H. 1968: The Origin of the Genetic Code. Journal of Molecular Biology 38, 367379.
Crick, F. H. 1970: Central Dogma of Molecular Biology. Nature 227, 561-563.
Christie, M. and Christie, J. R. 2000: "Laws" and "Theories" in Chemistry Do Not Obey
the Rules. In Of Minds and Molecules: New Philosophical Perspectives on
Chemistry (eds. N. Bhushan & S. Rosenfeld), pp. 34-50. Oxford: Oxford University
Press.
Ellington, A. D., Khrapov, M. and Shaw, C. A. 2000: The scene of a frozen accident. RNAA Publication of the RNA Society 6 (4), 485-498.
Godfrey-Smith, P. 1999: Genes and Codes: Lessons from the Philosophy of Mind? In
Biology Meets Psychology: Constraints, Conjectures, Connections (ed. V.
Hardcastle), pp. 305-311. Cambridge, MA: MIT Press.
Godfrey-Smith, P. 2000a: Information, Arbitrariness, and Selection: Comments on
Maynard Smith. Philosophy of Science 67, 202-207.
Godfrey-Smith, P. 2000b: On the Theoretical Role of "Genetic Coding". Philosophy of
Science 67, 26-44.
Henikoff, S. 2002: Editorial - Beyond the Central Dogma. Bioinformatics 18 (2), 223-225.
Illangasekare, M. and Yarus, M. 2002: Phenylalanine-binding RNAs and genetic code
evolution. Journal of Molecular Evolution 54 (3), 298-311.
21
Jacob, F. 1974: The Logic of Living Systems - A History of Heredity. London: Allen Lane.
Transl. of Jacob 1970, La Logique du vivant; une histoire de l'hérédité. Paris:
Éditions Gallimard.
Jacob, F. and Monod, J. 1963: Genetic repression, allosteric inhibition, and cellular
differentiation. In Cytodifferentiation and Macromolecular Synthesis (eds. M.
Locke), pp. 30-64. New York: Academic Press.
Keyes, M. E. 1999: The Prion Challenge to the 'Central Dogma' of Molecular Biology,
1965-1991. Part I: Prelude to Prions. Studies in the History and Philosophy of
Biology and Biomedical Sciences 30 (1), 1-19.
Knight, R. D., Freeland, S. J. and Landweber, L. F. 1999: Selection, history and chemistry:
the three faces of the genetic code. Trends in Biochemical Science 24, 241-247.
Knight, R. D., Freeland, S. J. and Landweber, L. F. 2001: Rewiring the keyboard:
Evolvability of the genetic code. Nature Reviews Genetics 2, 49-58.
Nelson, D. L. and Cox, M. M. 2000: Lehninger Principles of Biochemistry. 3rd ed. New
York: Worth.
Maynard Smith, J. 2000a: The Concept of Information in Biology. Philosophy of Science
67, 177-194.
Maynard Smith, J. 2000b: Reply to Commentaries. Philosophy of Science 67, 214-218.
Maynard Smith, J. and Szathmáry, E. 1995: The Major Transitions in Evolution. Oxford:
Oxford University Press.
Monod, J. 1971: Chance and Necessity. London: Collins. Transl. of Monod, 1970, Le
hasard et la necessité. Paris: Édition du Seuil.
Monod, J., Changeux, J.-P. and Jacob, F. 1963: Allosteric Proteins and Cellular Control
Systems. Journal of Molecular Biology 6, 306-329.
Monod, J. and Jacob, F. 1961: General Conclusions: Teleonomic mechanisms in cellular
metabolism, growth, and differentiation. Cold Spring Harbour Symposia on
Quantitative Biology 26, 389-401.
Sarkar, S. 2000: Information in Genetics and Developmental Biology: Comments on
Maynard Smith. Philosophy of Science 67, 208-213.
Seligmann, H. and Amzallag, G. N. 2002: Chemical interactions between amino acid and
RNA: multiplicity of the levels of specificity explains origin of the genetic code.
Naturwissenschaften 89 (12): 542-551.
22
Sterelny, K. 2000: The "Genetic Program" Program: A Commentary on Maynard Smith on
Information in Biology. Philosophy of Science 67, 195-201.
Thieffry, D. and Sarkar, S. 1998: Forty years under the central dogma. Trends in
Biochemical Science 23, 312-316.
Woese, C. R. 1967: The Genetic Code: The Molecular Basis for Genetic Expression. New
York: Harper and Row.
1
Semantic or intentional genetic information is information that meets conditions not
satisfied by information in the mathematical or natural sign sense. For example, semantic
information can be stored or remain unused and it can be false (e.g., Godfrey-Smith 1999).
2
Crick hypothesised primitive tRNAs with two separate binding sites, one for a codon and
one for an amino acid (1968, p. 372).
3
In fact, Maynard Smith and Szathmáry (1995) think that the concept of arbitrariness
arising from Crick’s frozen accident hypothesis is arbitrariness in this sense rather than in
the sense of early fixation by chance events: “The hypothesis asserts only that there is no
chemical reason why particular codons specify particular amino acids” (p. 93).
4
As noted before, Monod also associated the arbitrariness of the code with the frozen
accident hypothesis (1971: p. 135). He did not explore how arbitrariness in this sense
relates to arbitrariness in the chemical sense. One aspect of the frozen accident hypothesis
is that the codon-amino acid assignments are not due to direct stereochemical affinities
between codons and amino acids (Crick 1968). This might have attracted Monod to the
frozen accident hypothesis.
5
It is known today that an enzyme’s substrate binding site need not be complementary to
the substrate itself but rather to the transition state of the reaction catalysed by the enzyme
(e.g., Nelson and Cox 2000: pp. 252, 270). Nevertheless, complementarity is required for
the formation of enzyme-substrate complexes.
6
Monod and Jacob were careful enough to anticipate exceptions to the ‘principle of steric
analogy’ (Monod and Jacob 1961: p. 390; Jacob and Monod 1963: p. 32). Indeed, these
exceptions have been found, and it seems that the ‘principle of steric analogy’ is not
acknowledged anymore today for this reason (e.g., Nelson and Cox 2000: p. 266).
However, this is an empirical issue concerning competitive inhibition. My analysis that
23
Monod’s notion of chemical necessity appeals to chemical principles is not invalidated by
the finding that a particular principle, which has been hypothesised before, does not exist.
7
In DNA, cytosine occasionally gets transformed into uracil by spontaneous hydrolytic
deamination. After several cycles of replication, this leads to the replacement of the
original cytosine-guanine pair by a mutated thymine-adenine pair in some of the DNA
daughter strands. In order to avoid such consequences, a repair enzyme (uracil-DNAglycosidase) cuts out uracil bases in DNA. If DNA would contain uracil as a regular base
instead of thymine, then the repair enzyme could not discriminate between ordinary uracils
and uracil-turned deaminated cytosines.
8
The numerous objections to the central dogma (reviewed in Thieffry and Sarkar 1998)
might be taken to undermine the claim that replication, transcription, and translation are
typically regarded as processes of information transfer. If they are not informational
processes, then, obviously, chemical arbitrariness does not contribute to having
information. The interesting case is how arbitrariness relates to processes which are
regarded as informational. It is for the sake of argument, therefore, that I assume that they
are informational. Moreover, the objections raised against the central dogma do not
undermine the informational nature of the proposed transfers. Rather to the contrary, I
argue that they are targeted against the dogma’s limitations and support information
transferring processes in addition to those accepted by the dogma. For example, reverse
transcription refuted Watson’s version of the central dogma because it was seen as
demonstrating an information transferring process (from RNA to DNA) that Watson had
claimed would not occur (Keyes 1999: p. 7). Similarly, prions challenged both Crick’s and
Watson’s versions of the central dogma because prion replication involved, according to
some hypothesis, information flow from proteins to nucleic acids or among proteins
(Keyes 1999). Other challenges to the central dogma are RNA splicing and RNA-editing
which limit sequence predictability (Thieffry and Sarkar 1998). However, these processes
are secondary modifications to primary RNA transcripts and, therefore, they seem
compatible with an information transfer from the DNA template to primary transcripts.
Henikoff’s (2002) comments exemplify a criticism based on a dissatisfaction with the
central dogma‘s rather limited claims about information transfers.
24