Sunday, September 8, 2013

Signature in the Cell?

There is much abuzz in the ID-o-sphere regarding Stephen Meyer’s new book, “Signature in the Cell: DNA and the Evidence for Intelligent Design”.  The book is a lengthy recapitulation of the main themes that ID proponents have been talking about for the past 15 years or so; indeed, there will be precious little that is new for seasoned veterans of the internet discussions and staged debates that have occurred over the years.

Long though the book is, it is built around one central theme – the idea that the genetic code harbors evidence for design.  Indeed, the genetic code – the triplet-amino acid correspondence that is seen in life – is the “Signature in the Cell”.  Meyer contends that the genetic code cannot have originated without the intervention of intelligence, that physics and chemistry cannot on their own accords account for the origin of the code.

It is this context that a recent paper by Yarus et al. (Yarus M, Widmann JJ, Knight R, 2009, RNA–Amino Acid Binding: A Stereochemical Era for the Genetic Code, J Mol Evol  69:406–429) merits discussion.  This paper sums up several avenues of investigation into the mode of RNA-amino acid interaction, and places the body of work into an interesting light with respect to the origin of the genetic code.  The bottom line, in terms that relate to Meyer’s book, is that chemistry and physics (to use Meyer’s phraseology) can account for the origin of the genetic code.  In other words, the very heart of Meyer’s thesis (and his book) is wrong.

One interesting highlight from this review is the discernment of a set of rules (of sort) for RNA-amino acid interactions.  These rules follow from the structures of several RNA-amino acid complexes, specifically the structures of riboswitches* that bind methionine derivatives, lysine, and arginine.  Based on these structures, Yarus et al. propose that RNA recognizes primarily polar groups (including aromatic rings, that can “bond” with positively-charged groups via cation-pi interactions) in amino acids.  As stated in the paper:
Summary of a Polar Profile, Based on Met–, Lys–, and Arg–RNA Complexes
1. RNA fixes polar features of its ligands, often restraining them at the intersection of multiple directional bonds. Such restraint likely includes aromatic and heteroaromatic rings.
2. RNA can measure the distance between such polar features, possibly allowing substantial freedom in apolar bridging constituents by stacking them loosely.
3. RNA can also sterically limit the size, disposition, and/ or shape of apolar groups close to the specifically bound polar elements cited in item 1.
Of course, other specificities may be added as more RNA-ligand structures are studied. This is particularly true because this analysis is based on only a few amino acid side chains and a few high-resolution co-structures.

The authors then summarize many years of work involving the identification and characterization of RNAs that bind amino acids.  These RNAs have been identified using in vitro selection, usually starting with collections of RNA of random sequence.  Eight such amino acids have been studied to some extent in this regard.  What has been found is that, for six of the eight amino acids (arginine, histidine, phenylalanine, phenylalanine, tryptophan, and tyrosine), RNAs that bind with high affinity are very likely to possess either the cognate codon or anticodon triplet that is associated with the respective amino acid in the genetic code.  For two amino acids (glutamine and leucine), this is not the case.  Put more plainly, 75% of tested amino acids associate with their anticodon (in some cases, along with their codon) in these studies.  This is remarkable, as it is demonstrative of an underlying stereochemical basis for at least some of the genetic code.  As summarized in the abstract:

By combining crystallographic and NMR structural data for RNA-bound amino acids within riboswitches, aptamers, and RNPs, chemical principles governing specific RNA interaction with amino acids can be deduced. Such principles, which we summarize in a ‘‘polar profile’’, are useful in explaining newly selected specific RNA binding sites for free amino acids bearing varied side chains charged, neutral polar, aliphatic, and aromatic. Such amino acid sites can be queried for parallels to the genetic code. Using recent sequences for 337 independent binding sites directed to 8 amino acids and containing 18,551 nucleotides in all, we show a highly robust connection between amino acids and cognate coding triplets within their RNA binding sites. The apparent probability (P) that cognate triplets around these sites are unrelated to binding sites is [approximately] 5.3 x 10-45 for codons overall, and P [is approximately] 2.1 x 10-46 for cognate anticodons. Therefore, some triplets are unequivocally localized near their present amino acids. Accordingly, there was likely a stereochemical era during evolution of the genetic code, relying on chemical interactions between amino acids and the tertiary structures of RNA binding sites. Use of cognate coding triplets in RNA binding sites is nevertheless sparse, with only 21% of possible triplets appearing. Reasoning from such broad recurrent trends in our results, a majority (approximately 75%) of modern amino acids entered the code in this stereochemical era; nevertheless, a minority (approximately 21%) of modern codons and anticodons were assigned via RNA binding sites.

There is more in the review that is provocative.  Yarus et al. explain that, while 75% of tested amino acids have an affinity of sorts for cognate anticodons/codons, only 21% of the possible anticodon/codon triplets that we can get from the genetic code are identified in these studies.  Thus, we can discern that the genetic code as we understand it today likely evolved in several steps – a stereochemical era wherein a core set of triplet-amino acid correspondences was first established, followed by subsequent expansion of the assignments of other triplets and recruitment of other amino acids (typified by gutamine and leucine) via other mechanisms.
So what does this have to do with Meyer’s book?  The argument is best illustrated using Meyer’s own words.  Early in the book, Meyer lays out his challenge:
(pp 134-5)

“The picture of the cell provided by modern molecular biology has led scientists to redefine the question of the origin of life.  The discovery of life’s information-processing systems, with their elaborate functional integration of proteins and nucleic acids, has made it clear that scientists investigating the origin of life must now explain the origin of at least three key features of life.  First, they must explain the origin of the system for storing and encoding digital information in the cell, DNA’s capacity to store digitally encoded information. Second, they must explain the origin of the large amount of specified complexity or functionally specified information in DNA,  Third, they must explain the origin of the integrated complexity – the functional interdependence of parts – of the cell’s information-processing system.”

Later, in Ch. 11, Meyer argues that the genetic code transcends or is apart from physics and chemistry.  Early in this chapter, Meyer invokes Polyani to argue that “reductionism”, that is, chemistry and physics, cannot account for the origins of the genetic code:
(pp 238-40)

“Consider an illustration.  A 1960s vintage computer has many parts, including transistors, resistors, and capacitors.  The electricity flowing through these various parts conforms to the laws of electromagnetism, for example, Ohm’s law (E=IR, or volateg equals the current time resistance).  Nevertheless, the specific nature of the computer, the configuration of its parts, does not result from Ohm’s or any other law.  Ohm’s law (and, indeed, the laws of physics generally) allows a vast ensemble of possible configurations of the same parts.  Given the fundamental physical laws and the same parts, an engineer could build many other machines and structures: different model computers, radios, or quirky pieces of experimental art made from electrical components.  The physical and chemical laws that govern the flow of current in electrical machines do not determine how the parts of the machine are arranged and assembled.  The flow of electricity obeys the laws of physics, but wherethe electricity flows in any particular machine depends upon the arrangement of its parts – which, in turn, depends on the design of an electrical engineer working according to engineering principles.  And these engineering principles, Polyani insisted, are distinct from the laws of physics and chemistry that they harness.”

And later:
“Polyani argued that, in the case of communications systems, the laws of physics and chemistry do not determine the arrangements of the characters that convey information.  The laws of acoustics and the properties of air do not determine which sounds are conveyed by speakers of natural languages.  Neither do the chemical properties of ink determine the arrangements of letters on a printed page.  Instead, the laws of physics and chemistry allow a vast array of possible sequences of sounds characters, or symbols in any code or language.  Which sequence of characters is used to convey a message is not determined by physical law, but by the choice of users of the communications systems in accord with the established conventions of vocabulary and grammar – just as engineers determine the arrangement of the parts of machines in accord with the principles of engineering.
Thus, Polyani concluded, communications systems defy reduction to physics and chemistry for much the same reasons that machines do.  Then he took a step that made his work directly relevant to the DNA enigma: he insisted that living things defy reduction to the laws of physics and chemistry because they contain a system of communications – in particular, the DNA molecule and the whole gene-expression system.  Polyani argued that, as with other systems of communication, the lower-level laws of physics and chemistry cannot explain the higher-level properties of DNA.  DNA base sequencing cannot be explained by lower-level chemical laws or properties any more than the information in a newspaper headline can be explained by the chemical properties of ink.16  Nor can the conventions of the genetic code that determine the assignments between nucleotide triplets and amino acids during translation be explained in this manner.  Instead, the genetic code functions as a higher-level constraint distinct from the laws of physics and chemistry, much like a grammatical convention in a human language.”

In other words, Meyer is claiming that the genetic code is arbitrary, that there are no chemical or physical underpinnings to the codon-amino acid correspondence that we see in life.  It is because the code is arbitrary, Meyer implies that it must be designed:

“Polyani’s argument made sense to me.  DNA, like other communication systems, conveys information because of very precise configurations of matter.  Were there laws of chemistry or physics that determine these exact arrangements? Were there chemical forces dictating that only biologically functional base sequences and no others could exist between the strands of the double helix? After reading Polyani’s essays, I doubted this.
I realized that his argument also had profound implications of self-organizational theories of the origin of life.  To say that the information in DNA does not reduce to or derive from physical and chemical forces implied that the information in DNA did not originate from such forces. “

Note that all of this, which, I must emphasize, lies at the very heart of Meyer’s book, is grounded in the idea that the genetic code has no underlying chemical basis.  The experimental work that is summarized by Yarus et al. contradicts Meyer’s assertion, in that it suggests a clear stereochemical basis for at least part of the genetic code.  In other words, the information in DNA may indeed reduce to chemistry and physics.

In closing, I would point out a few things that are likely to arise when discussing things in the context of the ID controversy.  First, it is true that Yarus’ ideas, and the underlying experiments, are far from a direct and complete demonstration of the origination of the complete RNA decoding system that we see in modern cells.  However, the body of work discussed by Yarus et al. constitutes a significant and compelling set of positive experimental support for the hypothesis that the genetic code has an underlying chemical basis.  As such, it far outstrips the entire body of positive experimental support (there is none) for Meyer’s claim that there can be no way to explain the genetic code (the Signature in the Cell) in terms of chemistry and physics.  On a strictly evidential basis, Meyer’s thesis is found wanting.

Second, Yarus’ ideas are quite apart from the larger issue of the origin of life.  It is natural to insert the model into an RNA World context; indeed, the RNA World model is the inspiration for these studies, and these studies provide significant support for this model.  However, the probability of a stereochemical basis for the genetic code applies just as well to design models of the OOL.  In other words, we can consider Meyer’s assertion, that there is no chemical basis for the genetic code, in a design light.  Thus, Meyer’s claim would be that intelligence (a designer, or whatever) assigned triplets to amino acids in an arbitrary fashion.  The opposing design hypothesis would be that the genetic code has an underlying chemical foundation, and that design was implemented at some point before or after the origination of the genetic code.  The work summarized by Yarus et al. argues against Meyer’s claim, but is agnostic as to other possible design scenarios.  In other words, when viewed solely in terms of ID theory, Meyer’s assertion, the heart of his book, would seem to be wrong, and certainly less well-supported than other possible ID models.

The interesting first few paragraphs:

I am particularly struck by the difficulty of getting [the genetic code] started unless there is some basis in the specificity of interaction between nucleic acids and amino acids or polypeptide to build upon. (Woese 1967)
Nonetheless, it is clear that at some early stage in the evolution of life the direct association of amino acids with polynucleotides, which was later to evolve into the genetic code, must have begun. (Orgel 1968) 
Part I: The Observed Mechanism of RNA–Amino Acid Interaction 
Just above, Carl Woese and Leslie Orgel, writing at the dawn of molecular biology and coding, suppose that chemical interactions between nucleotide sequences and amino acids are an indispensable basis for the genetic code. It is the conclusion of the present narrative that such interactions are easily demonstrated, utilize plausible, simple chemistry, and can indeed be shown to echo part of the genetic code.

*Riboswitches are sites in mRNAs that bind ligands such as amino acids and thereby change conformations; these structural changes affect stability and/or translatability of the mRNAs and thus regulate gene expression.


  1. Hunt misses out on a much less theoretical objection Meyer had to the genetic code: that ribosomes, shorn of their sophisitcated proteins, are unable to produce polypeptides of appreciable length; branchings soon become inevitable.

    There are two weaknesses in Meyer's argument. One is that the rRNA component of the ribosome might have degenerated as a result of the addition of these dozens of accompanying proteins. The other is that Meyer nowhere takes advantage of the Achilles' heel of abiogenesis (of life as we know it): the protein takeover.

    There have been interesting and plausible speculative scenarios for the evolution of the genetic code that take us to the protein takeover. The best I have seen so far is a rather old one:

    AM Poole, DC Jeffares, D Penney, The path from the RNA world. J.
    Molecular Evolution 46: 1-17, 1998.

    But it stops at the threshold of the heart of the protein takeover, the replacement of almost all ribozymes by protein enzymes. I have never seen any attempt at a scenario for this, not even a highly speculative one.

    The most crucial for the genetic code (READ: the whole protein translation mechanism) is the advent of the highly diverse aa-tRNA synthetases. Their astonishing fidelity is presumably better than that of the hypothetical ribozymes they replaced, but we are in a catch-22 situation: as their conjectural precursors began aa-tRNA binding, they would perforce have had LESS fidelity than the ribozymes their "Darwinian" descendants ultimately replaced. And as such, they would be detrimental to the "fitness" of the cells in which they arose.

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  3. Rather than "it stops at the threshold," it would have been more accurate to say that Poole et. al. jumped over the protein takeover and went on to talk about such things as the following:

    "Our model for the genome of the last ribo-organism
    (Jeffares et al. 1997) is consistent with the hypothesis we
    propose here—that the last universal common ancestor
    had a genome that was more eukaryote-like than pro-

    The url I gave for their joint paper is no longer valid, but the following url provides a link to a pdf file of the paper.