According to both academic lore and history (Paulos, 1985; Ryerson, 2004), the late Sidney Morgenbesser, a professor of philosophy at Columbia and a renowned conversationalist and wit, was once listening to an Oxford colleague, J. L. Austin, lecturing on the philosophy of language. The eminent Professor Austin proceeded to claim that while a double negative can be taken as a positive, a double positive is never interpreted as a negative. Morgenbesser responded with as concise and incisive a rebuttal as one might ever hope to unleash,”Yeah, yeah,” thereby decisively demonstrating the extent to which the meaning of words can be shaped by the linguistic environment in which they are embedded.
Last month, a report in Nature (Netzer et al.) described one mechanism that causes even the genetic code to be read in a somewhat context-dependent manner.The authors of the study showed that viral infection, Toll-like receptor (TLR) ligands, and oxidizing agents can all increase significantly the frequency with which tRNA molecules, normally acylated by amino acids other than methionine, are misacylated with methionine. The basic phenomenon was demonstrated in HeLa cells (a human cell line) as well as in primary mouse cells (e.g., bone marrow-derived dendritic cells or liver cells). Netzer and colleagues note, however, that some immunity-associated stimuli, such as interferon-β or interferon-γ, do not elicit increased rates of methionine misacylation, so there is some specificity to the induction of the response. Furthermore, the authors describe a number of experimental results that suggest both that trivial mechanisms (i.e., not real misacylation) do not account for their results and that the misacylated tRNAs do actually influence the amino acid sequences of proteins undergoing translation at the time of the increase in misacylation events.
The authors hypothesize that this increase in methionine misacylation could represent an adaptation that serves to protect cells against oxidative stress, a common accompaniment of inflammation-inducing stimuli such as infection. In support of this possibility, they cite prior work showing that methionine can protect enzymes and cells (specifically E. coli cells) from damage mediated by reactive oxygen intermediates. According to this line of thinking, the increase in misacylation is a feature of cells due to natural selection and a possible example of the sort of biochemical tinkering that Francois Jacob (1982) claimed was of the essence in biological evolution.
Alternatively, the authors consider whether the increased rate of methionine misacylation might be an unwanted consequence of oxidative stress, i.e. a “bug” or weakness in cellular functioning. They note, for instance that the replacement of charged residues by methionine might facilitate protein aggregation, generally a damaging outcome for most cells. The authors explicitly recognize that a full elucidation of this interesting phenomenon and its implications will require additional investigation.
Paulos, J. A. I Think, Therefore I Laugh: An Alternative Approach to Philosophy. Vintage Books, Random House, Inc., New York, 1985.
Ryerson, J. Sidewalk Socrates. New York Times Magazine. December 26, 2004. http://www.nytimes.com/2004/12/26/magazine/26MORGENBESSER.html?
Netzer N, Goodenbour JM, David A, Dittmar KA, Jones RB, Schneider JR, Boone D, Eves EM, Rosner MR, Gibbs JS, Embry A, Dolan B, Das S, Hickman HD, Berglund P, Bennink JR, Yewdell JW, Pan T. Innate immune and chemically triggered oxidative stress modifies translational fidelity. Nature 2009 Nov 26;462(7272):522-6.
Jacob, F. The Possible and the Actual. University of Washington Press, Seattle, 1982.