The Genetic Code--Yesterday, Today, and Tomorrow

Translation: In retrospect and prospect

“…Purging past prejudices is a necessary step in establishing any new paradigm+ Template thinking, adaptor thinking, and A-site-P-site imagery must be put aside if we are to genuinely understand translation+ Looking back on the historical meanderings of the translation concept, it becomes evident "how little theory was able to contribute" (Crick, 1966)+ Yet, it is precisely the attempt to theorize our way to an understanding that created the (conceptual) bind translation is in today+ We would have been better off, in my opinion, had experimentalists like Zamecnik, Hoagland, Lipmann, and others been left to their own devices+ They were explorers wandering in an uncharted experimental wilderness, and so, open to all manner of possibilities and ideas+ This is precisely what was called for at that particular juncture+ A field tends to start with a simple mapping of the territory and identification of its "inhabitants+" This is best accomplished with a minimum of intellectual fetters+ The theoretical hoopla that initially surrounded translation surely aroused scientific interest, but it was needlessly prejudicing and turns out at very least to have misplaced the emphasis+ Our concept of translation today would have been quite different than it is, had we proceeded more innocently+ Not surprisingly, the templating, adaptor, and A-site-P-site notions suffer from the same basic defect: They are by nature overly static, and so influence us to use the wrong type of imagery in conceptualizing translation, and this, at best, amounts to emphasizing the wrong aspects of the problem+ Look at the templating notion+ Picture I: monomers aligned and oriented+ Picture II: monomers still in their places, but now chemically joined+ What could be more static? The adaptor hypothesis is based on templating and the A-site-P-site model on the adaptor hypothesis+ Seen through such eyes, the workings of this incredibly dynamic translation machine are lost+ Contrast imagery of this sort to that which stems from a tape reading perspective+ Tape reading is per se dynamic+ Process, not position, is primary; tape reading invites you to understand mechanism+ A true tape reading perspective would not settle for tRNA, the adaptor+ It demands to know what tRNA is doing during translation+ A tape reading perspective would not see translation solely in terms of sites+ Its focus would be on the changes that occur during the process, on states of the system and transitions among them+ This is the imagery for a dynamic concept of translation+ A second, particularly pernicious characteristic of the templating notion is that it overly reduces biology to chemistry, to static stereochemistry, and, thus, implies that the essence of a biological entity or process resides in some particular physical or chemical interaction+ This makes the evolutionary transition from a preexisting physical/chemical entity, process, and so forth, into a biological one simple and straightforwardleaving the original physical-chemical basis transparently displayed in the biological entity+ This may be true in some cases, say gene replication, but it certainly does not hold for translation and many other biological entities/processes+ Here the extensive evolution undergone obscures the entity's origin, and becomes its essence+ Let's face it+ Biologists have in effect been experimenting outside the purview of the conceptual trinity (templating, the adaptor hypothesis, and the A-site-site model) for a long time now, but they are still hidebound to the classical paradigm when it comes to putting the picture together+ Something has to give+ Isn't it time to say: "No, tRNA is not an 'adaptor'-a 'substrate' for the translation mechanism+ tRNA is probably a 'motor'-a central functioning part of the translation mechanism+" And, "No, it is not the sacrosanct 'A' and 'P' sites that are important, it is the molecular movements underlying and defining them that should be the focus of attention+" We are trying to reconstruct a mac...…”

Celebrating wobble decoding: Half a century and still much is new

“…3 At the time the Universal Genetic Code was unveiled, 4 there were several RNAs known to contain modified nucleosides, but their sequence locations and functions were a mystery before the evolution of RNA sequencing methods. By 1991, 25 years later, a sufficient number of modified nucleosides had been found to occupy the wobble position 34 of tRNA's anticodon that a Modified Wobble Hypothesis was advanced.…”

Frozen Accident Pushing 50: Stereochemistry, Expansion and Chance in the Evolution of the Genetic Code

“…Indeed, notwithstanding multiple code variants that continue to emerge through the study of protein coding in diverse life forms, the basic structure of the code and the majority of the codon assignments are truly universal [10,11]. When the codon table was settled in 1965, distinct patterns in the code begging for explanation became immediately apparent [9,12]. The 64 triplet codons are neatly organized in sets of 4 or 2, with the third base of a codon typically being synonymous.…”