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INTELLECTUAL TRADITIONS IN THE LIFE SCIENCES. II. STEREOCOMPLEMENTARITY SCOTTF. GILBERT* andJASON P. GREENBERGt Each generation ofbiological and medical researchers is subtly guided by intellectual traditions ofwhich it is largely unaware. In the first paper of this series [1], it was shown that the divergence of biochemistry and molecular biology during the middle of this century was due to rival traditions concerning the physical nature of life. In this study, we will discuss the research at the turn of the present century which formulated what has become the central theoretical assumption of contemporary biochemistry, cell biology, physiology, molecular biology, pharmacology, developmental biology, and endocrinology, namely, stereocomplementarity. It is hard to imagine any phenomenon on the cellular or molecular level which is not governed by lock-and-key stereocomplementarity. The "central dogma" of DNA replication, RNA transcription, and the translation of polypeptides is a tour-de-force of the lock-and-key principle, with certain elements (such as tRNAs and aminoacyl transferases) having multiple regions of complementarity. The proteins involved in and produced by polypeptide synthesis are also locks and keys. Stereocomplementarity has long been seen as responsible for the specificity of enzymes interacting with substrates and of antibodies interacting with antigens. Moreover, the ability of small molecules to allosterically affect the rate of enzyme catalysis and the ability of complement molecules to lyse cell membranes have been attributed to stereocomplementary binding at the nonreactive site of enzymes and antibodies, respectively. Structural proteins similarly accomplish their functions through lockand -key specificity. Hormone and drug receptors have specific binding sites for their respective compounds, cytoskeletal proteins form their fibers through the interactions of their respective amino acids, and the ?Department of Biology, Swarthmore College, Swarthmore, Pennsylvania 19081. tMedical student, Pennsylvania State University College of Medicine at Hershey, Pennsylvania 17033.© 1984 by The University of Chicago. AU rights reserved. 0031-5982/85/2801-0240$01 .00 18 I Scott F. Gilbert andJason P. Greenberg · Stereocomplementarity proteins of the extracellular matrix, such as fibronectin, often have multiple binding sites which enable them to join cells together with other matrix molecules. The ability to form lock-and-key structures with another compound has taken on a role as the "proof" of a substance's function. To Watson and Crick, the stereocomplementarity of the two DNA strands "suggested " its mode of replication. More recently, the observation that certain brain cells bind opium and its agonists is seen as showing that these neurons are involved in pain perception, and the observation that certain small nuclear RNA species have sequences complementary to those of the most common RNA splicingjunctions has been cited as evidence that these molecules function in the RNA processing mechanism. Our entire technology for determining nucleic acid complexity and for locating , isolating, and cloning genes depends on the stereocomplementarity of nucleic acid hybridization. It is apparent, then, that we, as scientists, are very much impressed by the argument for specificity based on stereocomplementarity. Stereocomplementarity has become our major way of relating molecular structure and function, and it currendy forms the basis for almost all our contemporary cellular biology and pharmacology . The concept of lock-and-key specificity is not so much studied as assumed . It is not so much a "fact" to be learned as it is a guiding principle for researchers in numerous biomedical fields. In this essay, we will attempt (a) to trace the emergence of this principle and its entry into biology and medicine, and (b) to place the original opposition to this concept into a larger controversy which characterized early twentiethcentury biology. I Although the lock-and-key model of enzyme catalysis is conventionally ascribed to Emil Fischer, one may readily trace the germ ofthe idea to Louis Pasteur's work under Auguste Laurent. It was the beginning of the era in which chemicals were thought to be structures made of atoms. Pasteur started his work with Laurent in 1846 after the latter had confirmed the "theory ofsubstitutions," which, according to Pasteur, saw chemicals as "molecular edifices, in which one element could be replaced by another without disturbing the structure ofthe edifice; as ifone were to replace, one by one, every stone of a monument by a new stone" (quoted in [2...


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