John Jacob Abel and the Crystallization of Insulin

fOHN JACOB ABEL AND THE CRYSTALLIZATION OF INSULIN JANE H. MURNAGHAN and PAUL TALALAY* The isolation ofcrystalline insulin in 1926 and the demonstration ofits protein nature were events ofprofound and far-reaching importance not only for endocrinology but also for the development ofmodern concepts ofprotein structure and the relation ofthis structure to specific biological activity. The credit for these germinal discoveries belongs very appropriately toJohnJacob Abel, professor ofpharmacology at TheJohns Hopkins School of Medicine and the founding father of pharmacology in the United States, an outstanding expert on hormones, and an ardent proponent of chemistry in the service of medicine. The experiments Abel initiated on insulin led in time to the inescapable conclusion that insulin is a complicated protein, composed entirely ofamino acids and devoid of any extraneous active group. This concept could not be reconciled with the contemporary theories on proteins, which were regarded as hopelessly complex arrangements of amino acids, lacking the type of structural uniformity and precision that might be anticipated of molecules with highly specific physiological or pharmacological properties. Proof that the very selective and potent biological activity of insulin resided in a pureprotein called for a complete revision ofviews about the fundamental characteristics and architecture of proteins. It is not surprising that the scientific community was extremely reluctant to accept Abel's evidence and clung to the belief that his insulin crystals must in reality consist of the true hormone, of unknown chemical nature, adsorbed upon a protein carrier. The early discussions ofthe chemistry of insulin thus bear a complete parallel to the classic controversy that arose at exactly the same * Department of Pharmacology and Experimental Therapeutics, TheJohns Hopkins University School of Medicine, Baltimore, Maryland. Publication costs in part were kindly contributed to Perspectives by the Squibb Institute for Medical Research. 334 Jarte H. Murnaghan and Paul Talalay · JohnJacob Abel Perspectives in Biology and Medicine · Spring 1967 time over the chemical identity ofenzymes, following the crystallization of urease by Sumner in 1926 and the claim that it was a pure globulin. Although the obvious connection between these scientific developments was seldom mentioned by Abel or his contemporaries, there is a remarkable similarity between Abel's struggle for recognition of his crystalline protein as insulin itself, and not merely a case of adsorption, and the acrimonious battle by Sumner, Northrop, and other American scientists to establish the protein nature of purified enzymes in opposition to Willstätter and the German school. The chemical secrets ofthe very beautiful crystals ofinsulin were what fascinated Abel, rather than the intricate role they appeared to play in controlling metabolic processes, and his confident prediction that the isolation ofpure insulin would open the door to exciting new discoveries about the chemistry ofthe molecule, ifnot its mode ofaction, has been amply fulfilled by subsequent investigators. It will be recalled that using insulin, Sanger in 1955 reported for the first time the complete amino acid sequence of a specific protein [1], and received the Nobel Prize for this remarkable achievement. Studies by Sanger and his colleagues on the minor variations in structure between insulin in different species, including man, have contributed to our understanding ofthe underlying principles relating biological activity to molecular structure and have given evidence for the genetic control ofprotein structure in animal systems. Experiments with insulin haveplayed a major role in the analysis ofthe molecular structure ofproteins and the importance ofsulfhydryl and disulfide groups in maintaining this structure. These are but a few ofthe instances in which the solution ofbasic problems in biochemistry has depended in large measure upon the availabUity ofpure insulin. The ultimate step that Abelpredicted, the synthesis ofinsulin, has been realized recently, and this first synthesis ofa large protein opens new vistas that even Abel with his imaginative optimism could not have foreseen in 1926 [2]. For a number ofreasons, Abel's part in this sequence ofdiscoveries has not been accorded the attention it merits. Banting and Best deservedly received universal acclaim for the introduction ofinsulin preparations into therapy in 1922, and many unfamiliar with the details assumed that they were also responsible for its isolation as a chemical entity. The dramatic clinical benefits ofthis newly discovered hormone were immediately apparent to all, while its importance to...