Alloxan Diabetes a Discovery, Albeit a Minor One
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HISTORY ALLOXAN DIABETES A DISCOVERY, ALBEIT A MINOR ONE N.G.B. McLetchie, Retired Pathologist, Gilford, New Hampshire, US The remarkable discovery that a single injection of alloxan diabetogenic. Moreover, in vitro, tested against cultures can produce diabetes mellitus in laboratory animals was of the pancreas, alloxan and the products mentioned made in 1942, in Glasgow, by John Shaw Dunn and above produce necrosis of beta cells, while the alpha Norman McLetchie. Alloxan, a simple nitrogenous and delta cells and pancreatic exocrine cells are organic compound, had made a long journey to get to unaffected. This provides a striking demonstration of the Glasgow – it belongs to the very origins of systematic high selectivity of the cytotoxic action of alloxan and its organic chemistry – from Germany. It was discovered derivatives. by the fathers of this science, Frederick Wöhler and Justin J. Liebig, beginning with the synthesis of urea in 1828, Early work investigated further the synthesis and testing then of uric acid and the naming of some 13 derivatives of N-alkyl substitutes of alloxan, such as methylalloxan, of uric acid, including alloxan. The name ‘alloxan,’ given and this has continued into a series of N-alkyl substitutes by Wöhler and Liebig, is recorded as being derived from of alloxan such as ethyl-, propyl- and butylalloxan. Some a combination of allantoin (a product of uric acid among are diabetogenic on injection, others are not; their clinical others excreted by the fetus into the allantois) and effects fall off as the chain of substitution lengthens. ‘oxalsaüre’ (oxaluric acid derived from oxalic acid and Somewhat startling is the fact that all are toxic to beta urea, found in the urine). cells in vitro whilst alpha, delta and exocrine cells are spared. Among other things, this raises issues of Alloxan was originally obtained by the action of dilute differences derived from pharmacologic delivery to the nitric acid on uric acid. Unlike its parent, uric acid, which target site.1, 2 presents as a stable crystalline compound insoluble in water, alloxan presents as brownish-red crystals with great In 1937, Jacobs reported that injections of alloxan in avidity for water and is very unstable with a half life of a rabbits produced a transitory hyperglycaemia followed few minutes in water at room temperature, and less at by a profound hypoglycaemia.1 This was quite unknown body temperature. It is also reported to be capable of to Shaw Dunn at the time of the discovery of alloxan developing explosive properties when stored as crystals. diabetes. As to how often this fatal toxicity misled The name alloxan has survived although Wöhler was investigators is a matter of conjecture. Also, given the aware that in 1880 Brugnatelli, working and publishing fatal hypoglycaemia, it has to be remembered that many in Italy, had identified the compound, naming it (in general poisons often produced fluctuation of blood sugar translation from the Greek) erythric acid after the red and frequently ended in hypoglycaemia; this was staining it caused to fingers. Liebig would go on to commonly attributed to liver damage. However, until introduce improved oxidants for the synthesis of alloxan 1942, alloxan remained strictly in the domain of chemistry. from uric acid. He also investigated the possibility of a physiological role for it. Alloxan’s extreme ability made MUIR’S PATHOLOGY its reported finding in body fluids a matter of doubt and The Institute of Pathology at the University and Western ideas of physiological action unlikely. In the period 1945– Infirmary, Glasgow, was dominated during his professional 50 important work was done on the chemistry and lifetime by Sir Robert Muir. An Edinburgh honours synthesis of alloxan and its derivatives, and their possible graduate in medicine, he trained there under Greenfield diabetogenicity by refugees from Germany working in to become pathologist to Edinburgh Royal Infirmary. After Israel and Switzerland in continuation of earlier work scarcely a year as professor at Dundee, he moved to done in Germany. Glasgow in 1899. A procession of assistants, almost all local honours medical graduates with doctoral theses in Alloxan is a strong oxidising agent. Its reduction product hand, moved to occupy chairs in pathology, some in is dialuric acid. Alloxan and dialuric acid form a bacteriology, a few in clinical subjects. And so, the very compound, alloxantin, which in water can dissociate into epitome of a scholar and a gentleman, adorned with the alloxan and dialuric acid. Claims were made, and later academic distinctions of his time – Ph.D., M.D., D.Sc., disputed, that dialuric acid and alloxantin were F.R.S., a knighthood to boot – Muir became the father- diabetogenic. In any case, since dialuric acid can be image of pathology in Britain. Sir Robert retired at age oxidised to alloxan, it could be assumed that in vivo both 72, in 1936, to be succeeded by John Shaw Dunn. It is compounds reverted to alloxan. In recent years it has said that Muir stayed on until he was 72, not uncommon been confirmed that the compounds are indeed in those times, because there was no pension scheme. 134 J R Coll Physicians Edinb 2002; 32:134–142 HISTORY Looking back, some would say that he had stayed on too was still around. He had, by history and clinical long, and that Muir’s magic had ended in 1931 with the examination, diagnosed a ball thrombus in the left atrium transfer of his assistant, Daniel Cappell, to the chair at that was proven by autopsy. Furthermore, it was Dundee. Along with academic freedom and a very liberal rumoured that T.K. Munro, the regius professor of physic attitude, Muir’s latter years had produced an extreme had repeated the trick when JSD arrived at the Western institutional aestheticism. There were never pep talks, and his clinical diagnosis was again proven by autopsy. departmental meetings or bulletin boards. Now things Even though the golden years of morbid anatomy were seemed frozen in time. Before World War I, clinical slipping away, JSD was the ultimate master of the autopsy. bacteriology, clinical chemistry and haematology had been His very expertise at gradually working up the history moved over to premises in the hospital generally referred and findings to the grand finale – a sharp slice right on to by the pathology staff as ‘the other side’ (rather than target to unfold the bisected organ on a platter for all to the clinical laboratory). Muir’s protégé, Carl Browning, inspect the causal lesion. went to Ehrlich’s laboratory, and headed up the Division of Chemotherapy. Via a chair in London during World In their long and laudatory obituary Muir and Browning War I, Browning came back to Glasgow at the end of the admit that at formal lectures JSD’s delivery was poor, as war as the first professor of bacteriology. Browning he seemed to talk into his collar, and they also point out commanded the entire top floor of the Institute for his that he was extremely reticent. He was also given to work on chemotherapy, and also directed the clinical very tortuous argument. I was appointed to the staff by bacteriology on the ‘other side’; he enjoyed the standing JSD at the outbreak of war in 1939, and was for some as one of the country’s leading scientists. years the only one appointed by him; I was cultivated by him as his protégé (Figure 2). Being young, I saw things In time, senior posts were created to direct haematology in the best of light so what I write is largely in retrospect and clinical chemistry in the hospital. Somehow, the work and from a long distance away. For thinking humankind became very much separated from the mainstream of there is an eternal conflict between expediency and pathology, to the extent that, when research work in morality sharply focused by the soldier in the jungle: pathology included the above fields, it commonly ended should I abandon my sick and wounded comrade and up with the investigator acquiring the knowledge and move on, hoping to save at least myself, or should I stay equipment as best could be and carrying out the work and probably die with him? JSD tended to an extreme in the pathology department. The problem, at least in morality, much of which seemed harsh, and he was given part, rested on the fact that each ward system had its to unnecessary judgements. His reticence was received own clinical side room for urinalysis and the complete badly, serving only to isolate him in an institute where it blood counts of the time. Calls for special tests demanded had been very much established you in your small corner that the house doctor obtain the specimen and take it and I in mine. down to the clinical laboratory which, in this way, was divorced from direct contact with the wards. JOHN SHAW DUNN Addressed as Shaw Dunn (JSD) by his fellows, a Glasgow M.A. and honours medical graduate (Figure 1), he trained under Muir to finally be appointed Director of the Clinical Laboratory. Throughout World War I, JSD served as a pathologist – first in France, then, under Sir Joseph Barcroft, in experimental pathology at Porton’s division of gas warfare. Returning from military service, he successively occupied chairs of pathology at Birmingham, Manchester and the Royal Infirmary, Glasgow, which had the ‘junior’ chair of pathology. With Muir’s retiral in 1936 JSD, now 53, moved over from the Royal to the Western. He had arrived in the country at the very summit of classical pathology with credentials which eventually claimed an obituary, including bibliography and portrait, in the Journal of Pathological Bacteriology of some 16 pages, the largest by far ever in the journal; it was compiled by Muir and Browning.3 JSD was very much at home and happy when he attended autopsies which always started at 10·00 a.m.