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THE SEARCH FOR THE SPECIFIC FACTOR IN SCURVY S. R. DICKMAN* The conquest of disease often requires isolating and identifying the causative agents. In infectious diseases, the identification of the invasive organism often precedes the selection of the most effective antibiotic or other therapy. In the nutrient-deficiency diseases, however, therapy has often preceded scientific identification of the missing nutrient. The prevention and cure of scurvy by the addition of citrus fruits, sauerkraut, or other foods to the diet was known for hundreds of years before the concept of deficiency diseases or vitamins was thought of. In this brief review I will not cover the history of scurvy in any detail, nor will I describe the isolation and identification of ascorbic acid. My objective, rather, is to emphasize the creative associations which were necessary to link scurvy to ascorbic acid deficiency, to mention those which showed the connection between ascorbic acid and collagen synthesis , and finally to examine those which linked collagen synthesis to the hydroxylation of proline. As a final topic, I will review the studies on the specificity of ascorbic acid as an antiscorbutic agent and as a coenzyme for prolyl hydroxylase. As recently as 100 years ago, scurvy was a fatal disease in many parts of the world and one for which there was no cure. Through research, it is now recognized that the inhibition of a single reaction due to the lack of ascorbic acid may be responsible for most of the symptoms of the disease . A BriefHistory of Scurvy Scurvy has probably afflicted mankind since prehistoric times. The first known written description of the disease occurs in the Ebers papyrus found at Thebes and dated at about 1500 b.c. Scurvy was also known to Hippocrates (460-370 b.c.), although the disease was rare in the Mediterranean countries. ?Department of Biochemistry, University of Utah, Salt Lake City, Utah 84108.© 1981 by The University of Chicago. 0031-5982/81/2403-0222$01.00 382 I S. R. Dickman ¦ Specific Factor in Scurvy Numerous accounts indicate that scurvy was quite common among northern European populations for centuries before the age of discovery [I]. The long, cold winters of northern Europe often resulted in a shortage of fresh fruits and vegetables. When this situation occurred, scurvy was common the following spring. It is not surprising that the word "scurvy" is of Norse and Teutonic origin [2]. Apparently the Greeks did not have a word for it. The use of fresh fruits for the cure of scurvy was apparently discovered accidentally by the Dutch in the sixteenth century. According to one account, the crew of a ship that was carrying citrus fruits came down with scurvy. Those men who ate the fruit were "miraculously cured" [I]. This cure was lost and rediscovered many times in the next few centuries . Numerous anecdotes such as this one probably flourished in Renaissance Europe. The age of miracles was dying and that of rationality was arising. It was natural that explanations should take a nonmystical course. Many dietary cures for scurvy were suggested. Even so, 150 years were to elapse before the scientific method was applied to the problem of the cure and prevention of scurvy. The classical experiment of Dr. James Lind of the British Navy was published in 1753 [3]. In his article, Lind described what is probably the second controlled experiment in nutrition.1 He divided scorbutic sailors into six groups as follows: the control group continued to receive the scorbutic diet; the others, in addition, received either sea water, dilute sulfuric acid, cider, vinegar, or citrus fruits. The group receiving citrus recovered quickly, those receiving cider, slowly, and the others remained scorbutic. The significance of the Lind experiment does not lie in the originality of the therapies. They had all been suggested as curative at one time or another in isolated observations. Lind's brilliance lay in his including a control group against which the others could be compared. Citrus fruits had been mentioned from time to time as a curative and as a preventative of scurvy ever since the Dutch report almost 200 years previously. But there was no basis for believing this particular anecdotal "cure" over...


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