WINDAUS, ADOLF OTTO REINHOLD

(b. Berlin, Germany, 25 December 1876; d. Gottingen, Germany, 9 June 1959)

chemistsry.

Windaus came from a family that had a strong technological background. The ancestors of his father, Adolf, had been weavers and clothing manufacturers for two hundred years. The family of his mother, Margarete Elster, consisted mostly of artisans and craftsmen. A few of his ancestors had held academic positions, but none had been physicians or scientists.

The boy received his elementary education at the French Gymnasium in Berlin, where almost no science was taught and the emphasis was on literature. In his final year, however, Windaus learned of the bacteriological work done by Koch and Pasteur, and was much impressed with the benefits of their studies for humanity. He therefore decided upon a career in medicine, thereby disappointing his widowed mother, who had hoped that he would enter the family business.

Windaus entered the University of Berlin in 1895 and almost at once began to attend Emil Fischer’s lectures on chemistry. He was particularly struck by the physiological applications of Fischer’s work and began to develop what later became the basis for his approach to chemistry, an interest in the general physiological mechanisms of the compounds he studied. Windaus was awarded the bachelor’s degree in 1897 and then decided to attend the University of Freiburg im Breisgau, where Heinrich Kiliani taught chemistry. For a time Windaus continued his medical studies, but he began to neglect medicine more and more, and finally gave it up entirely. At Kiliani’s suggestion he started to study the chemistry of the glycosides of digitalis, and in 1899 he received the Ph.D. with a dissertation on those substances. The next year was spent in military service at Berlin, but during the summer semester Windaus was able to assist Fischer in a study of the formation of quaternary ammonium compounds from aniline. At the end of 1901 he returned to Freiburg to devote himself entirely to chemistry.

Kiliani suggested that Windaus begin a study of cholesterol, a compound about which almost nothing was known. Windaus felt that a substance so widely distributed in animal cells, and in related forms in plants, must have close connections with other physiologically important compounds. He thus entered on studies that occupied much of the rest of his life. In 1903 he presented his inaugural dissertation, “Cholesterin,” and became a Priratdozent at Freiburg, with promotion to a professorship three years later.

In 1913 Windaus accepted the chair of medical chemistry at Innsbruck, where he remained for two years. In 1915 he was called to the University of Göttingen as successor to Otto Wallach. Until his retirement he was professor of chemistry and director of the chemical laboratory at Gättingen. Windaus continued active research even during the period of National Socialism. Although he was not in sympathy with the Hitler regime, he was allowed to continue his work because of the reputation he had established. He ceased active investigation in 1938, and after his retirement in 1944 he published no further papers.

The course of Windaus’ scientific activity was determined by his early studies on digitalis and cholesterol. His work always had some relation to natural products; and although he was mainly concerned with the structure of cholesterol, he investigated many other sterols and established the membership of these substances in a group that he called the “sterines,” In 1908 Windaus found that cholesterol formed an insoluble compound with digitonin. This explained the action of cholesterol in preventing the hemolytic activity shown by the saponins, of which digitonin was one. Thereafter he included studies of the structure of the saponins in his research program.

During this period Windaus’ friend Heinrich Wieland, at Munich, was studying the structure of the bile acids; and among the derivatives of these substances he had prepared a compound that he called cholanic acid. In 1919 Windaus prepared the same acid from cholesterol, thus demonstrating the close chemical relationship between the sterines and the bile acids. The results obtained by the workers at Göttingen and Munich could now be combined. Active study at the two institutions finally led to the determination of the correct structure for the sterol ring in 1932.

Even before the structure of cholesterol was completely established, there had been indications that the substance was involved in some way in vitamin activity. By the early 1920’s it was known that rickets could be cured by administration of certain fish liver oils. The study of vitamins was widespread at the time, and it was assumed that the liver oils contained a specific substance, called vitamin D, that was responsible for the cure. It also had been found however, that exposure of the patient to ultraviolet light could bring about a cure. The studies of A. F. Hess had established this fact firmly. A dilemma thus arose: Was a chemical or a physical process responsible for the favorable effect? Most physiologists assumed that two different processes were involved. It was believed that the vitamin cured rickets specifically, just as vitamin C cured scurvy, but that exposure to ultraviolet light raised the general level of resistance to the disease.

In 1924 Harry Steenbock and Alfred Hess independently showed that exposure of certain foods to ultraviolet light made them active in curing rickets. This indicated that some compound was photochemically converted into vitamin D, and thus the concept of a provitamin was developed Hess found that the provitamin occurred in the sterine fraction of the irradiated foods, and in 1925 he sought Windaus as a collaborator in determining the chemical nature of the vitamin and its precursor. Windaus was eager to accept the invitation because of his approach to the general chemistry of natural products. Although many chemists believed that he was concerned only with cholesterol, he said that he was not interested in the chemical composition of any particular substance, but only in the major relationships between natural products. The collaboration between Hess (in New York City) and Windaus resulted in the development at Göttingen of an active center for vitamin research. Rosenheim (in London) soon joined the project, and the results of studies in the three cities confirmed each other.

It was at first thought that cholesterol was the provitamin, since irradiation of a supposedly pure sample produced an active product. When a more highly purified sample failed to yield the same result, it was recognized that this idea was incorrect. Robert Pohl, working at Göttingen, showed by a study of absorption spectra that a very small amount of an impurity was present in the original cholesterol sample; and in 1927 Hess and Windaus identified the impurity as the fungus sterol ergosterol. Windaus soon demonstrated that the conversion of ergosterol to the vitamin involved an isomerization. Attempts to isolate the pure vitamin apparently were successful when a crystalline compound had been so well established that the name vitamin D ₁ was applied to it; and when a pure vitamin finally was isolated from irradiated ergosterol, it was called vitamin D ₂, or calciferol.

It was assumed that ergosterol was the only provitamin, but Windaus continued to seek other sterols that could serve as precursors of vitamin D. In 1932 he and his co-workers prepared 7-dehy-drocholesterol and showed that it also was a provitamin. The name vitamin D ₂ was retained for the substance obtained from ergosterol, and the new vitamin was named D ₃. It proved to be even more important than vitamin D ₂, since it was obtained by activation of a sterol synthesized by the animal body. Hand Brockmann, working in Windaus’ laboratory, confirmed this fact when he isolated pure vitamin D ₃ from tuna liver oil.

Knowledge of the structure of the various D vitamins soon followed. During the rest of his working life, Windaus was occupied with a study of the structural features necessary for a sterol to qualify as a provitamin, and with determining the course of the photochemical reactions by which activation of the provitamins occurs. He identified and characterized the other compounds formed in these reactions: lumisterol, tachysterol, and the suprasterols.

By 1927 the work on the structure and chemistry of the sterols and of vitamin D, although by no means complete, had proceeded so far that the importance of the results was clear. The brilliance of the contributions made by Wieland and Windaus was equally obvious. In 1927 Wieland was awarded the Nobel Prize in chemistry for his work on the bile acids, and in 1928 the same prize was given to Windaus for his studies on the constitution of the sterols and their connection with other substances occurring in nature.

As soon as the sterol ring structure was determined (1932), it became possible to assign structures to many other biologically important sterols. Adolf Butenandt, an assistant to Windaus, was able almost at once to present the structures of the male and female sex hormones, even though he had only 25 mg. of the male hormone available for study. Adrenal cortical hormones, saponins, glyco sides, and even the poisonous substances found in the skin of certain toads (substances that Windaus had done much to characterize) were found to belong to the same group; and the term “sterine” was replaced by the more significant name “steroid”

Another important result of Windaus’ studies on steroid structure arose from his discovery that in saturated derivatives of cholesterol there is a type of isomerism due to the cis- or trans-fusion of two saturated rings. This opened the field of the stereochemistry of condensed ring systems, a subject developed in detail by another student of Windaus,’ Walther Hückel.

At the time of his early work on cholesterol, Windaus also had undertaken a study, in collaboration with the biochemist Franz Knoop, of the reaction of sugars with ammonia. They hoped to convert the sugars into amino acids, and thus to establish the possibility of converting carbohydrates into proteins. To Windaus’ surprise, when he treated glucose with ammoniacal zinc hydroxide. he obtained derivatives of imidazole. From a study of these compounds he discovered that the amino acid histidine was an imidazole derivative. In the course of this work he discovered the physiologically very important compound histamine, which became commercially available as a result of his work. These investigations brought Windaus into contact with the chemical industry, and he retained close connections with industrial chemists for the rest of his life. Chemical concerns supplied him with many of the substances he needed in his research and often suggested problems.

After his early work on the imidazoles, Windaus abandoned this line of research until 1929. He was induced to return to the field because two Dutch chemists, B. C. P. Jansen and W. F. Donath, had claimed that the antineuritic vitamin, B₁or thiamin, contained an imidazole ring. In their analysis, however, they had overlooked the presence of sulfur in the compound. On the basis of a correct analysis, Windaus was able to assign the proper empirical formula and to show that the compound contained not an imidazole, but a thiazole and a pyrimidine ring. He isolated the pure vitamin B₁from yeast, and his work helped greatly in the final synthesis of the vitamin by Robert R. Williams.

Windaus’ other major field of research was the determination of the structure of colchicene, a substance that proved to have strong mutagenic properties for plants.

Although Windaus had been almost alone in his early investigations on cholesterol, the field he had pioneered quickly became a major branch of organic chemistry and biochemistry. He always worked closely with his colleagues in Germany and abroad, and gave his students great freedom in their research, as well as full credit for their contributions.

Besides the Nobel Prize, Windaus received many honorary degrees and memberships in scientific societies. He was awarded the Baeyer, Pasteur, and Goethe medals. Windaus served on the editorial board of Justus Liebigs Annalen der Chetnie ; and volumes 603 and 604 of that journal were dedicated to him in 1957, to celebrate his eightieth birthday.

BIBLIOGRAPHY

Windaus’ scientific papers are listed in Poggendorff, V, 1380: VI, 2901–2902: Vl1a, 1016–1018

The most complete biography is the Windaus memorial lecture by Adolf Butenandt, in Proceedings of the Chemical Society (1961), 131–138. Further details are in Gulbrand Lunde, “The 1927 and 1928 Chemistry Prize Winners, Wieland and Windaus,” in ,Journal of Chemical Education, 7 (1930), 1767–1777. A survey of the significance of the work on steroids and its relation to the work of others is H. H. Inhoffen, “50.lahre Sterin–Chemie,” in Natmuissettschuften,38 (1951), 553–558.

Henry M. Leicester