The discovery of vitamin D: the contribution of Adolf Windaus.

The Nobel prize for chemistry for 1928 was awarded to Adolf Windaus “for his studies on the constitution of the sterols and their connection with vitamins” (1), the first person to receive an award mentioning vitamins. What was the contribution Windaus made to our knowledge of vitamins that deserved the highest scientific accolade? The vitamin in question was vitamin D. It had a long history before Windaus appeared on the scene. Rickets, the bone disease caused by vitamin D deficiency, was known in antiquity and was described in detail by F. Glisson in 1650 (2). Many causes and cures for rickets had been proposed. Although cod-liver oil had been used medicinally for a long time, D. Scheutte (2) in 1824 was the first to prescribe it for the treatment of rickets. It was not until 1906 that Hopkins (3) postulated the existence of essential dietary factors necessary for the prevention of diseases such as scurvy or rickets. The first scientific approach to the disease was made by McCollum and his co-workers. In their early research (4) in 1914, they isolated a fat-soluble, nonsaponifiable factor from butterfat, necessary for normal growth and prevention of the eye disease xerophthalmia in young rats. They named this factor “fat-soluble factor A,” later “vitamin A.” The notion of a fat-soluble essential dietary factor for health led Mellanby (5) in 1919 to experiment with puppies in which he succeeded in producing a bone disease by feeding them a diet of low-fat milk and bread. He diagnosed rickets by X-ray examination, bone-calcium assay, and histology of bone, and noted that the gross appearance of the dogs was quite similar to that of rachitic children. Even adding yeast to the dogs’ diet (to provide the water-soluble B-vitamins) and orange juice (to prevent scurvy), did not prevent the appearance of rickets within 3–4 mo. Rickets was prevented by the addition of butterfat to their diet or, most effectively, of cod-liver oil. He wrote: “Rickets is a deficiency disease which develops in consequence of the absence of some accessory food factor or factors. It therefore seems probable that the cause of rickets is a diminished intake of an anti-rachitic factor, which is either [McCollum’s] fat-soluble factor A, or has a similar distribution to it” (5). A landmark investigation was that of Hariette Chick and her co-workers (6) who, in 1922, working with malnourished children in a clinic in post-World War I Vienna, showed that rickets prevalent in the children could be cured by whole milk or cod-liver oil. In 1920 Hopkins (7) found that the fat-soluble factor A in butterfat could be destroyed by heating and aeration. Butterfat so treated no longer had growth-promoting activity; the rats fed the treated butterfat developed xerophthalmia and died within 40–50 d. The key experiment was performed by McCollum and his co-workers (8) in 1922, when they observed that heated, oxidized cod-liver oil could not prevent xerophthalmia but could cure rickets in the rats. “This shows that oxidation destroys fat-soluble A without destroying another substance which plays an important role in bone growth” (8). They concluded that fat-soluble factor A consisted of 2 entities, one later called “vitamin A,” the other being the newly discovered antirickets factor. Because the water-soluble factors then discovered were termed vitamin B and the known antiscurvy factor was called vitamin C, they named the new factor vitamin D. In the meantime, an entirely different cure for rickets appeared, in the role of UV light. A long-standing tradition held that fresh air and sunshine were good for the prevention of rickets. Hess and Unger (9), in 1921, put forward the explanation of their clinical observations that “seasonal incidence of rickets is due to seasonal variations of sunlight.” In her work with children, Chick and her team (6), mentioned above, observed that sunlight would cure rickets just as well as cod-liver oil. The field received a new impetus when Huldschinsky (10) in 1919 argued that, if sunlight at the seaside or in the mountains can prevent or cure rickets, then artificial sunlight, simulating light at mountain heights (“Höhensonne”) should do the same. He exposed severely rachitic children to irradiation with a quartz-mercury lamp (emitting UV light) every other day for 2 to 20 min for 2 mo and observed great improvement, including fresh calcium deposition, as revealed by X-rays. He was careful to make sure that the children had not been exposed to sunlight or received any supplements to their diet during those months. The thinking at that point was that rickets can be prevented or cured by a component of butterfat or cod-liver oil that was distinct from the fat-soluble factor A (vitamin A). It can also be cured by an entirely different process, by sunlight or UV light irradiation simulating sunlight, perhaps as the result of generally improved health. This dichotomy was jolted by the most surprising observations, made simultaneously in 1924 in 3 different laboratories. Hume and Smith (11,12) found that rats suffering from rickets induced by a low-phosphate diet (13) benefited from irradiation by UV light, not only by irradiation of the rats themselves, but also by irradiation of the “air” in the glass jars from which they had been removed and then put back after irradiation. It turned out that it was the irradiated sawdust, feces, 1 To whom correspondence should be addressed. E-mail: [email protected].