Many of us take a daily supplement of vitamins and minerals, but rarely do our thoughts turn to what those compounds do, much less to how they were discovered as essential for good health. Nevertheless, the history of vitamins is an interesting mix of medical sleuthing and basic research, quite worthy of some attention. Vitamins B, C and D, for instance, were all discovered as a result of research on diseases (beriberi, scurvy and rickets, respectively) that plagued various groups of people from the 1700s through, in some cases, the early 1900s. Supplementing the imbalanced diets eaten by many people during those times with certain foods was shown to prevent each of these diseases. Subsequently, purification and analysis of the disease-preventing compounds in these foods established a new class of nutrients — in addition to proteins, fats and carbohydrates — that are now known to be essential for human health. The paper on page 131 of this issue of Nature Structural Biology furthers our understanding of one of these vitamins — vitamin D — by describing how it interacts with the protein that carries it and many of its metabolites through the bloodstream. Moreover, this work serves as a reminder that the history of this vitamin's discovery is more interesting than most, since several lines of research contributed to its detection.
Our bodies are capable of producing vitamin D — we are not entirely dependent on obtaining it from food, as is the case with other 'true' vitamins. In fact, we can produce enough vitamin D to maintain essential processes when our skin is adequately exposed to the ultraviolet rays in sunlight. The precursor 7-dehydrocholesterol, which is found in the skin, is converted to vitamin D3 through irradiation, and vitamin D3 is further metabolized in the liver and kidneys to the bioactive forms of the molecule. These metabolites are secreted from the kidneys and build up in target organs such as the intestine, where they help to regulate the absorption of calcium and phosphorous. Having too little of these vitamin D metabolites in the body results in the failure to control calcium homeostasis, causing osteoporosis, osteomalacia and rickets. Rickets is a particularly devastating disease characterized by softened bones (leading to deformity) as well as muscle spasms and seizures. The discovery of vitamin D in food and the realization that the body can produce vitamin D independently are both intimately tied to research into the cause and prevention of childhood rickets.
Rickets was first identified as a rare disorder in the 1600s. However, in the late 1700s, it became rampant in Europe as people began to stay indoors and live in large, polluted cities, with reduced exposure to sunlight. In the 1890s, scientists began to search for specific foods that could prevent rickets. Such reasoning was rooted in the knowledge that two other diseases, scurvy and beriberi, could be prevented by the addition of certain foods (such as citrus fruits, which contain vitamin C, and whole grain rice, which contains vitamin B1) to the diet.
Those pursuing this dietary hypothesis for a cure were rewarded when it was shown that cod liver oil could prevent rickets. However, other researchers had stumbled onto the fact that exposure to sunlight was also completely effective in curing and preventing the disease. Eventually, these two cures for rickets were merged in the demonstration that simply eating food that had been irradiated was sufficient (although the realization that this could be done was not straightforward as implied here). Therefore, irradiating certain foods became standard practice in the 1920s for preventing rickets in the general population. The chemical compound responsible for this success, vitamin D, was unambiguously identified in the 1930s, thanks to the work of researchers studying the chemical structures of members of the cholesterol family.
Today, companies such as Hoffmann-La Roche and BASF produce large quantities of the primary form of vitamin D, also known as vitamin D3 or cholecalciferol. In general, they purify cholesterol from animal products (such as lanolin from sheep wool) and use it as starting material for purification of the precursor 7-dehydrocholesterol, which is then converted into vitamin D3 by irradiation. This synthetic vitamin D3 is added to many foods, particularly milk products; it is also a key ingredient in the multivitamin supplements that many people take regularly. With such an interesting history, it's surprising that we hardly think about it when taking our daily dose of vitamins.
For additional summaries of the discovery of vitamin D, see the following web sites:
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A dose of vitamin D history. Nat Struct Mol Biol 9, 77 (2002). https://doi.org/10.1038/nsb0202-77