The vitamine doctrine: Although diseases resulting from
vitamin deficiencies have been known for millennia, such disorders were generally attributed to toxic or infectious causes until the "
vitamin doctrine" was developed in the early 20th century. In the late-19th century, a physiologically complete diet was believed to require only sufficient
proteins,
carbohydrates,
fats, inorganic
salts, and water. From 1880-1912, Lunin, Pekelharing, and Hopkins found that animals fed purified mixtures of known food components failed to grow or even lost weight and died, unless the diet was supplemented with small amounts of milk, suggesting that "accessory food factors" are required in trace amounts for normal growth. By this time, Funk suggested that deficiencies of trace dietary factors, which he labeled "vitamines" on the mistaken notion that they were "vital
amines," were responsible for such diseases as
beriberi,
scurvy,
rickets, and
pellagra.
Vitamin A deficiency eye disease:
Night blindness was recognized by the ancient Egyptians and Greeks, and many authorities from Galen onward advocated liver as a curative. Outbreaks of
night blindness were linked to nutritional causes in the 18th and 19th centuries by von Bergen, Schwarz, and others. Corneal ulceration was reported in 1817 by Magendie among
vitamin A-deficient dogs fed for several weeks on a diet limited to
sugar and water, although he erroneously attributed this to a deficiency of dietary
nitrogen (i.e.
protein). Subsequently, corneal epithelial defects, often in association with
night blindness, were recognized in malnourished individuals subsisting on diets now recognizable as deficient in
vitamin A by Budd, Livingstone, von Hubbenet, Bitot, Mori, Ishihari, and others. During World War I, Bloch conducted a controlled clinical trial of different diets among malnourished Danish children with
night blindness and
keratomalacia and concluded that whole milk, butter, and
cod-liver oil contain a fat-soluble substance that protects against
xerophthalmia. Early
retinal photochemistry: In the 1870s, Boll found that light causes bleaching of the
retinal pigment, and suggested that the outer segments of the rods contain a substance that conveys an impression of light to the brain by a photochemical process. Shortly thereafter, Kühne demonstrated that the bleaching process depends upon light, and was reversible if the retinal pigment epithelium was intact. Kühne proposed an "optochemical hypothesis," a prescient concept of photochemical transduction, attributing vision to a photochemical change in
visual purple (
rhodopsin) with resulting chemical products stimulating the visual cells and thereby conveying a visual image.
Vitamin A: In 1913, Ishihara proposed that a "fatty substance" in blood is necessary for synthesis of both
rhodopsin and the surface layer of the cornea, and that
night blindness and
keratomalacia develop when this substance is deficient. That year McCollum and Davis (and almost simultaneously Mendel and Osborne) discovered a fat-soluble accessory food factor (later called "fat-soluble A") distinct from the water-soluble anti-
beriberi factor (later called "fat-soluble B"). By 1922 McCollum and colleagues distinguished two
vitamins within the fat-soluble fraction, later named
vitamins A and D. In 1925 Fridericia and Holm directly linked
vitamin A to
night blindness in animal experiments using rats, and in 1929 Holm demonstrated the presence of
vitamin A in
retinal tissue. In the 1930s, Moore, Karrer, Wald, and others established the
provitamin role of
beta-carotene. Karrer and colleagues isolated
beta-carotene (the main dietary precursor of
vitamin A) and
retinol (
vitamin A), and determined their chemical structures. In 1947, Isler and colleagues completed the full chemical synthesis of
vitamin A. Modern
retinal photochemistry: Beginning in the 1930s, Wald and colleagues greatly elaborated the photochemistry of vision, with the discovery of the visual cycle of
vitamin A, demonstration that
rhodopsin is decomposed by light into
retinal (the
aldehyde form of
vitamin A) and a
protein (
opsin), elaboration of the enzymatic conversions of various elements in the
rhodopsin system, and discovery that the
rhodopsin system is dependent on a photoisomerization of
retinal. In 1942, Hecht and colleagues demonstrated that a single photon could trigger excitation in a rod. In 1965, Wald suggested that a large chemical amplification was necessary for this degree of
light sensitivity, likely by a cascade of enzymatic reactions. Later studies elaborated this cascade and found that an intermediary in the photoisomerization of
retinal interacts with
transducin, a
G-protein, to activate
phosphodiesterases that control
cyclic GMP levels, which in turn modulate the release of
neurotransmitter from the rod cell. Public health: Although the availability of
vitamin A through food fortification and medicinal supplements virtually eliminated ocular
vitamin A deficiency from developed countries by the second half of the 20th century,
vitamin A deficiency remains a serious problem in developing countries as indicated by global surveys beginning in the 1960s. Millions of children were shown to be
vitamin A deficient, with resultant
blindness, increased susceptibility to
infection, and increased childhood mortality. Beginning in the 1960s, intervention trials showed that
vitamin A deficiency disorders could be prevented in developing countries with periodic
vitamin A dosing, and in the 1980s and 1990s, large randomized, double-blind, placebo-controlled clinical trials demonstrated the marked efficacy of
vitamin A supplementation in reducing childhood mortality.