MILESTONES IN BIOLOGICAL RESEARCH A History of Vitamin A and Retinoids

Vitamin A has probably been known for at least 3500 years as a factor that can cure a deficiency disease. Ancient Egyptians appear to have recognized night blindness, which we now know to be caused by vitamin A deficiency, and found a cure for it (1). However, this view has been disputed by modern scholars (2): the papyrus Ebers (ca. 1500 B.C.) (1) mentions an unspecified eye disease, sharew, but not night blindness; the word “night” does not appear. The recommended cure was “roasted ox liver, pressed, applied [to the eye], really effective.” Vitamin A deficiency can affect two parts of the eye: the epithelial covering (cornea and conjunctiva) and the retina (rhodopsin and iodopsin). Normally, the vitamin is delivered to the cornea via the tears and by diffusion through eye tissue. Vitamin A deficiency leads to destruction of the cornea, a major cause of blindness in children. It can be treated topically with vitamin A or retinoic acid. On the other hand, vitamin A is delivered to the retina via the bloodstream; hence night blindness, caused by loss of rhodopsin from the retina, would not yield to topical treatment. Therefore, topically applied juice of ox liver, though rich in vitamin A, would not be effective as a cure for night blindness. Egyptian medical practice was partly empirical, partly magical. The ox supplied many medicaments with the idea of “transfer” of the strength of the animal to the afflicted part. Thus, juice of ox liver applied to the night-blind eyes would be a typical example of Egyptian medical ritual. An amusing sidelight onto this “magic” treatment of night blindness was thrown by Hussaini et al. (3): these authors observed several treatment sessions in rural Java in our own days (1978). The juice of lamb liver was applied topically to the eyes of night-blind children. The procedure was exactly as described by the ancient Egyptians, “except for one small addition: rather than discarding the remaining organ, the [practitioners] fed it to the affected child...This was never considered part of the therapy itself.” Similarly, in 1928 Aykroyd (4) wrote: “I have been told of a custom of steaming the eyes over cooking liver, which is then eaten,” as a remedy for night blindness in Newfoundland. Perhaps the ancient Egyptian ritual treatment also ended with the patient eating the liver. Another ancient Egyptian papyrus, Kahun 1 (ca. 1825 B.C.) (2), a gynecological treatise, mentions “instructions for a woman [with] sickness [so that] she cannot see: then you shall cause her to eat raw liver of an ass” (2). The sickness may have been night blindness, and the cure more rational. The case for the ancient Egyptians thus is not proved, but it is strong; the connection between liver, the richest source of vitamin A in food, with blindness is highly suggestive. The first indisputable recognition of night blindness was made by the ancient Greeks, who called it nyktalopia (nyx, nyktos, night; alaos, blind; ops, opteos, eye). Hippocrates (460-327 B.C.) described “nyktalopia” in the second book of “Prognostics” (5). This description has given rise to some controversy: the collection of writings that has come down to us states “those who do see at night, whom we call nyktalopes, experience the disease when young, as children or youths”; this clearly means patients who can see at night (italics added). It was interpreted as “day blindness” by 19th century scientists (6). However, a handwritten text by Hippocrates in the 14th century, discovered by the Greek philologist A. Korais (1748-1833), shows a gap in the text between “do” and “see,” and in the margin is written the word “not,” resulting in “those who do fbI see at night” (7). This interpretation seems by far the most sensible, because later Greeks, like Galen (129-199 A.D.), a follower of Hippocrates, very clearly described nyktalopia as night blindness (7). Oribasius, a follower of Galen, born ca. 325 A.D., defines night blindness as: “vision is good during the day and declines at sundown; one cannot distinguish anything any longer at night” (8). Also convincing for this interpretation is the cure for nyktalopia, mentioned in the collection from the school of Hippocrates (ca. 300 B.C.), entitled Concerning Vision (5). There,