TABLE 1.
Historical accounts in the discovery and history of vitamin A research and biomarker development1
| Year | Discovery |
| 460–325 bc | Ancient Egyptians and Greeks cured nightblindness with roasted oxen liver (2) |
| 1860–1863 | von Hubbenet associated nightblindness with eye defects and Bitot described conjunctival xerosis by identifying “Bitot’s spots” (reviewed in references 2 and 3) |
| 1861 | Schwarz diagnosed nightblindness as a nutritional disease during a naval expedition (reviewed in reference 2) |
| 1904 | Mori reported “Hikan” in Japanese children, which responded to cod liver oil and liver (reviewed in reference 2) |
| 1913 | McCollum and Davis (4) and Osborne and Mendel (5) discovered “fat-soluble A” in rat feeding studies |
| 1919 | Bloch (6) found xerophthalmia in Danish orphans subsisting on a fat-free milk, oatmeal, and barley diet |
| 1919–1920 | Steenbock and Gross (7, 8) identified a yellow pigment (β-carotene) that was converted to active colorless vitamin A |
| 1928 | Green and Melanby (9) first coined the term “anti-infective” for vitamin A |
| 1930 | Moore (10) purified yellow pigment from plants, butter fat, and egg yolk as carotene and showed that it was converted to vitamin A |
| 1931 | Karrer et al. (11) isolated and described the chemical structures of retinol and β-carotene (Figure 1) |
| 1931 | Green et al. (12) showed that cod liver oil reduces puerperal fever |
| 1932 | Ellison (13) reported that vitamin A reduces measles fatality |
| 1935 | Wald (14) described “the visual cycle” |
| 1937 | Holmes and Corbet (15) isolated and crystallized pure vitamin A from fish liver oil |
| 1947 | Isler et al. (16) synthesized retinol |
| 1960 | Gopalan et al. (17) drew global attention to endemic vitamin A deficiency in India |
| 1965 | Olson and Hayaishi (18) discovered β-carotene 15,15′-dioxygenase as the core enzyme in the conversion of provitamin A carotenoids to vitamin A in the intestine |
| 1966 | McLaren et al. (19) published detailed photo accounts of xerophthalmia |
| 1967 | Wald (20) received the Nobel Prize in physiology for describing the visual cycle |
| 1974 | The International Vitamin A Consultative Group was established (21) |
| 1978 | Loerch et al. (22) proposed the principle of the relative-dose-response test in rats |
| 1986 | Sommer et al. (23) reported that vitamin A can reduce child mortality in Indonesia followed by recommendations by UNICEF and WHO for the use of high-dose vitamin A supplements (21) |
| 1987–1988 | Petkovich et al. (24), Giguere et al. (25), and Benbrooke et al. (26) simultaneously discovered the retinoic acid receptors in cell nuclei |
| 1988 | Tanumihardjo and Olson (27) proposed vitamin A2 in a modified-relative-dose-response test |
| 1989 | Furr et al. (28) published the use of deuterated retinyl acetate for vitamin A assessment of humans |
| 1990 | Beaton et al. (29) summarized 16 studies using vitamin A supplementation, concluding an average childhood mortality reduction of 23% |
| 1992 | At the International Conference on Nutrition in Rome, countries committed to preventing vitamin A deficiency (21) |
| 1995 | Bioavailability of provitamin A carotenoids in green leafy vegetables challenged by de Pee et al. (30) in Indonesia |
| 1998 | Christian et al. (31, 32) in Nepal revealed maternal nightblindness as an indicator of maternal vitamin A deficiency, poor health, and survival |
| 1999 | West et al. (33) in Nepal reported that vitamin A or β-carotene supplementation can lower maternal mortality |
| 2001 | The Institute of Medicine (34) in the United States revised the β-carotene:retinol bioconversion ratio from 6 μg β-carotene:1 μg retinol to 12:1 and the ratio for other provitamin A carotenoids from 12:1 to 24:1 |
| 2003 | Thurnham et al. (35) systematically showed the influence of inflammation on serum retinol concentrations |
| 2003 | Ramathullah et al. (36) reported from India a 23% reduction in infant mortality by giving newborns a single ∼50,000 IU oral dose of vitamin A, affirming earlier work by Humphrey et al. (37) in Indonesia |
| 2011 | The WHO (38–42) revised vitamin A supplementation recommendations for women and children on the basis of the current evidence base |
| 2013 | Awasthi et al. (43) found a nonsignificant 4% decrease in mortality of Indian children given periodic 200,000-IU supplements |
| 2014 | Large randomized, double-blind, placebo-controlled trials in Ghana (44) and Tanzania (45) showed no impact, whereas India showed a 10% reduction (46) in infant mortality after 50,000 IU vitamin A was administered at birth |
1
Although comprehensive, the table does not include all of the important discoveries for applications of vitamin A.