In the 1930s, Lucy Wills identified a ‘new hemopoietic factor’ in yeast and liver which cured tropical macrocytic anemia in humans and experimental anemia in monkeys. Janet Watson and William B. Castle named the unknown substance, which would ultimately become a form of folate, ‘Wills’ factor’. Further studies with this unknown substance showed that it was active against nutritional pancytopenia in monkeys and experimental anemia in chicks, leading to various designations such as vitamin M (monkey) and vitamin Bc (chick). Other factors with growth-promoting activity for microorganisms such as Lactobacillus casei were given the interim names including folic acid – in recognition of extracts from leafy greens. Competing pharmaceutical research groups headed by Robert Stokstad at Lederle Laboratories and Joseph John Pfiffner at Parke-Davis Research Laboratory independently isolated factors bearing the biological properties of Wills’ factor and other unknown related factors including folic acid, Lederle Laboratories from a bacterial culture and Parke-Davis Laboratory from yeast and liver as a conjugate of folate. The new vitamin then was crystallized, chemically identified, and synthesized as pteroylglutamic acid and named folic acid between 1943 and 1945. Further studies of the monoglutamic folic acid and the yeast isolate polyglutamyl folate followed through the 1950s and to the present.

1.
Angier RB, Boothe JH, Hutchings BL, Mowat JH, Semb J, Stokstad EL, Subbarow Y, Waller CW, Cosulich DB, Fahrenbach MJ, Hultquist ME, Kuh E, Northey EH, Seeger DR, Sickels JP, Smith JM Jr: Synthesis of a compound identical with the L. casei factor isolated from liver. Science 1945;102:227–228.
2.
Wills L: Treatment of ‘pernicious anemia of pregnancy’ and ‘tropical anemia’ with special reference to yeast extract as a curative agent. Brit Med J 1931;1:1059–1064.
3.
Wills L, Clutterbuck PW, Evans BDF: A new factor in the production and cure of certain macrocytic anaemias and its relation to other haemopoietic principles curative in pernicious anaemia. Biochem J 1937;31:2136–2147.
4.
Watson J, Castle WB: Nutritional macrocytic anemia, especially in pregnancy; response to a substance in liver other than that effective in pernicious anemia. Am J Med Sci 1946;211:513–530.
5.
Day PL, Langston WC, Darby WJ: Failure of nicotinic acid to prevent nutritional cytopenia in the monkey. Proc Soc Exp Biol Med 1938;38:860–863.
6.
Langston WC, Darby WJ, Shukers CF, Day PL: Nutritional cytopenia (vitamin M deficiency) in the monkey. J Exp Med 1938;68:923–940.
7.
Stokstad ELR, Manning PDV: Evidence of a new growth factor required by chicks. J Biol Chem 1938;125:687–696.
8.
Schumacher AE, Heuser GF, Norris LC: The complex nature of the alcohol precipitate factor required by the chick. J Biol Chem 1940;135:313–320.
9.
Hogan AG, Parrott EM: Anemia in chicks due to vitamin deficiency. J Biol Chem 1939;128:46–47.
10.
Hogan AG, Parrott EM: Anemia in chicks caused by a vitamin deficiency. J Biol Chem 1940;132:507–517.
11.
Snell EE, Peterson WH: Growth factors for bacteria: X. Additional factors required by certain lactic acid bacteria. J Bact 1940;39:273–285.
12.
Wills L, Clutterbuck PW, Evans BDF: A new factor in the production and cure of certain macrocytic anaemias. Lancet 1937;1:311–314.
13.
Hutchings BL, Bohonos H, Peterson WH: Growth factors for bacteria: XIII. Purification and properties of an eluate factor required by certain lactic acid bacteria. J Biol Chem 1941;141:521–528.
14.
Mitchell HK, Snell EE, Williams RJ: The concentration of ‘folic acid’. J Am Chem Soc 1941;63:2284.
15.
Mitchell HK: Folic acid: I. Concentration from spinach. J Am Chem Soc 1944;66:267–268.
16.
Stokstad ELR: Some properties of a growth factor for Lactobacillus casei. J Biol Chem 1943;149:573–574.
17.
Pfiffner JJ, Binkley SB, Bloom ES, et al: Isolation of the antianemia factor (vitamin Bc) in crystalline form from liver. Science 1943;97:404–405.
18.
Briggs GM Jr, Luckey TD, Elvehjem CA, Hart EB: Studies on two chemically unidentified water-soluble vitamins necessary for the chick. J Biol Chem 1943;148:163–172.
19.
Briggs GM Jr, Luckey TD, Elvehjem CA, Hart EB: Studies on vitamins B10 and B11 and related substances in chick nutrition. J Biol Chem 1945;158:303–312.
20.
Binkley SB, Bird OD, Bloom ES, Brown RA, Calkins DG, Campbell CJ, Emmett AD, Pfiffner JJ: On the vitamin Bc conjugate in yeast. Science 1944;100:36–37.
21.
Bird OD, Bressler B, Brown RA, Campbell EJ, Emmett AD: A micro-biological assay of vitamin Bc conjugate. J Biol Chem 1945;159:631–636.
22.
Pfiffner JJ, Calkins DG, O’Dell BL, Bloom ES, Brown RA, Campbell CJ, Bird OD: Isolation of an antianemia factor (vitamin Bc conjugate) in crystalline form from yeast. Science 1945;102:228–230.
23.
Pfiffner JJ, Calkins DG, Bloom ES, O’Dell BL: On the peptide nature of vitamin Bc conjugate from yeast. J Amer Chem Soc 1946;68:1392.
24.
Baugh CM, Krumdieck CL: The solid phase synthesis of polyglutamates of folic acid. Fed Proc 1968;27:455 (abstract).
25.
Krumdieck CL, Baugh CM: The solid phase synthesis of polyglutamates of folic acid. Biochemistry 1969;8:1568–1572.
26.
Godwin HA, Rosenberg IH, Meienhofer J: Absorption of synthetic ‘cold’ and tritium-labeled pteroylheptaglutamic acid. J Clin Investig 1970;49:35 (abstract).
27.
Rosenberg IH, Godwin HA: The digestion and absorption of dietary folate. Gastroenterol 1971;60:445–463.
28.
Bird OD, Binkley SB, Bloom ES, Emmett AD, Pfiffner JJ: On the enzymic formation of vitamin Bc from its conjugate. J Biol Chem 1945;157:413–414.
29.
Campbell CJ, Brown JA, Emmett AD: Influence of crystalline vitamin Bc on hematopoiesis in the chick. J Biol Chem 1944;152:483–484.
30.
Jukes TH, Stokstad ELR, Belt M: Deficiencies of certain vitamins as studied with turkey poults on a purified diet. I. Pteroylglutamic acid, riboflavin, niacin and inositol. J Nutr 1947;33:1–12.
31.
Stokstad ELR, Koch J: Folic acid metabolism. Physiol Rev 1967;47:83–116.
32.
Spies TD, Wilter CF, Koch MB, Caldwell MH: Observations of the antianemic properties of synthetic folic acid. South Med J 1945;38:707–709.
33.
Moore CV, Bierbaum OS, Welch AD, Wright LD: The activity of synthetic Lactobacillus casei factor (‘folic acid’) as an antipernicious anemia substance. J Lab Clin Med 1945;30:1056–1069.
34.
Davidson LSP, Girdwood RH: Folic acid as a therapeutic agent. Brit Med J 1947;1:587–591.
35.
Swendseid ME, Bird OD, Brown RA, Bethell FH: Metabolic function of pteroylglutamic acid and its hexaglutamyl conjugate. II. Urinary excretion studies on normal persons. Effects of a conjugase inhibitor. J Lab Clin Med 1947;32:23–27.
36.
Bird OD, Robbins M, Vandenbelt JM, et al: Observations on vitamin Bc conjugase from hog kidney. J Biol Chem 1946;163:649–659.
37.
Spray GH: The utilization of folic acid from natural sources. Clin Sci 1952;11:425–428.
38.
Spray GH, Witts LJ: The utilization of folic acid given by mouth. Clin Sci 1952;11:273–281.
39.
Jandl JH, Lear AA: The metabolism of folic acid in cirrhosis. Ann Intern Med 1956;45:1027–1044.
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