The discovery of vitamin B12, the elucidation of its role in metabolism, and the effects and treatment of its deficiency occurred in distinct phases over more than 100 years, and it was the subject of two separate Nobel Prizes. The valuable contribution of clinical reports and studies of patients with pernicious anemia throughout the 19th century resulted in enough clinical definition to allow Minot and Murphy to put together the first hallmark study on treatment of the condition, leading them to a Nobel Prize. These researchers were not the first to suggest that an inadequacy of nutrients was the cause of pernicious anemia, but their particular input was a carefully designed intervention in well-characterized pernicious anemia patients, of a special diet containing large amounts of liver. They found consistent improvement in the clinical and blood status of all subjects, most of whom remained on remission indefinitely. After the successful intervention studies, the next advance was made by Castle who discovered that a gastric component, which he called intrinsic factor, was missing in pernicious anemia. Many years later, intrinsic factor was found to be a glycoprotein that formed a complex with vitamin B12, promoting its absorption through ileal receptors. The vitamin was isolated by two groups simultaneously and was crystallized and characterized in the laboratory of Dorothy Hodgkin, contributing to her Nobel Prize in 1964. Subsequently, the various biochemical roles of vitamin B12 were elucidated, including its important interaction with folate and their common link with megaloblastic anemia. Many of the early clinical studies recognized that vitamin B12 deficiency also caused a severe neuropathy leading to paralysis and death, while post mortem analysis demonstrated spinal cord demyelination. Vitamin B12 is still the subject of intense research and, in particular, its role in preventing these irreversible neurological lesions remains unclear.

Keywords:
Intrinsic factor, Pernicious anemia, Megaloblastic anemia, Methionine synthase, Methylmalonyl CoA mutase, Subacute combined degeneration, Vitamin B12, Cobalamin
1.
Stubbe J: Binding site revealed of nature’s most beautiful cofactor. Science 1994;266:1663–1664.
2.
Whitby L: The evolution of the treatment of Addisonian anaemia. Br Med J 1955;1:1401–1406.
3.
Chanarin I: The Megaloblastic Anaemias, ed 1. Oxford and Edinburgh, Blackwell Scientific Publications, 1969.
4.
Huser HJ: A note on Biermer’s anemia. Med Clin North Am 1966;50:1611–1626.
5.
Russell JS, Batten FE, Collier J: Subacute combined degeneration of the spinal cord. Brain 1900;23:39–110.
6.
Whipple GH, Hooper CW, Robscheit FS: Blood regeneration following anemia, iv: influence of meat, liver and various extractives, alone or combined with standard diets. Am J Physiol 1920;53:236–262.
7.
Sinclair L: Recognizing, treating and understanding pernicious anaemia. JLL Bulletin: Commentaries on the History of Treatment Evaluation.
8.
Lynch RG: Pernicious anemia. Milestones in Investigative Pathology 2009;32–33.
9.
Minot GR, Murphy WP: Treatment of pernicious anemia by a special diet. JAMA 1926;87:470–476.
10.
Elders C: Tropical sprue and pernicious anaemia: aetiology and treatment. Lancet 1924;1:75–77.
11.
Liver extract for pernicious anaemia. Can Med Assoc J 1927;17:646.
12.
Liver extract for pernicious anemia. Science 1927;65:x.
13.
Liver extract in the treatment of pernicious anaemia. Br Med J 1928;1:398–399.
14.
Cohn EJ, Minot GR, Fulton JB, Ulricks HF, Sargent FC, Weare JH, Murphy WP: The nature of the material in liver effective in pernicious anemia. J Biol Chem 1927;vii:lxix–lxxiii.
15.
Wyckoff HA, Bloomfield AL: Liver extract in pernicious anemia – its effects: with report of cases. Cal West Med 1929;30:225–231.
16.
Liver extract for the treatment of pernicious anaemia. Br Med J 1928;1:463.
17.
Collip JB: A method of preparation of a liver extract powder for the treatment of pernicious anaemia. Can Med Assoc J 1928;18:392–393.
18.
Davidson LS: Observations on intramuscular liver extract therapy in the treatment of pernicious anaemia. Br Med J 1932;1:269–272.
19.
Gibbons H: Pernicious anemia – maintenance dose of liver extract necessary. Cal West Med 1933;38:428–431.
20.
Scowen EF, Spence AW: A concentrated liver extract for parenteral administration in pernicious anaemia. Br Med J 1935;1:246–248.
21.
Hurst AF: The clinical importance of achlorhydria. Br Med J 1934;2:665–669.
22.
Castle WB: The aetiological relationship of achylia gastrica to pernicious anaemia. Proc R Soc Med 1929;22:1214–1216.
23.
Castle WB, Ham TH: Observations on the etiologic relationship of achylia gastrica to pernicious anemia. V. Further evidence for the essential participation of extrinsic factor in hematopoietic responses to mixtures of beef muscle and gastric juice and to hog stomach mucosa. JAMA 1936;251:514–521.
24.
Castle WB: Treatment of pernicious anemia: historical aspects. Clin Pharmacol Ther 1966;7:147–161.
25.
Rickes EL, Brink NG, Koniuszy FR, Wood TR, Folkers K: Crystalline vitamin B12. Science 1948;107:396–397.
26.
Shorb MS: Activity of vitamin B12 for the growth of lactobacillus lactis. Science 1948;107:397–398.
27.
Smith EL: Purification of anti-pernicious anaemia factors from liver. Nature 1948;161:638.
28.
Smith EL, Parker LF: Purification of anti-pernicious anaemia factor. Biochem J 1948;43:viii.
29.
Smith EL: Presence of cobalt in the anti-pernicious anaemia factor. Nature 1948;162:144.
30.
Rickes EL, Brink NG, Koniuszy FR, Wood TR, Folkers K: Vitamin B12, a cobalt complex. Science 1948;108:134.
31.
Reisner EH Jr: The present status of vitamin B12 in pernicious anemia. Bull N Y Acad Med 1949;25:429–433.
32.
West R, Reisner EH Jr: Treatment of pernicious anemia with crystalline vitamin B12. Am J Med 1949;6:643–650.
33.
Brink NG, Kuehl FA Jr, Folkers K: Vitamin B12: the identification of vitamin B12 as a cyano-cobalt coordination complex. Science 1950;112:354.
34.
Brink C, Hodgkin DC, Lindsey J, Pickworth J, Robertson JR, White JG: X-ray crystallographic evidence on the structure of vitamin B12. Nature 1954;174:1169–1171.
35.
Howard JA: Dorothy Hodgkin and her contributions to biochemistry. Nat Rev Mol Cell Biol 2003;4:891–896.
36.
Hodgkin DC, Kamper J, Mackay M, Pickworth J, Trueblood KN, White JG: Structure of vitamin B12. Nature 1956;178:64–66.
37.
Smith EL, Mervyn L, Johnson AW, Shaw N: Partial synthesis of vitamin B12 coenzyme and analogues. Nature 1962;194:1175–1175.
38.
Hogenkamp HPC, Oikawa TG: The synthesis and properties of 2’,5’-dideoxyadenosylcobalamin and 5’-deoxythymidylcobalamin. J Biol Chem 1964;239:1911–1916.
39.
Barker HA, Weissbach H, Smyth RD: A coenzyme containing pseudovitamin B(12). Proc Natl Acad Sci USA 1958;44:1093–1097.
40.
Barker HA: Corrinoid-dependent enzymic reactions. Annu Rev Biochem 1972;41:55–90.
41.
Drennan CL, Huang S, Drummond JT, Matthews RG, Lidwig ML: How a protein binds B12: A 3.0 a X-ray structure of B12-binding domains of methionine synthase. Science 1994;266:1669–1674.
42.
Mancia F, Keep NH, Nakagawa A, Leadlay PF, McSweeney S, Rasmussen B, Bosecke P, Diat O, Evans PR: How coenzyme B12 radicals are generated: the crystal structure of methylmalonyl-coenzyme A mutase at 2 A resolution. Structure 1996;4:339–350.
43.
Scott JM, Weir DG: The methyl folate trap. A physiological response in man to prevent methyl group deficiency in kwashiorkor (methionine deficiency) and an explanation for folic-acid induced exacerbation of subacute combined degeneration in pernicious anaemia. Lancet 1981;2:337–340.
44.
Smulders YM, Smith DE, Kok RM, Teerlink T, Swinkels DW, Stehouwer CD, Jakobs C: Cellular folate vitamer distribution during and after correction of vitamin B12 deficiency: a case for the methylfolate trap. Br J Haematol 2006;132:623–629.
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2012
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