Evidence is presented for a hypothesis that megaloblasts are red blood cell precursors with a prolonged resting phase between mitoses, allowing a longer time for dispersion of the chromatin throughout the nucleus. Anything that retards the rate of cell division can produce cells of similar appearance, but the conditions most conducive to megaloblastic blood formation are states in which vitamin B12 or folic acid are deficient. These two substances function in the synthesis of nucleoproteins as co-enzymes or their precursors concerned with the transfer of one-carbon units. In their absence the synthesis of the extra amounts of deoxyribonucleic acid essential for mitosis can go on but slowly, and the marrow becomes crowded with cells waiting to divide.

The principle source of the extra DNA is cytoplasmic RNA which appears to supply the ribonucleotide precursors of several deoxyribose containing compounds. Most important among these is deoxyuridylic acid which is methylated to form thymidylic acid. The failure of these reactions to occur in the absence of the essential co-enzymes leads to a persistence of RNA in the megaloblastic cytoplasm during the maturation phase, and this is probably responsible for their development into macrocytes.

This hypothesis accounts for the occasional presence of megaloblasts in conditions other than pernicious and related deficiency anemias and the occurrence of "macronormoblastic" or "megaloblastoid" marrows in intrauterine life and liver disease. The hypothesis also explains the rapid replacement of megaloblasts by normoblasts in the marrow following specific therapy.

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