Anaemia is a condition in which red blood cells or haemoglobin are deficient, lowering the blood’s oxygen-carrying capacity. In the early 20th century, pernicious anaemia was often fatal. Whipple showed in bleeding-dog experiments that liver accelerated the return of red blood cells. Building on this, Minot and Murphy conducted clinical trials in which patients ate large quantities of raw liver and experienced remarkable recovery. Their work clarified the link between nutrition and blood formation, paving the way for the later discovery of vitamin B12 and folic acid and greatly advancing haematology and nutrition science.

Whipple used systematic animal models to search for nutrients essential for post-hemorrhagic regenerative haematopoiesis and reported that liver, rich in iron and proteins, was particularly effective. Minot and Murphy translated this finding to the clinic, giving more than 200 g of raw liver daily to patients with pernicious anaemia and observing rapid rises in reticulocyte counts and clinical recovery. The therapeutic effect implied an unknown “liver factor,” finally isolated in 1948 as vitamin B12. Vitamin B12 is indispensable for methyl-group transfer and DNA synthesis; its deficiency causes megaloblastic anaemia. The work integrated haematopoietic physiology, iron metabolism and nutritional therapy, and is regarded as an early exemplar of evidence-based medicine.

Using a repeated-bleeding canine model, Whipple demonstrated that a liver diet significantly enhanced reticulocytosis, plasma iron turnover and haemoglobin re-synthesis. Minot and Murphy administered a quantified liver-feeding protocol to 31 pernicious-anaemia cases; mean reticulocyte counts increased more than ten-fold within seven days, accompanied by striking clinical and haemoglobin improvement. Because the effect persisted in patients with achlorhydria and intrinsic-factor deficiency, the active principle was inferred to be a gastresistant macromolecular complex. Subsequent work by Castle identified intrinsic factor, and Rickes et al. crystallised the compound as cyanocobalamin (vitamin B12); X-ray crystallography later revealed its planar corrinoid structure. The discovery laid the foundation for differential diagnosis of megaloblastic, sideroblastic and anaemia of chronic disease and facilitated elucidation of disorders such as transcobalamin II deficiency.