George Hoyt Whipple discovered that liver/meat diets are effective treatments for anemia and that iron is an essential dietary ingredient.

Pernicious anemia is one of several forms of anemia in which there is a severe reduction in the number of red blood cells (erythrocytes) in the affected individual’s bloodstream. Accompanying this severe reduction of red blood cells is a decreased level of blood hemoglobin, the most important protein found in blood cells and blood plasma. Hemoglobin is a tetrameric (that is, four-subunit) protein that transports oxygen from an individual’s lungs throughout the bloodstream to every cell in the body, where it is used to drive the production of energy molecules (that is, adenosine triphosphate—ATP) via the Krebs cycle. Hemoglobin carries waste carbon dioxide back to the lungs via the bloodstream for exhalation. If a person has a low red blood cell count (anemia), then his or her body will not be producing enough hemoglobin to transport oxygen to all the cells in the body. Consequently, these cells will be incapable of producing enough energy for the chemical reactions needed to survive. Many cells will die, and often the affected individual will die as well. [kw]Whipple Discovers Importance of Iron for Red Blood Cells (1925)
[kw]Iron for Red Blood Cells, Whipple Discovers Importance of (1925)
[kw]Red Blood Cells, Whipple Discovers Importance of Iron for (1925)
[kw]Blood Cells, Whipple Discovers Importance of Iron for Red (1925)
[kw]Cells, Whipple Discovers Importance of Iron for Red Blood (1925)
Blood cells;red
Blood;iron
Nutrition;iron
Medicine;anemia
Anemia
Iron as dietary ingredient
Hemoglobin
Pernicious anemia
[g]United States;1925: Whipple Discovers Importance of Iron for Red Blood Cells[06270]
[c]Science and technology;1925: Whipple Discovers Importance of Iron for Red Blood Cells[06270]
[c]Biology;1925: Whipple Discovers Importance of Iron for Red Blood Cells[06270]
[c]Health and medicine;1925: Whipple Discovers Importance of Iron for Red Blood Cells[06270]
Whipple, George Hoyt
Robscheit-Robbins, Frieda S.
Minot, George Richards
Murphy, William Parry

George Hoyt Whipple.

(The Nobel Foundation)

In 1905, George Hoyt Whipple received his medical degree from The Johns Hopkins Medical School in Baltimore, Maryland, and continued researching blood and liver disorders. He and a colleague, John H. King, King, John H. studied liver necrosis (decay) in dogs exposed to chloroform and discovered that the dogs’ livers regenerated rapidly after being damaged by this chemical. Whipple became very interested in the interrelationship between the liver and the bloodstream. He and King subsequently concentrated on the disease obstructive jaundice (icterus), where liver damage results in the release of yellowish bile pigments that concentrate in the victim’s skin. They demonstrated that obstructive jaundice was caused by the escape of bile pigments into the bloodstream and not into the lymphatic system.

The liver, the largest organ in the body, has numerous functions essential for survival, including bile production, hemoglobin recycling, sugar storage (as the carbohydrate glycogen), protein and carbohydrate metabolism, blood filtering and detoxification, and storage of essential vitamins and minerals. All these functions are closely interrelated, and the liver’s storage of vitamins and minerals is of special importance. Many of the body’s enzymes—proteins that control the rate of cellular chemical reactions—require the assistance of minerals (for example, iron, copper, molybdenum) and vitamins (for example, vitamins A, B₁₂, C, D, niacin). For example, hemoglobin requires iron in order to transport oxygen.

In 1914, Whipple continued his studies of icterus with Charles W. Hooper Hooper, Charles W. at the University of California in San Francisco. After they discovered that the liver filters hemoglobin from the blood and recycles the protein as a bile pigment called bilirubin, Whipple and Hooper considered the possibility that the liver may be involved in certain types of anemia, including pernicious anemia. Their experiments were performed on dogs obtained from local pounds and involved changing diets as well as periodic bleeding to induce anemia. The goal of their experiments was to determine how the dogs’ bodies responded to conditions of artificially induced anemia. Despite the fact that these experiments were performed humanely and the dogs usually survived, Whipple and his colleagues were criticized heavily by the general public, politicians, and animal rights groups, and they were forced to battle these groups legislatively for several years to defend their research.

Whipple and Hooper periodically bled dogs to maintain artificially induced anemia. These dogs had low red blood cell and hemoglobin counts as a result. Whipple and Hooper attempted several techniques at rapidly increasing hemoglobin production in these animals—rates faster than the body would normally recover on its own. They varied the dogs’ diets and found different degrees of success. A diet composed of carbohydrates (for example, bread and milk) was ineffective, requiring one to five months for hemoglobin regeneration. A diet of rice and potatoes was somewhat more effective; meat-rich diets were very effective. Diets composed of liver, lean scrap meat, and beef heart stimulated complete hemoglobin regeneration within two to four weeks.

Whipple and Hooper developed liver and meat extracts that produced the same dramatic results in artificially anemic dogs. In 1918, Hooper was the first physician to administer a liver extract to human victims of pernicious anemia. The three anemic patients’ conditions improved considerably. Nevertheless, various clinical doctors ridiculed Hooper and his treatment. As a result, Hooper discontinued his research. Seven years would pass before the Harvard University physicians George Richards Minot and William Parry Murphy would use virtually the same treatment, save many lives, and subsequently receive a Nobel Prize. Nobel Prize recipients;George Richards Minot[Minot]
Nobel Prize recipients;William Parry Murphy[Murphy]

Whipple continued his liver extract work with Frieda S. Robscheit-Robbins at the new School of Medicine and Dentistry at Rochester University in New York. From 1923 to 1929, they performed an extensive and elaborate series of dietary administration experiments on artificially anemic dogs. During these years, Whipple and Robscheit-Robbins defined the necessary dietary constraints for treating pernicious anemia. They tested various substances isolated from liver and muscle extracts of cow, pig, and chicken. They developed new extracts that, in conjunction with products from Minot’s group at Harvard University and the Eli Lilly Pharmaceutical Company of Indianapolis, Indiana, became effective treatments for human patients suffering from pernicious anemia. Thousands of lives were saved by these extracts.

In 1925, Whipple and Robscheit-Robbins discovered that the most effective mineral found in beef and liver extract that would stimulate hemoglobin regeneration was iron. They reported their results in an article titled “Blood Regeneration in Severe Anemia: III. Iron Reaction Favorable—Arsenic and Germanium Dioxide Almost Inert,” which appeared with three additional articles in volume 72 of the American Journal of Physiology. They found that iron by itself is a very effective hemoglobin regenerator, which is not surprising given that iron is the central active portion of each hemoglobin protein subunit. They also discovered that beef liver was the most effective dietary treatment, causing hemoglobin and red blood cell regeneration from one-third of normal to normal in as little time as two weeks. Other effective dietary supplements included chicken gizzard smooth muscle, pig kidney, and beef kidney. They also discovered that the liver recycles hemoglobin into bile pigments (for example, bilirubin) and bile pigments into hemoglobin. Whipple and Robscheit-Robbins continued this research into the 1930’s and 1940’s.

Although iron is an essential component of the pernicious anemia meat/liver extracts, vitamin B₁₂
Vitamins;vitamin B₁₂ was later shown to be equally as important. In 1949, vitamin B₁₂ was isolated from liver extracts by the American biochemist Karl Folkers and the English biochemist Alexander Todd. Diets of iron and vitamin B₁₂ are modern treatments for individuals suffering from pernicious anemia.

Whipple shared the 1934 Nobel Prize in Physiology or Medicine with Minot and Murphy. Nobel Prize recipients;George Hoyt Whipple[Whipple] Minot and Murphy had applied Whipple’s beef/liver extracts to treating human pernicious anemia patients beginning in 1925.

George Hoyt Whipple’s contributions to medicine and to biology are multifold: First, Whipple discovered a treatment for pernicious anemia, thereby saving countless thousands of lives. Second, he discovered that the mineral iron, stored in the liver, is essential for hemoglobin regeneration. Third, he unraveled several basic recycling enzymatic pathways within the mammalian body, including the recycling of hemoglobin and bile pigments. Finally, he improved the understanding of human liver and blood physiology, breaking new ground in the study of blood disorders. The 1934 Nobel Prize in Physiology or Medicine, along with other awards, demonstrated the importance of his lifesaving work.

The use of liver extracts to treat human victims of pernicious anemia saved countless individuals from a disease that many scientists had thought to be untreatable. It is regrettable that Whipple and Hooper’s 1918 treatment of patients had been ridiculed; many lives might have been spared during the seven-year interval between this event and its ultimate acceptance by the medical community. The liver extracts led eventually to the isolation of the important active ingredients for hemoglobin regeneration, including the mineral iron and vitamin B₁₂.

Iron is one of many minerals stored by the liver for later use in the body’s cells. Iron serves as a cofactor, or helper substance, in the active centers of protein enzymes—the cellular molecules that control essential life chemical reactions in cells. Iron is essential for proper functioning of the protein hemoglobin, a molecule that is mass produced by red blood cells for the transport of oxygen to the cells of the body to drive cellular energy production reactions. Hemoglobin is nonfunctional without iron. The phrase “iron-poor blood” indicates a semianemic physical state. Whipple showed that iron can regenerate hemoglobin rapidly in only a few weeks. Hemoglobin is regenerated in the liver, one of the few body tissues capable of regeneration when it is not too severely damaged. This regenerative capacity of liver could be caused somehow by the fact that the liver is a storage center for virtually every type of material needed by the body. The liver controls the buildup and breakdown of the body’s food reserves according to the body’s needs. The liver can split hemoglobin into two sections: a heme component, which is iron, and the precursor of a bile pigment, bilirubin. The second section is a globin component, which is protein. The globin is recycled back into the body’s protein metabolism; the heme is used to construct bile, a substance released from the liver into the small intestine to emulsify fat, thereby allowing the body to absorb the essential fat-soluble vitamins A, D, E, and K. Bile pigments can be reabsorbed back into the blood, returned to the liver, and used to construct the heme component of hemoglobin or more bile.

Whipple’s achievements greatly improved the understanding of organisms as intricately interconnected organ systems. His work demonstrated the interplay between the liver, blood, and digestive systems. His studies would pioneer later research into other types of anemia, including the inherited thalassemia and sickle-cell anemia. Blood cells;red
Blood;iron
Nutrition;iron
Medicine;anemia
Anemia
Iron as dietary ingredient
Hemoglobin
Pernicious anemia

• Alberts, Bruce, et al. Molecular Biology of the Cell. 4th ed. New York: Garland, 2002. Comprehensive introductory molecular biology textbook for undergraduate biology majors offers a theoretical survey of cell biology by several leading scientists. Features excellent photographs, diagrams, and reference lists. Includes a good discussion of liver function and its regenerative capacity.
• Corner, George W. George Hoyt Whipple and His Friends: The Life of a Nobel Prize Pathologist. Philadelphia: J. B. Lippincott, 1963. A touching portrait of not only a great scientist and physician but also a wonderful man by a close friend and colleague. Provides a detailed and enjoyable summary of both the scientific and private sides of Whipple’s life.
• Garrison, Fielding H. An Introduction to the History of Medicine. 4th ed. Philadelphia: W. B. Saunders, 1963. Comprehensive history of medical research from ancient times up to 1928. Includes a year-by-year chronology and extensive references. Notes the contributions of Whipple, Minot, Murphy, and other twentieth century pathologists.
• Goldman, Lee, and Dennis Ausiello, eds. Cecil Textbook of Medicine. 22d ed. Philadelphia: W. B. Saunders, 2003. Enormous medical reference work is a tremendously informative source on anatomy, physiology, pathology, hematology, and more. Features detailed graphs, tables, and diagrams as well as an extensive reference list. Provides considerable information on all types of anemia.
• Nobelstiftelsen. Nobel: The Man and His Prizes. 3d ed. New York: Elsevier, 1972. An excellent history of the Nobel Prize, beginning with Alfred Nobel and including the Nobel laureates in all fields up through the 1960’s. Discusses each laureate’s work within the context of the history of his or her own field.
• Whipple, George H. “Autobiographical Sketch.” Perspectives in Biology and Medicine 2 (Spring, 1959): 253-289. Brief autobiography presents a personal summary of Whipple’s life and his thoughts about science, academia, and his colleagues. Emphasizes his undergraduate and medical school days as well as his experiences in supervising two medical schools and makes clear his love for teaching and research.

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