George Hoyt Whipple

Physician

• Born: August 28, 1878
• Birthplace: Ashland, New Hampshire
• Died: February 1, 1976
• Place of death: Rochester, New York

American pathologist

Using anemic dogs, Whipple studied the effects of many foods on the regeneration of hemoglobin. Along with two others, he won the Nobel Prize in Physiology or Medicine in 1934 for the discovery that liver was valuable in the treatment of pernicious anemia.

Areas of achievement Medicine, physiology

Early Life

George Hoyt Whipple (WIH-puhl) was the son of Ashley Cooper Whipple and Frances Hoyt Whipple. Both his father and grandfather were physicians. Ashley Cooper died of typhoid fever when George was only two years old. Supportive of her son’s desire to become a physician, Frances secured a first-rate education for him. He entered Phillips Academy, a preparatory school in Andover, Massachusetts, in 1892 and Yale University in 1896.

After graduating from Yale, Whipple chose to attend Johns Hopkins University School of Medicine, which, though it had been founded only in 1893, had quickly become the best environment for medical students. At the beginning of his second year in medical school, Whipple began an association with the preeminent pathologist William Henry Welch and his six associates, all of whom had distinguished careers. This team ensured that the instruction of pathology was of the highest quality.

Graduating fourth in his class, Whipple qualified for one of twelve highly prized internships. He chose to become an assistant in pediatric pathology spending many hours performing autopsies and studying the effects that disease had on bodily tissues. At the end of the year, he asked for and received a second appointment, which gave him the rank of instructor. Soon Whipple decided to devote his career to pathology.

One of the first diseases that he studied was tuberculosis, on which he authored his first paper in 1906. The following year, he accepted a position as assistant to the chief pathologist studying tropical diseases in Ancon Hospital in the Panama Canal Zone, alarming his mother, who expected him to open a private practice. In Panama he studied blackwater fever, an often fatal malarial disease, and published a paper that drew praise.

In 1909, Whipple returned to Johns Hopkins as the senior member of Welch’s staff and also as the resident pathologist. That summer, he traveled to Heidelberg, Germany, and gained exposure to an outstanding European laboratory. Back at Johns Hopkins, he continued studies on the effects of chloroform, an anesthesia then widely used, and discovered that it interfered with blood clotting and damaged the liver. Chloroform poisoning also produced jaundice, which occurs when bile salts get into the blood in cases of liver damage.

In the following years, Whipple’s interests changed from pathological anatomy, or the description and classification of disease-produced changes, to physiological pathology, the study of abnormal body states using chemistry and physiology. After another trip to Europe, Whipple researched liver function, blood coagulation, pancreatitis, and intestinal obstruction. During the period from 1912 to 1914, he and his coworkers published twenty-one research papers. In 1914, Whipple married Katherine Ball Waring, with whom he had two children, George Hoyt and Barbara.

Life’s Work

In 1914, Whipple left Johns Hopkins and accepted an invitation to organize the Hooper Foundation and become its director at the University of California Medical School in San Francisco, where, with Charles Hooper, he resumed research on the role that the liver played in the production of bile pigments. Experimenting on dogs that had bile fistulas (tubes surgically placed through the abdominal wall into the gall bladder), they found that bile secretion was influenced by dietary changes: Carbohydrates increased the production of bile pigments, and proteins diminished it. The dogs, however, did not thrive when deprived of their bile, and Whipple discovered that their health could be maintained by adding pig’s liver to their diets. This unexpected discovery led Whipple to hypothesize that the liver made a prehemoglobin substance. He further speculated that if it could be established that liver cells formed such a substance, great progress would have been made toward understanding the complicated issue of hemoglobin metabolism.

Hooper then wondered if pernicious anemia, a fatal anemia, might result when the production of the hypothetical prehemoglobin was disturbed. He made an extract from liver tissue and gave it to six patients. Some cases experienced remission. Since pernicious anemia cases did experience spontaneous remissions, hospital officials gave Hooper and Whipple no encouragement to continue this work. Whipple, however, continued his research on hemoglobin production with Hooper and Frieda Robscheit-Robbins. He and his coworkers bled dogs to make them anemic for a short time and then tested the effects of various foods and drugs to identify which best regenerated the depleted blood. Lean scrap meat regenerated the blood in two to four weeks, mixed table scraps in four to seven weeks, and high carbohydrate diets in four weeks to five months. Iron pills, contrary to expectations, did not help. They reported these results to the American Physiological Society in December, 1917, and published an abstract in 1918. In 1920, the American Journal of Physiology published a series of five papers that provided more details.

During his tenure at the Hooper Foundation, Whipple and his associates studied several other problems. They examined the formation of the bile salts and determined that their production was separate from that of the bile pigments. They also studied how the liver detoxifies poisonous metabolic products by combining them with other substances, thus rendering them harmless and promoting excretion in the urine. Finally, he studied toxicity resulting from injury to body tissues, extending the idea to the disease process. He discovered that septic states resulted not simply from the invading microorganism but were caused by the primary injury and autolysis (breakdown of the tissue) of the proteins in the injured tissue. Whipple then linked these results to radiation poisoning described in medical literature. On postmortem examination, he and a student, Charles Hall, discovered that there was only microscopic injury to the lining of the intestine in dogs exposed to intense radiation. In their 1919 report, Whipple and Hall gave the first warning that radiation affected the intestinal tract.

In 1920, Whipple became dean of the University of California Medical School. On July 1, 1921, he accepted the appointment as dean of the new School of Medicine and Dentistry at Rochester University in New York, which he held until 1953, and professor of pathology, which he held until 1955. He selected the faculty and designed a large tic-tac-toe-shaped building to house the entire medical school, thus fostering close communication among all departments. The first medical class entered in September, 1925.

During the early 1920’s, Whipple remained in contact with his coworkers in San Francisco. He had left a large backlog of research, and during the transition years at Rochester, he continued to write and edit research papers. By 1923, Frieda Robscheit-Robbins and the dog colony had moved to Rochester. Unlike their earlier research, in which dogs were made anemic by a few large bleeds, the dogs in this research were kept in an anemic state by repeated small bleeds, thus eliminating the possibility of spontaneous recovery. A whole range of foodstuffs was tested to identify the substance that improved the anemia. Liver had the most beneficial properties, followed by beef heart and then meats. Milk did not improve the anemia. These studies resulted in a series of papers on “Blood Regeneration in Severe Anemia” published in the American Journal of Physiology in 1925 and 1927. Whipple and his coworkers attempted but failed to extract the specific hemoglobin-producing substances in the liver by making various fractions.

In 1926, Harvard University’s George Richards Minot, with the help of pathologist William P. Murphy, tested a liver diet on patients with pernicious anemia. Keeping close records of the microscopic blood picture, they found the treatment effective. They published their findings in the Journal of the American Medical Association in August, 1926, attracting worldwide attention. Minot’s group then was able to obtain a liver extract of high potency, which the pharmaceutical firm Eli Lilly mass produced. In 1934, Minot, Murphy, and Whipple received the Nobel Prize in Physiology or Medicine.

After he won the Nobel Prize, Whipple led three teams doing research on hemoglobin formation, iron metabolism, and the utilization of proteins. Whipple and Robscheit-Robbins continued to search for the specific dietary factors in the production of hemoglobin. He also undertook important investigations of iron absorption, discovering that the body takes only what it needs via the alimentary tract. At first, it was impossible to distinguish iron already present in the body from iron recently ingested. Developments in physics helped physiologists because the production of radioactive isotopes became possible, and, beginning in 1938, Whipple’s team began to use the radioactive isotope Fe59 to trace the path of ingested iron.

Whipple’s study of hemoglobin led him to investigate proteins in general. With his coworkers, he fed severely anemic dogs diets low in protein. They found that the dogs built up hemoglobin by taking protein from the blood plasma and other bodily tissues. Whipple called this give-and-take between body and plasma protein “the dynamic equilibrium of protein.” Resuming his earlier line of research, Whipple tested the effects of various dietary substances on dogs with low protein levels. He linked this work to the study of amino acids done by other researchers. In 1944 Whipple’s team began to use the radioactive isotope N15 in amino acid research and in studies of the dynamic equilibrium of protein.

Besides the Nobel Prize, Whipple was awarded the Popular Science Monthly Gold Medal and Annual Award in 1930 and the William Wood Gerhard Gold Medal of the Philadelphia Pathological Society in 1934. He died in Rochester, New York, on February 1, 1976, at age ninety-seven.

Significance

The discoveries of Whipple, Minot, and Murphy did not completely explain pernicious anemia. Whipple was not surprised to discover that the liver extract prepared by Minot and Murphy worked for people with pernicious anemia but not for dogs with severe experimental anemia. He reasoned that there was a difference between primary (pernicious) and secondary (experimental or dietary) anemia and speculated that pernicious anemia was a deficiency disease. In 1948 the active principle was isolated from the liver simultaneously by investigators in Great Britain and the United States. This substance was called vitamin B₁₂ and became the standard treatment for pernicious anemia. Whipple studied the distribution of vitamin B₁₂ labeled with Co₆₀ and published papers on it with W. D. Woods and W. B. Hawkins in 1958 and 1960.

Bibliography

Corner, George W. George Hoyt Whipple and His Friends: The Life-Story of a Nobel Prize Pathologist. Philadelphia: J. B. Lippincott, 1963. This useful biography published thirteen years before Whipple died details his scientific, administrative, and honorary accomplishments. It contains photographs, citations from personal correspondences, and a list of papers published through 1961.

Holmgren, I. “Presentation Speech by Professor I. Holmgren, Member of the Staff of Professors of the Royal Caroline Institute.” In Les Prix Nobel en 1934. Stockholm: Imprimerie Royale, P. A. Norstedt and Soner, 1935. This is the speech presented at the ceremony awarding Whipple, Minot, and Murphy the Nobel Prize for their work on pernicious anemia. Presents the historical background of the nineteenth century and places Whipple’s work in the context of Minot and Murphy.

Raju, Tonse N. K. The Nobel Chronicles: A Handbook of Nobel Prizes in Physiology or Medicine, 1901-2000. Bloomington, Ind.: First Books Library, 2002. A collection of Raju’s articles about Whipple and other Nobel Prize-winners that originally appeared in Lancet, a British medical journal.

Rapport, Samuel, and Helen Wright. Great Adventures in Medicine. 2d ed. New York: Dial Press, 1961. Contains a selection written by Minot, one of Whipple’s corecipients of the Nobel Prize. Minot describes the symptoms of pernicious anemia and explains treatment of it in easily understandable language.

Wailoo, Keith. Drawing Blood: Technology and Disease Identity in Twentieth-century America. Baltimore: Johns Hopkins University Press, 1977. Wailoo discusses the history of the progress made in understanding several diseases of the blood. Contains a chapter on pernicious anemia, the disease Whipple’s work helped to elucidate. The author interprets this disease in its social context and explores the role of the pharmaceutical industry in defining disease through manufacturing, packaging, advertising, and cure promotion.

Whipple, George H. “Autobiographical Sketch.” Perspectives in Biology and Medicine 2 (Spring, 1959): 253-289. A short sketch outlining the main events in Whipple’s life. Straightforward presentation of useful facts.

‗‗‗‗‗‗‗. “Hemoglobin Regeneration as Influenced by Diet and Other Factors.” In Les Prix Nobel en 1934. Stockholm: Imprimerie Royale, P. A. Norstedt and Soner, 1935. A nine-page account in Whipple’s own words of the history of the work leading to the experiments on anemic dogs for which Whipple received the Nobel Prize. It includes citations of papers he published.

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