The Nobel Prize in Physiology or Medicine, because of its relationship to human health and well-being, is the one that can be identified most readily by the public as meeting Nobel’s intent to recognize the accomplishment that is a benefit to mankind. The prize in physiology or medicine has not been awarded every year. For example, no prizes were offered for several years during the First and Second World War and in several years in which an appropriate candidate was not identified. From 1901 to 2016, 107 awards have been made to 210 laureates, of whom 12 were women.20,21 Approximately one-third of the prizes were given to one laureate, one-third was shared by two awardees, and one-third was shared by three awardees. The Nobel Prize in Physiology or Medicine has been awarded without interruption from 1943 to 2016.
Prior to World War II, Europe was the center of scientific research, and European scientists received most of the prizes for physiology or medicine. From 1901 to 1939, only three prizes for physiology or medicine were won or shared by North Americans: the first to Canadians, Frederick Banting and John James Rickard Macleod, for the isolation and clinical use of insulin in 1923; the second to Thomas Hunt Morgan for his early studies of genetics and inheritance, pioneering the use of Drosophila melanogaster (the fruit fly) for genetic research; and the third in 1934, for the cure of pernicious anemia, was shared by George Richards Minot, William Parry Murphy, and George Hoyt Whipple, to be discussed subsequently in this paper.
Following the Second World War, with the massive disruption and destruction in Europe and the establishment of the National Science Foundation and the expansion of the National Institutes of Health, the United States became the home of the most generously supported and largest biomedical research establishment in the world. From 1943 until the current time, over 70% of the laureates in physiology or medicine have been either native or naturalized US citizens.
In the pre-World War II period, 42 of the 45 laureates in physiology or medicine held a medical degree, and many practiced medicine. The Nobel Prize in Physiology or Medicine reflected successes in the late nineteenth and early twentieth century in conquering diseases caused by microbes and elucidating major physiologic functions of the body. Robert Koch, Paul Ehrlich, Élie Metchnikoff (one of only two Russian, more specifically Ukrainian, laureates in physiology or medicine), Jules Bordet, Ivan Pavlov (the other Russian), and Karl Landsteiner are only a few of the laureates on the list, which is a treasure trove of great European physicians of the late nineteenth and early twentieth century.
Following the Second World War, the awards began to focus on fundamental biochemical or molecular discoveries—including such areas as the physical and chemical basis of nerve conduction, the chemical basis of vision, investigations of tumor viruses, the genetic basis of atherosclerosis, the action of cell growth factors, the cellular origin of cancer genes, the fundamentals of bacterial or viral genetics, DNA replication in bacteria, the structure of DNA, the biosynthesis of DNA and RNA, pluripotential stem cell biology, basic elements of the immune system, and so on—making the direct benefit to mankind demanded by Nobel’s will less apparent to the lay observer and certainly less immediate.
Despite the focus on basic discoveries, at least two awards in the modern era were made to practicing physicians: the 1990 prize shared by Edward Donnall Thomas, an oncologist, and Joseph Edward Murray, a transplant surgeon, for the development of hematopoietic stem cell transplantation and renal transplantation, paving the way for liver, heart, lung, and other solid organ transplantation. The 2005 award was shared by a clinical pathologist, John Robin Warren, and an internist-gastroenterologist, Barry James Marshall, for the discovery of Helicobacter pylori and its role in gastric inflammation and peptic ulcer development. Later the organism was shown to cause gastric carcinoma and gastric mucosa-associated lymphoid tissue lymphoma.
One Nobel Prize in Physiology or Medicine was awarded for what proved to be erroneous research, the award in 1926 to Johannes Andreas Grib Fibiger, a Danish professor of pathological anatomy, who reported the discovery of a worm that caused cancer of the rat stomach, which he designated Spiroptera carcinoma. The lesions were later shown to be hyperplastic, not neoplastic.18 Remarkably, three reports that were contemporaneous with Fibiger’s showing that coal tar produced cancer of the skin of animals; that a putative cancer virus could transmit fowl tumors; and that Schistosoma haematobium infection can result in bladder cancer were overlooked.22 The discovery of a transmissible agent that caused fowl sarcoma by Peyton Rous was recognized by the Nobel Foundation approximately a half century later. Each of these three mechanisms of cancer initiation has stood the test of time.
A second prize may have been premature, and certainly controversial, namely the 1949 Nobel Prize in Physiology or Medicine to António Egas Moniz, a Portuguese neurologist, for the treatment of severe psychiatric disorders, especially schizophrenia, by prefrontal lobotomy.23 The prize was shared with Walter Rudolf Hess for his neurophysiological studies of the diencephalon. A notable victim of the lobotomy procedure was Rosemary Kennedy, sister of US President John Fitzgerald Kennedy, an attractive, interactive woman, whose functional state was converted to a vegetative state by the procedure inflicted on her at the insistence of her father in 1941.
Today, with a research establishment that spans the world and with several hundred accomplished nominees each year, it is very difficult to award the Nobel Prize in Physiology or Medicine to the most deserving scientist or physician. Indeed, laureates recognize that their work would not have been possible without the discoveries of other scientists whose work had not been recognized by the Foundation.24 A former chairman of the Nobel Foundation, Arne Tiselius, himself a laureate, in response to a query about how laureates are selected, indicated that one cannot in practice apply the principle that the Nobel Prize should be given to the person who is best; it is impossible to define who is best. Hence, there is only one alternative: to try to find a particularly worthy candidate.
The Nobel Prize in Physiology or Medicine awarded in 1934 for the treatment of pernicious anemia holds special significance for the University of Rochester School of Medicine and Dentistry, which was nine years old in 1934, the first post-Flexnerian medical school established in the United States, when its founding Dean, George Whipple, shared the prize for his work on the repair of anemia in chronically bled dogs and the importance of liver in the diet to repair the anemia most efficiently.25
In the late nineteenth and early twentieth century, patients in North America and Europe with an eventually fatal type of severe anemia were being described. The affected patients also had severe neurologic damage, and the outcome of the disease, although more protracted, was similar to adults with acute leukemia, invariably resulting in death. The patients often had pancytopenia, profoundly proliferative and dysplastic marrow cells, and neurological impairment. In 1908, Richard Cabot of Boston provided a comprehensive clinical description of the disease and an analysis of 1,200 patients. He found that survival after onset was 1 to 3 years.26 The anemia was referred to as “pernicious.”
In 1918, Whipple began his experiments on dogs bled to half normal hemoglobin levels. A basal diet of canned salmon and bread allowed periodic withdrawal of blood to maintain the low blood hemoglobin. If a diet was introduced that contained beef liver or muscle, hemoglobin production increased. Whipple and his co-worker, Frieda Robscheit-Robbins, published a paper in the American Journal of Physiology on blood regeneration and severe anemia in the 1920s that highlighted the favorable influence of liver in the diet on the regeneration of red blood cells in their dog model of anemia. They stated: “Liver feeding in these severe anemias remains the most potent factor for the sustained production of hemoglobin and red cells.”25 In publications in 1922 and 1925, Whipple encouraged physicians to consider dietary factors in the management of anemic patients based on his studies in dogs.25
In 1925, William Murphy had one year earlier gone into medical practice and was on the staff of the Peter Bent Brigham Hospital in Boston. He agreed to work with George Minot, who was a physician-investigator on the faculty of the Harvard Medical School and the Huntington Memorial Hospital, on a project to determine if a form of diet therapy could help patients with pernicious anemia, a disease in which Minot had a special interest. Minot’s view that a dietary factor may play a role in the development of pernicious anemia grew out of the notion that “good food makes good blood,” which was a general theme during the late nineteenth and early twentieth centuries. In 1926, Minot and Murphy astounded the world of medicine with the announcement at the meeting of the Association of American Physicians at its annual gathering in Atlantic City that they had cured the anemia in a series of 45 patients. These patients had been fed a special diet that contained up to one-half pound of lightly cooked beef liver, daily, for several months. This was an unappetizing diet, especially in patients seriously ill with loss of appetite and other gastrointestinal disturbances. Nevertheless, the effect of this discovery was not only to reverse the death sentence for these patients but to encourage and stimulate research concerning diseases of the blood.
Minot credited Whipple for highlighting the importance of nutrition as a potential factor in anemic patients and for focusing on liver. In their paper in the Journal of the American Medical Association in 1926, Minot and Murphy reported the salutary effects of liver feeding in pernicious anemia patients. Minot’s and Murphy’s paper had several references to Whipple’s and Robscheit-Robbin’s work and one reference to their own prior work, although none of these prior reports had anything to do with dietary treatment of pernicious anemia.27
Some observers felt that Whipple’s role was not consequential enough to merit his sharing the prize. In a monograph entitled Anemia in practice: Pernicious anemia, written by Murphy and published in 1939, he wrote in his chapter entitled “The Introduction of Liver Therapy” that,
It became our task then to prove the practicability of an idea which had up to this time received no intensive study or definite confirmation. Some years previously Whipple and his co-workers had demonstrated that liver had a rather unusual value for the production of hemoglobin in dogs made anemic by bleeding. Because this worked entirely with the production of hemoglobin as opposed to the maturation of erythrocytes, the latter being the problem chiefly concerned in recovery in pernicious anemia, because it was carried out entirely on animals, rather than human beings, and because the results of the study had no bearing upon or reference to pernicious anemia as observed in mankind, the study which we were to undertake was of a pioneering nature. No background evidence proved that it would be beneficial, except that a few patients who had been advised by Dr. Minot to ingest some liver together with red muscle meat, as part of their diets, had apparently remained in better health during short periods of time, than those who had not used liver.28
Whipple was studying the response of iron deficiency anemia produced by chronic bleeding of his dogs, whereas Minot and Murphy were later shown to be studying vitamin B12 deficiency. Liver was a rich source of iron and vitamin B12 and, thus, reversed the iron deficiency anemia in Whipple’s dogs and the anemia in humans with pernicious anemia by happenstance and for quite different reasons. Minot and Murphy did not know the pathogenesis of pernicious anemia, only that something in liver could reverse its expression. In the context of the late 1920s and early 1930s, this finding justified their selection. They cured a fatal disease. The reason liver feedings worked was that the daily requirement for vitamin B12 is minuscule, approximately one millionth of a gram per day. The vitamin B12 contained in liver is very large in comparison, and sufficient liver was eaten by patients to provide this minuscule amount of vitamin B12 across the intestinal wall by mass action in the absence of intrinsic factor in gastric juice, normally required for vitamin B12’s absorption.
In 1927 and 1928, a Harvard physician-scientist, William Castle, published a series of ingenious experiments in humans showing that a missing factor, secreted by the stomach, which he referred to as an intrinsic factor, was necessary for the absorption of something from food sources to maintain blood production and nervous tissue integrity, including the brain and spinal cord. The factor in food was referred to as the extrinsic factor, later found to be vitamin B12. It was much later determined that pernicious anemia was an autoimmune disease in which an autoimmunological attack was directed at the stomach lining cells leading to gastric atrophy and the inability to secrete hydrochloric acid and intrinsic factor, normal constituents of the gastric juice. Intrinsic factor is required to complex with vitamin B12 from food sources to permit that vitamin’s absorption in a specific area of the terminal small intestines. Some thought Castle should have shared the Nobel Prize with Minot and Murphy, not Whipple. Vitamin B12 was characterized in 1948 and intrinsic factor in 1961.
Minot had become a severe diabetic as a young adult. He was cared for in Boston by Elliot Joslin with a severely restricted sugar diet. Joslin later founded the Joslin Clinic, a pioneering institution for diabetic care. Minot was alive to make this contribution because of the discovery of insulin in 1922, for which the Nobel Prize in Physiology or Medicine was awarded in 1923 to Frederick Banting and John Macleod. The omission of Charles Best, Banting’s colleague in the laboratory, who was integral to the research as one of the awardees in 1923, angered Banting. This dispute was yet another controversy over a Nobel selection decision. Banting shared his monetary award with Best. Because of the long and arduous sea voyage to Stockholm, and an unfamiliar medical environment, a physician accompanied Minot to administer insulin, assist in his rigid low-sugar diet, and to attend to his diabetes, should it go out of control. This medical support allowed him to accept the prize in person, generally a requirement of the Nobel Foundation for receipt of the prize.
Many deserving scientists have been overlooked, too numerous to cite. The so-called forty-first chair is so designated because of the 40 places available in the French Academy; it represents the deserving scientists who just missed selection. For a short period after the establishment of the prizes, the Nobel Foundation published the names of runners-up or honorable mentions, but they stopped doing so. These holders of the forty-first chair include among them people who should have won the prize, but did not, in some cases because they died before their work was recognized as ground-breaking. Since 1974, a Nobel Prize may not be awarded posthumously. Only two prizes were awarded posthumously prior to 1974: one for peace and one for literature. One prize in physiology or medicine was made posthumously because the recipient, Ralph Steinman, working at the Rockefeller University, who discovered the dendritic cell and its function in the immune system, died a few days before the announcement of his selection in October 2011, unbeknownst to the Nobel Foundation. Having made the announcement not knowing he had died, the Foundation proceeded to make the award, posthumously, in that December.
One of the most notable omissions in the Nobel Prize for Physiology or Medicine was Jonas Salk.29 In 1955 the announcement was made that polio was conquered as a result of the singular efforts of Salk to develop, manufacture, and field test the first vaccine. Polio was a scourge in most industrialized countries. In the United States, summers were periods of terror for parents who often kept children from contact with playmates in camps, swimming pools, or sharing a water fountain, and applied other restrictions in the hopes of minimizing viral transmission. The vaccine made unnecessary the need to warehouse the numerous “iron lungs,” respirators used to ventilate children and young adults with “bulbar” polio, previously stored at the ready in most major hospitals for the summer polio season. In July 1960 one iron lung remained at the Strong Memorial Hospital, the University of Rochester Medical Center; it was used it to manage a young man with Guillain–Barré syndrome with respiratory muscle paralysis.
Salk’s work was viewed as applied and only a technical achievement (low-brow) by some of his influential peers. Perhaps, it was not “high science,” but who better would have fit Nobel’s desire to give the prize to someone who benefited mankind in the previous year? This achievement was among the most impactful on human health in the last 70 years. Salk was neither elected to the National Academy of Sciences nor to the American Philosophical Society, although the membership of both organizations included the country’s leading medical investigators.
Some Nobel Prizes in Physics or in Chemistry honored discoveries that later were seen to be important basic contributions to medicine. One of the most important was the initial Nobel Prize in Physics in 1901 given to Wilhelm Roentgen for his discovery of a new form of ray, which he called X-rays, using the mathematician’s symbol “X” for its then unknown properties. Few discoveries have had such a profound and lasting impact on medical diagnosis and therapy.
In 1962, Francis Harry Compton Crick, James Dewey Watson, and Maurice Hugh Frederick Wilkins shared the Nobel Prize in Physiology or Medicine for the elucidation of the structure of DNA. Another controversy in the selection of awardees surrounded the omission of Rosalind Franklin whose crystallographic images of DNA were instrumental in deducing its structure. Her X-ray diffraction pictures of DNA taken in a different physical state, not strictly crystalline, established the helical structure of the molecule and that its diameter indicated that it must be made of two intertwined chains. No scientist had imagined DNA had a multi-chained structure. She also corrected the erroneous belief that the phosphate-sugar backbone was in the interior of the molecule with the bases pointing outward. This information was essential for Watson and Crick to build their 3-dimensional model that met the most satisfactory configuration. Their landmark paper was published in the journal Nature in April, 1953, immediately followed in that issue by a paper by Wilkins and another by Franklin. They summed to confirm the double helical structure of DNA, each strand bound together by specific base pairing of nucleotides: adenine and thymine or cytosine and guanine. The paper by Watson and Crick was one page long, a model of brevity in scientific exposition. In retrospect, their paper may have been the most important contribution to the life sciences since Darwin’s book On the origin of species in 1859, 94 years earlier. Yet, it took the Nobel Foundation nearly a decade to honor its significance, by which time Franklin had died of ovarian cancer. She had not been nominated during her lifetime.
In 2013, 51 years after the award, the family of Crick, by then deceased, sold his Nobel Prize medal at auction to the CEO of a Chinese biomedical firm for over two million dollars.30 A seven-page letter by Crick to his 12-year-old son, explaining his discovery, which pre-dated the publication of the seminal paper in Nature, was sold to an anonymous buyer for over six million dollars, exceeding by two-fold the previous highest price paid for a letter of historical importance, one written by Abraham Lincoln opposing slavery.31 A year and a half later, James Watson sold his Nobel Prize medal for over four million dollars.32 The proceeds of both sales were intended to be shared with academic institutions important to the careers of both scientists.30,32