5
Scientific knowledge advances haltingly and is stimulated by contention and doubt.
THE BIRTH OF A SCIENCE OF NUTRITION
There was no eureka moment when a single brilliant researcher discovered vitamins. Nobody deserves the sole credit. Rather, incremental advances punctuated distinct lines of research, and strokes of good luck alternated with bewildering wrong turns. Some investigators wore blinders formed by outmoded and inappropriate disease models. However, persistence and luck led to the eventual recognition of what we now take for granted: nutrients in foods present in only trace amounts are essential for health.
The systematic investigation of human nutrition began in 1815 when the French Academy formed the Gelatin Commission to find ways to feed the growing numbers of urban poor.1 The Gelatin Commission started with the belief that there are only two basic nutritional requirements: enough total calories to provide energy and adequate protein to repair tissues. If true, the poor could subsist on bread to provide the calories and any source of protein. The commission hoped that gelatin could provide that protein cheaply.
Gelatin is the product of boiling animal parts that are composed mainly of connective tissue—skin, tendons, hooves, and bones—in water or a weak acid. The boiling extracts the collagen protein from the tissues and makes it digestible. The Gelatin Commission hoped that after slaughterhouses stripped carcasses of meat to feed the well-off, gelatin prepared from the offal could feed the poor.
The chair of the Gelatin Commission, the noted physiologist Francois Magendie, performed a series of groundbreaking experiments between 1816 and 1841. He fed dogs restricted diets, including sugar alone, bread alone, gelatin alone, and bread and gelatin. Despite having as much food as they wanted, all the dogs fed these restricted diets lost weight and died. This surprised and disappointed the commission, as it meant that its supposition was wrong: bread and gelatin by themselves could not sustain life.
Even though he did not discover a cheap way to feed the poor, Magendie introduced two innovations that paved the way to the discovery of vitamins. First, he used animals as models of human physiology. He assumed that processes essential to life, such as nutrition, are similar in all mammals. Previously, animals had been used in nutrition research only in animal husbandry investigations. For example, investigators compared the amount of milk produced by corn-fed dairy cows to those fed barley. The Gelatin Commission wanted to understand the nutrition of people, not farm animals.
The second innovation was the use of simplified diets. Rather than feeding complete natural foods, such as grains or meat, Magendie fed the dogs refined sugar and gelatin. The animal experiments proceeded in parallel with advances in chemistry, mainly in Germany, that produced a more detailed understanding of the composition of foods. Researchers could exploit this knowledge to test chemically defined ingredients. The Gelatin Commission failed to feed the poor, but it began a line of investigation to define minimum nutritional requirements.
The experiments were simple in principle: feed the purified food components to groups of animals, weigh the animals periodically, observe their general health, and see how long they live. In practice, many details required attention. Did the animals in fact eat the food, or was it so unappetizing that they starved themselves? Did they eat enough at first but then tire of eating the same food day after day? Even if they ate the food, was it absorbed from the intestine or merely excreted in feces? How was the food prepared? Was it fresh or had it been stored for weeks? Had it been heated to prevent bacterial growth? Rigorous experiments demanded labor and resources. Researchers paid variable attention to the crucial details.
A MEDICAL STUDENT MAKES A BIG DISCOVERY
From the time of the Gelatin Commission until the turn of the twentieth century, the infant science of nutrition grew into a major scientific effort and attracted public attention. Continuing the line of research initiated by Magendie, investigators found that animals required a mixture of protein, fat, carbohydrates, inorganic salts, and water to survive. Chemists measured the energy content of foods, expressed in calories. Physiologists exploited advances in chemistry to study diets of purified nutrients to define minimum nutritional requirements.
Nikolai Lunin, a Russian medical student working at the University of Basel in Switzerland, made a major advance.2 He knew that mice could live indefinitely fed only whole cows’ milk. Lunin’s innovation was to separate the milk into its major known components: casein (the main milk protein), milk fat, lactose (the sugar in milk), and inorganic salts. He then mixed them back together and fed the mixture to mice. The mice all died in a few weeks. In the process of purifying the major components of milk, Lunin had lost something that was present in only small amounts but that his mice required to live. In his 1881 paper, he concluded, “a natural food such as milk must therefore contain besides those known principal ingredients small quantities of unknown substances essential to life.”
This was a revolutionary insight. Lunin was the first to recognize the existence of essential nutrients present in natural foods but not present in their purified major ingredients. If anyone deserves sole credit for the discovery of vitamins, it is Lunin. His was the first mention in the medical literature that a disease could be caused by the lack of a nutrient other than carbohydrates, protein, and fats. We now term this class of substance micronutrients and Lunin deserves credit for their discovery.
The work of this Russian medical student attracted little attention, even though he worked in the laboratory of the noted physiologist Gustav von Bunge, who referred to the work in his widely read textbook. For almost three decades, no one searched for what Lunin had lost when he split the milk into separate components.
SCIENCE IN THE JUNGLE: BERIBERI
The next breakthrough came not from university laboratories in Europe but from a military outpost in Indonesia. During the nineteenth century, tropical beriberi had become common in regions where white rice was the staple of the diet: Southeast Asia, India, Japan, and the Philippines.3 The disease, now known to result from a deficiency of the B vitamin thiamin, produced degeneration of the peripheral nerves, beginning in the legs and causing weakness, muscle wasting, and numbness. As the disease progressed, the legs and abdomen swelled, and eventually the victim died of heart failure. By the late nineteenth century, beriberi had become a cause of death equal to infectious diseases in South Asia.
A kernel of rice has three layers: an outer, indigestible husk, several layers of cells that form a thin silverskin, or bran (the pericarp), and the white core (the endosperm). The germ, the actual seed, is at the base of the core. Grinding off the husk, leaving the core and a layer of silverskin produces brown rice. Polished white rice requires grinding off the silverskin, an outer layer of cells of the core and the germ. The silverskin and the germ contain thiamin. The white core is almost entirely starch.
Most people preferred white to brown rice but polishing rice by hand with a mortar and pestle was laborious. Consequently, white rice was a luxury through the eighteenth century. With the invention of steam-powered milling machines in the early nineteenth century, white rice became cheap enough to replace brown rice as the main component of the diet in most Asian countries. As the Medical Research Council of Britain stated, beriberi became common in “rice-eating districts of the East when they had been invaded by milling machinery from the West.”4
Yet no one understood this at the time. After Louis Pasteur and Robert Koch discovered disease-causing bacteria in the 1870s, the germ theory dominated medical thinking, and investigators began looking for the germ that caused every mysterious disease. The prevailing wisdom was that beriberi occurred when people in some tropical countries became infected with a bacterium or parasite that produced a neurotoxin.
The first evidence that this was wrong came from a Japanese naval physician, Kanehiro Takaki.5 On returning to Japan in 1880 from medical studies in London, he noted that beriberi afflicted only common seamen, whose diet was mainly white rice supplemented with a little fish. Ships’ officers, who ate a more varied diet, never developed the disease.
Takaki understood that this was not the pattern of an infectious disease, which would have spread among all the men on a ship regardless of rank. He surmised that beriberi was the result of an inadequate diet, although he thought the deficiency was of protein.
Despite being wrong about what was lacking in the diet, he convinced the Imperial Japanese Navy to supplement the diet of common sailors with barley. This simple change in diet eliminated beriberi from the Japanese navy. As an example of the refusal of human beings to alter thinking in the face of evidence, most Japanese physicians continued to believe that beriberi was caused by an infection. The Japanese army refused to add barley to the diet, and the disease continued to kill its soldiers by the thousands.6 However, Takaki won naval honors and the nickname “Barley Baron.”
Doctors in Europe had not heard of Takaki. In 1886, Holland, following the conventional wisdom, dispatched Christiaan Eijkman to the island of Java to find the microbe that was causing the outbreak of beriberi in its Southeast Asian colonies.7 Eijkman was perfect for the job. He was a physician and physiologist who had worked with Robert Koch, the founder of microbiology.
In Java, Eijkman toiled in a bare-bones laboratory attached to a military hospital on the outskirts of Djakarta, then called Batavia. He conducted his initial experiments with rabbits, but he soon switched to chickens, probably because they were cheaper. He injected groups of chickens with the blood of beriberi patients, expecting it to transfer the causative microbe. He left control groups uninjected for comparison.
He made no progress, until suddenly in 1889, all his chickens, whether injected with patients’ blood or not, developed leg weakness and died. He performed postmortem examinations and found that the chickens suffered the same nerve degeneration as humans with beriberi. Being conservative, Eijkman was unwilling to assume that his chickens had developed beriberi, so he named the avian disease polyneuritis gallinarum, meaning inflammation of the nerves of chickens. Nonetheless, he had in fact produced an experimental model of tropical beriberi.
Sticking to his belief that beriberi was an infectious disease, he started over with new chickens and investigated the possibility that an airborne organism had killed the first group. After making no progress for a few months, he got another surprise. The disease mysteriously disappeared as suddenly as it had appeared. His chickens stopped developing leg weakness and remained healthy.
On further investigation, he discovered that the original practice in the laboratory had been to feed the chickens uncooked whole-grain rice, the cheapest form of rice. The chickens had their own milling mechanisms in their gizzards to remove the husks. However, the assistant responsible for the care of the chickens wanted to save even more money and arranged for the hospital cook to donate the polished white rice left over from feeding the patients. Shortly after this change in diet, the chickens developed nerve degeneration. A few months later, a new cook arrived and “refused to allow military rice to be taken for civilian chickens.”8 Returning to a diet of whole-grain rice, the chickens remained healthy.
Unwilling to abandon the germ theory, Eijkman tried to fit the data to the theory. He proposed that a toxin-producing microbe infected the rice kernel and that a substance in the bran was an antitoxin. He still thought that diseases had to be caused by some active agent—a microbe or a toxin. A negative factor, such as a nutritional deficiency, was alien to his way of thinking.
Despite his incorrect assumptions, he performed the correct experiments. He verified that a diet of only white rice led to the peripheral nerve degeneration and that the condition could be reversed by adding back the silverskin. He also showed that the material in the silverskin that protected the chickens was soluble in water.
Eijkman continued to work in Java until 1896, when he became ill with malaria and returned to Europe to assume a prestigious professorship at the University of Utrecht, the preeminent medical school of that time. He left Java still clinging to the germ theory and believing that beriberi was caused by a microbe.
Gerrit Grijns, a physiologist who had never worked directly with Eijkman, took over the work in Java and approached the problem with an open mind. He repeated Eijkman’s experiments with the same results. He also showed that carbohydrate diets other than white rice, including milk sugar and potato flour, led to nerve degeneration. These results made the infected rice theory unlikely.
Grijns recognized that beriberi was a nutritional disease and concluded that there was some essential, water-soluble nutrient in the bran that was missing in the milled grains. He finally convinced Eijkman of this obvious conclusion, which Grijns published in 1901.9
Working in an isolated hospital and using the most basic tools, these two researchers verified Lunin’s conclusion: even when provided adequate calories and basic nutrients, a deficiency of some unknown substance could lead to a fatal disease. Thus, they verified Lunin’s novel disease model and established another milestone in the history of nutrition research.
Eijkman won the Nobel Prize in Physiology and Medicine in 1929. He was too ill to travel to Stockholm for the award ceremony and sent a lengthy letter of acceptance as a substitute for a Nobel Prize address delivered in person.10 He did not mention his colleague Grijns, without whose insight Eijkman may have continued looking for a germ and never won any prizes.
PARADIGM SHIFT: A DIFFERENT KIND OF DISEASE
Thomas Kuhn in his influential essay The Structure of Scientific Revolutions, published in 1962, described the uneven nature of scientific progress.11 He used the word paradigm to refer to an accepted model of how nature functions. A paradigm includes both the theories and the experimental methods that are applied to expand and test the model. Isaac Newton’s laws of motion are an example of such a paradigm, and for more than two hundred years it guided astronomers in their observations and explanations of the movement of the planets and other heavenly bodies.
Kuhn pointed out that science does not progress smoothly. Rather, periods of “normal science,” guided by a reigning paradigm, are punctuated by sudden jumps, which he called paradigm shifts, revolutions in scientific thought that result in a new model and fresh ways of viewing a problem.* Albert Einstein’s theory of relativity was a paradigm shift in understanding the laws of motion. It led astronomers to analyze the movement of heavenly bodies in new ways, to ask new questions, and to design novel ways of observing the skies.
Between revolutions, “normal science” proceeds as investigators apply the reigning paradigm and perform experiments that fill the gaps of knowledge about old problems and explore new questions. Normal science proceeds until observations are made that the old paradigm cannot explain, requiring a new way of thinking, a new paradigm.
The work of Eijkman and Grijns is a prime example of a paradigm shift. Eijkman started out doing normal science in Java. He applied the reigning paradigm, the germ theory, to design and interpret experiments with his chickens. He did this until things happened to his chickens that the germ theory could not explain. He was eventually forced, by his observations and by the arguments of Grijns, to accept a new disease model, that of a nutritional explanation for beriberi. And this new model permitted breakthroughs in understanding other diseases. The first was scurvy.
SCURVY FINALLY EXPLAINED
In 1907, Norwegian naval authorities commissioned two researchers, Axel Holst and Theodor Frølich, to investigate the cause of ship beriberi, which was afflicting Norwegian sailors returning from the East Indies. Although the disease was not the same as tropical beriberi, Holst and Frølich set out with the assumption that it was. They first verified the findings of Eijkman and Grijns.12 They fed milled grain to pigeons and produced the same degeneration of peripheral nerves as Eijkman had produced in chickens.
They then tried to create a model of tropical beriberi in mammals by feeding guinea pigs a diet of milled grains similar to that which had produced nerve degeneration in pigeons. They never explained why they chose guinea pigs, but it was one of the strokes of luck that punctuated vitamin research. Guinea pigs, like humans, cannot synthesize vitamin C.
The cereal diet produced a fatal disease in the guinea pigs, but it was not beriberi. There was no degeneration of the peripheral nerves. Moreover, unlike avian beriberi, it made no difference if the guinea pigs ate white or brown rice. As long they ate only cereal grains, whether it was rice, barley, or oats, they developed the disease.
Holst and Frølich were not the first to produce this disease in guinea pigs. Theobald Smith, a physician and bacteriologist working for the U.S. Department of Agriculture, had done so in 1895 by feeding the animals a diet of oats and bran.13 The guinea pigs died with bleeding into deep tissues. If he supplemented their diet with grass, clover, or cabbage, the guinea pigs remained healthy.
Smith did not know what was killing his guinea pigs. His main interest was microbes that infect pigs, so he never followed up his observations. He went on to a distinguished career in microbiology. By discovering that insects could transmit infectious diseases, he became one of the first American medical scientists to achieve international recognition. But he missed his chance to discover the cause of scurvy.
Holst and Frølich did not waste their opportunity. They made the astute observation that their guinea pigs had abnormalities of the bones identical to those described in 1883 by Thomas Barlow in fatal cases of infantile scurvy. Furthermore, when the guinea pigs’ diet of grains was supplemented with lemon juice, apples, potatoes, or cabbage, the guinea pigs either did not develop the bone disease or showed only slight abnormalities.
Holst and Frølich correctly concluded that they had produced scurvy in the guinea pigs and that scurvy was a nutritional deficiency disease caused by a “one-sided diet” lacking in some essential substance or substances. They also found that cabbage heated in an autoclave for a half hour in pressurized steam at 120 degrees Celsius was less effective in protecting the animals than if only heated in unpressurized boiling water. Hence, they concluded that strong heating could inactivate the antiscorbutic factor, an observation that explained why citrus juice preserved by prolonged boiling and the canned foods fed to the Norwegian sailors were ineffective in preventing scurvy.
With their 1907 publication, Holst and Frølich at long last showed that scurvy was a disease caused by a restricted diet. The paradigm shift of Eijkman and Grijns bore fruit in understanding another disease. With the work of Holst and Frølich, suddenly much of the confusion concerning scurvy was swept away.
However, when a paradigm shift occurs, investigators who have invested their careers in the previous way of thinking may resist challenges to that model. Charles Darwin’s theory of evolution met strong resistance from many naturalists, and some molecular biologists resisted the concept that a protein, termed a prion, could cause infections even though it did not carry genetic information. Similarly, some researchers continued to question the conclusion of Holst and Frølich and continued looking for other explanations.14
Rats, which can synthesize vitamin C from glucose, do not develop scurvy if given the same diet that produces the disease in guinea pigs. This observation contributed to the confusion about the cause of scurvy. Some investigators refused to believe that there were fundamental differences in basic nutritional requirements among mammals, and they continued to seek other explanations. Meanwhile, more flexible minds explored the new paradigm.
VITAMINES AND VITAMINS
In 1912, an English scientist, Frederick Gowland Hopkins, published a paper that essentially repeated Lunin’s work. But unlike Lunin, Hopkins garnered attention from his fellow scientists.15Hopkins was a member of the British academic establishment. He was on the faculty of Cambridge University, having been educated at the University of London and Guys Hospital. Although the term “biochemist” did not exist at the time, he was in fact one of the first. He was interested in how cells generate their energy. This led him to study the effects of diet on the growth of young rats.
Possibly following up on the inability to find a milk substitute to feed infants during the Siege of Paris, Hopkins studied young, growing rats. Hopkins found that young rats fed a basic, chemically defined diet similar to that used by Lunin remained healthy for only two weeks, at which point they began to lose weight and died by about four weeks. When he supplemented the diet with a small amount of cows’ milk, less than half a teaspoon per day (less than 4 percent of the animals’ food), the young animals grew normally and survived to adulthood.
Like Lunin, Hopkins concluded that there was a substance or substances in milk essential for normal growth and survival of young animals, but it was required in only small amounts. In his 1912 paper, he termed these “accessory factors in normal dietaries,” which he later modified to “accessory food factors.”
The terminology became a matter of contention. Hopkins had a rival, Casimer Funk, a Polish-born chemist.16 Whereas Hopkins was a member of the Oxbridge elite, Funk was an outsider. As a Jew, he had to leave Poland to pursue his university education in Switzerland. Subsequently, whether as a cause or a result of his feelings of alienation, he continued to move around.
Funk became interested in nutrition while studying in Berlin with Emil Fischer, a pioneer of organic chemistry. There, Funk investigated the nutritional properties of proteins, a line of research that later led others to identify essential amino acids, those that could not be synthesized by mammals and are required in the diet.
In 1911, after moving to the Lister Institute in London, Funk took up beriberi research. Following on the work of Eijkman and Grijns, he set out to isolate the antiberiberi substance. Although he was unsuccessful in these efforts, he wrote a review article published in 1912, the same year as Hopkins’s landmark paper. In that paper, he proposed his deficiency theory of disease.17 He reasoned that diseases such as pellagra and rickets, beriberi and scurvy, were caused by a lack of a substance present in only small amounts in certain foods. In his review, Funk coined the term vitamine to refer to these substances. (He likely pronounced it veetameen.)
Funk’s coinage was a combination of vita, Latin for life, and amine, meaning a nitrogen-containing compound. He later termed the antiberiberi factor vitamine B. Funk thought these substances were all nitrogen containing—that is, amines—hence the final e. He did not have strong evidence for that assertion, so his term vitamine was controversial among nutrition researchers. It quickly caught on with the public and continued in common use until 1920, when through the diplomatic suggestion of another nutrition researcher, Jack Cecil Drummond, it was shortened to vitamin.18
F. Gowland Hopkins continued to take issue with this term, with or without a final e, and championed his terminology, “accessory food factors.” It is easy to understand why “vitamin” won out. The argument over terminology was a surrogate for claiming credit for the discovery of vitamins, which neither of them deserved. If anyone merited that distinction, it was Lunin, based on his work decades earlier. Nonetheless, a Russian medical student did not command the same respect as a Cambridge professor.
THE DEMANDS OF WAR
The outbreak of World War I gave nutrition research increased urgency. Beriberi devastated both British and Turkish troops during the disastrous Gallipoli campaign. British troops in India and the Middle East developed scurvy and got no help from the same preparation of lime juice that had failed the polar explorers. The military needed foods that were easy to transport, could tolerate both hot and cold climates, and could nourish the Allied soldiers fighting around the world.
On the British home front, men left their jobs to join the military, leaving women to step into leadership positions in science.19 Harriette Chick was one of those women.20 She was born in 1875 into an upper-middle-class London family with a legacy of independent women who had built the family’s lace business. Her father was a conservative Protestant fundamentalist, but he enrolled Harriette in a high school that was ahead of its time in teaching mathematics and science to girls. Harriette was a star student and, along with four of her sisters, was among only the second generation of women to attend a British university.
She studied botany at University College London and, after her undergraduate degree, did microbiology research. In 1904 she earned a doctor of science degree from University of London for work on algae in polluted waters. Subsequently, over the vehement opposition of two members of the all-male faculty, she won a fellowship to work at the Lister Institute for Preventive Medicine in London, the major scientific research institution in Great Britain prior to World War I.
She first worked on disinfectants and related protein chemistry, continuing her interest in microbiology. With the onset of war, almost the entire male staff at the institute left to join the army. To contribute to the war effort, Chick dropped her own research and moved to producing antisera to diagnose and treat battlefield infections. The director of the Lister Institute, Charles Martin, had gone to the Greek island of Lemnos to serve as pathologist in a military hospital. When he saw troops returning from Gallipoli suffering from beriberi, he asked Harriette Chick to hand over the routine antisera work to others and take charge of nutrition research at the institute. Casimer Funk had moved to the United States, opening the door for Harriette Chick to take over.
This was a turning point in Harriette Chick’s life. She took to the new assignment with gusto and became one of the most important nutrition researchers of the twentieth century. With colleagues Margaret Hume and Ruth K. Skelton, Chick carried out a series of meticulous feeding experiments to quantify the ability of various foods to prevent beriberi and scurvy.21 Unlike other investigators, these women cared for the animals themselves, feeding them by hand to ensure that they ate exactly what the experimental protocol prescribed.
They made several crucial observations. First, that lime juice prepared from limes from the West Indies, even when fresh, had only one-quarter the antiscorbutic potency of lemon juice prepared from Mediterranean lemons. They tested samples of the navy’s preserved lime juice and found that it lacked any antiscorbutic activity. They showed that the antiscorbutic value of other foods also decreased over time with storage and verified that it was destroyed by strong heating. They also quantified the antiscorbutic activity of a variety of fresh fruits and vegetables.
Alice Henderson, also at the Lister Institute, complemented these laboratory findings with a historical study of the use of anti-scorbutics in the Royal Navy.22 Her papers, published in 1919 after the war had ended, documented that scurvy had all but disappeared among British sailors when the navy provided them juice of Maltese lemons. However, in the 1860s, when the military switched to juice prepared from West Indian limes, scurvy reappeared among polar explorers and soldiers in the Middle East. The findings of Chick and Hume showed why that switch resulted in scurvy persisting more than four hundred years after the crew of Vasco da Gama recognized the curative effects of fresh fruit.
Most of the women who pursued science during World War I married and gave up their careers when the war ended. During that era, married women were virtually excluded from professional positions in Britain. Harriette Chick remained single and continued her work at the Lister Institute, going on to a distinguished career in nutrition research.
Her most important work concerned rickets, the disease that caused weak and deformed bones in children and is now known to result from a deficiency of vitamin D. She, along with colleagues from the Lister Institute, traveled to Vienna in 1919 and 1920 to study malnutrition in that war-ravaged city. Working in a children’s hospital, she showed that giving children cod liver oil or exposing them to sunlight or to an ultraviolet lamp prevented rickets.23 She continued to do nutrition research until her retirement in 1945. After that, she remained on the board of the Lister Institute and active in the Nutrition Society, to which she gave a talk two weeks before her hundredth birthday.
Chick’s discoveries concerning rickets were on par with the work of Eijkman in their impact on public health. Eijkman received the Nobel Prize, whereas Harriette Chick received little recognition beyond her professional circle. A pediatrician would most likely give a blank stare if asked about Harriette Chick.
HOLDOUTS
Some researchers could not accept the paradigm shift brought on by the nutritional deficiency hypothesis. One holdout was the prominent American physiologist, Elmer V. McCollum. He worked at the University of Wisconsin and later assumed the prestigious chair of the newly formed Department of Chemical Hygiene at Johns Hopkins University.
McCollum reported his discovery of the fat-soluble factor A required for the growth of young rats in a 1913 paper.24 Turning to scurvy research, he and his coworker W. Pitz produced the disease in guinea pigs but not in rats, and they did not believe that animal species would differ markedly in their nutritional requirements. Inexplicably, they also failed to prevent scurvy in guinea pigs fed a diet of oats and milk, a regimen that had been successful for Holst and Frølich.25
They found that their scorbutic guinea pigs had impacted fecal material in their colons and concluded in a 1918 publication that a toxin present in the impacted feces caused scurvy, concluding that the benefit of citrus juices resulted from the laxative properties of citric acid. However, when McCollum learned of the meticulous work of Chick and Hume, he realized his error and recanted.
THE VITAMIN ALPHABET
In 1913, the year after the publications of Hopkins and Funk, E. V. McCollum and Marguerite Davis at the University of Wisconsin published a paper showing that the substance or substances in milk that supported the growth of young rats in Hopkins’s experiments was present in the butterfat and was lipid soluble.26 The essential material was also found in egg yolk. Since it was lipid soluble, it was distinct from the water-soluble antiberiberi substance.
Hence, there was a fat-soluble substance in butterfat and egg yolk needed to support the growth of young animals, and there was a water-soluble substance found in the bran of grains (and also found in yeast) needed to prevent beriberi. These were initially termed fat-soluble A and water-soluble B, respectively, and later became vitamin A and vitamin B. Neither was the antiscorbutic substance.27
In 1919, Jack Cecil Drummond made the definitive pronouncement on the cause of scurvy.28 He and others had found that rats can grow on a diet of purified protein, butterfat, salts, and carbohydrates supplemented with yeast extract. Drummond showed that they grow slightly better if also supplemented with orange juice. Although the relation of these findings to scurvy is unclear, it convinced the remaining doubters that there was a “water-soluble C,” the antiscorbutic factor. Finally, after more than four hundred years of uncertainty, scurvy became universally accepted as a nutritional deficiency disease. And water-soluble C became vitamin C.
But these factors were more complicated than initially thought. The lipid-soluble material turned out to be a mixture of two substances. One retained the name vitamin A and the other became vitamin D, since C was already taken. And the material in bran and yeast was a mixture of several substances required for health. They all kept the name vitamin B but were given numbers in addition. The antiberiberi substance kept its first place in line as vitamin B1. The other B vitamins were associated with other diseases, mainly skin diseases and anemia, and were numbered two through twelve. A few dropped by the wayside, hence there are a total of eight B vitamins. Subsequently two more fat-soluble vitamins were discovered and termed vitamin E and vitamin K.
Vitamin C kept its place in the alphabet.
NOMENCLATURE AND NOBEL PRIZES
Through the first three decades of the twentieth century, the new science of nutrition was a major focus of medical research. In the Journal of Biological Chemistry and the Biochemical Journal, the primary journals of biochemistry, a sizable portion of articles during those years dealt with nutrition. It was then, as it is now, of great interest to the public. During World War I, it had taken on importance for the defense of nations. Hence, understanding vitamins offered researchers academic prestige and public recognition. It engaged the egos of many investigators and did not always bring out their best.
In 1906, the Cambridge professor F. Gowland Hopkins gave a speech to the Royal Society of Chemistry, mainly dealing with mundane administrative matters. Toward the end of the speech, he switched topics and predicted that rickets and scurvy were diseases caused by a lack of dietary “minimal qualitative factors.”29 This speech turned out to be important in the subsequent battles over credit for the discovery of vitamins. It is unclear at what point Hopkins turned to vitamin research in his own laboratory. He stated that his 1912 paper reported results “I obtained as far back as 1906–1907.” Funk took issue with this claim and said that prior to a conversation he had with Hopkins during the 1910 Christmas break, Hopkins had performed no experiments with milk. Funk implied that he had given Hopkins the idea for the nutrition experiments.
In his 1912 paper, Hopkins renamed the unknown substances in milk essential to the growth of rats “accessory food factors.” He admitted that he did not know the nature of these factors, but he offered three hypotheses. One was that they were substances that were not required for energy but were required for tissue repair. Second, they were substances required to synthesize other molecules, such as enzymes, that are essential for life. Third, and closest to the truth, they were substances that either served as catalysts or were required for the catalytic function of enzymes.
In the same year, Casimer Funk coined the term vitamine, later shortened to vitamin. Subsequently, he and Hopkins engaged in a long-running dispute. A Hungarian Jew outsider clashed against a bastion of the British academic establishment. The outsider won the battle over nomenclature, but he lost the war. The 1929 Nobel Prize in Physiology and Medicine went to Hopkins and Eijkman.
Eijkman was deserving, as he had explained the first disease, tropical beriberi, caused by vitamin deficiency and produced a paradigm shift. Hopkins’s contributions were less original. He essentially repeated the work of Nikolai Lunin. Other investigators, notably McCollum and Davis and Osborne and Mendel in the United States, did similar work around the same time as Hopkins.
Casimer Funk was nominated for the Nobel Prize, but he did not share it. Although in his review paper he had enunciated the concept of nutritional deficiency disease, his original experimental work was of minor importance, and he never could purify the antiberiberi factor. Inexplicably, Holst and Frølich did not win the Nobel Prize. Hopkins at least acknowledged them, along with Lunin, in his Nobel Prize lecture. However, he devoted most of his speech to disputing the priority claims of Funk.
To give Hopkins his due, he was instrumental in founding biochemistry as an academic discipline. He was to make another important contribution to vitamin C research. He mentored another scientist with a big ego, Albert Szent-Gyorgyi.
- *Although Kuhn’s essay was a major contribution to the history of science, it did a disservice to the language. Now almost every scientific publication, no matter how trivial, promises a paradigm shift.