The Vital Amines
Assembling the consensus on the necessity of vitamins.
This is Part 5 of a blogged essay “Steampunk Data Science.” A table of contents is here.
At the same time that Stephen Babcock was moving from New York to Wisconsin, Christian Eijkman departed the Netherlands for a new position in the Dutch Colony of Batavia. Eijkman would be credited with discovering Vitamin B, but his path to discovery was markedly different than the one taken in Wisconsin.
Eijkman was sent to Batavia, which we now know as Jakarta, to investigate the disease Beriberi. Plaguing much of Asia, beriberi caused nervous system disorders, including loss of the ability to walk and loss of reflexes. As was the style at the time, Eijkman was convinced beriberi was an infectious disease, and he set out upon a series of experiments to isolate the responsible germ.
Eijkman’s first attempts involved transfusing human blood into animals in the hope of inducing Beriberi. He first tried to infect monkeys, to no avail. He next experimented with rabbits but also failed to induce beriberi. His third animal model was chickens. Even in the 1800s, a non-mammalian test subject was outlandish, but chickens could succumb to a beriberi-like illness called polyneuritis, which caused a similar pattern of neural dysfunction. Moreover, Eijkman had grown frustrated with failures.
To his surprise and delight, Eijkman found that chickens often developed polyneuritis after receiving his beriberi transfusions. However, there was one perplexing glitch with his experiment: He observed an equal incidence of polyneuritis in the treatment and control groups. How was this possible? Eijkman tried and failed to cultivate the infecting substance from the afflicted chickens. None of the germ theory he had learned studying with Robert Koch could explain the outbreak of polyneuritis in his experimental fowl. Miraculously, in one of those mythologized moments of scientific luck, Eijkman happened upon an impossible answer by accident.
To save precious research funds, the lab assistant assigned to care for the chickens had been feeding them the leftover rice from the military mess hall adjacent to Eijkman’s facility. But the food supply was cut off after a new barracks chef, in Eijkman’s words, “refused to allow military rice to be taken for civilian chickens.” The lab keeper had to resort to purchasing bargain-basement brown rice for the chickens. Once the rice was switched, the chickens were cured of polyneuritis.
What was different about the barracks rice and the new civilian rice? The military rice was white. White rice is polished brown rice. Eijkman was convinced that something about the polishing turned the rice into a beriberi vector.
Unfortunately, he had no idea what that something was. He had a difficult time shaking the germ theory instilled in him by Koch. Perhaps polishing the rice allowed some bug to flourish in the white rice. Perhaps the brown rice contained something that killed an unknown pathogen. Determining what precisely was special about the brown rice would take decades.
Multiple investigations confirmed Eijkman’s observations over the subsequent years. For example, in 1897, Adolphe Vorderman observed that prisons that fed prisoners white rice had a considerably higher incidence of beriberi than those that fed brown rice. You might say that Eijkman’s observation in chickens had been “replicated” in humans in this observational study. But researchers at the time were as wary of confounding in non-interventional explanations as they are today.
It wasn’t until 1901 that an experiment seemed to definitively confirm that there was something valuable in the rice bran itself. Eijkman’s successor in Batavia, Gerrit Grijns, demonstrated that chickens would not develop polyneuritis on a diet of meat and rice bran. Grijns confidently (and correctly) declared there was something essential to the diet in the rice bran. It took another decade for scientific consensus to accept Grijns was right.
The case for vitamins would finally be closed by Casimir Funk, who wrote an audacious meta-analysis in 1912. In his report, he boldly claimed that beriberi, scurvy, and pellagra were all caused by the lack of some food substance in a person’s diet. Part of Funk’s evidence was epidemiological. He noted these afflictions only occurred in countries where people ate unvarying, monotonous diets, like those based on polished rice. However, not all monotonous diets were necessarily perilous. Russians who lived on a diet of cabbage, potatoes, and bacon seemed to avoid this cluster of illnesses. Some diets were missing yet-to-be-identified nutrients, and people couldn’t live without them. He called the missing components “vital amines” or “vitamines” for short.
Funk, a biochemist at the Lister Institute of Preventive Medicine in London, had been investigating the properties of rice polishing, his interest piqued by the findings from Indonesia. He devised multiple chemical mechanisms to extract the curative component from the discarded rice shavings. He found that it would take tremendous quantities of rice to yield tiny amounts of this substance, but only a small amount was required to cure pigeons of polyneuritis .
These experiments and the evidence from Asia convinced Funk. Germ theory, toxic theory, and hormonal theory were each insufficient to explain the evidence. Instead, Funk invented a new classification: deficiency diseases. He proposes that small changes in diet could reliably cure these diseases.
Wisconsin investigators McCollum and Davis soon confirmed Funk’s vitamin theory. Their fat-soluble compound could not sustain rats fed only polished rice. However, adding the water-soluble compound found in the rice polishings allowed the rats to thrive.
There are necessary for normal nutrition during growth two classes of unknown accessory substances, one soluble in fats and accompanying these in the process of isolation of fats from certain foodstuffs, and the other soluble in water, but apparently not in fats.
Thus, McCollum and Davis showed that multiple compounds were necessary to sustain the life of their rats, and these compounds were not proteins, fats, or carbohydrates. Having grown more adept with rat experiments, Davis now included a much more extensive collection of rodent growth curves, demonstrating the existence of at least two vitamins.
The fat-soluble vitamin was A. The water-soluble vitamin was B.1
Funk also called out Scurvy as a deficiency disease. Though the British Navy knew that scurvy could be treated with lemons, they did not understand its etiology at all. Axel Holst and Theodor Frolich had induced scurvy in guinea pigs by a deficient diet and then cured the condition using lemon juice or cabbage. Funk concluded that the vitamin associated with scurvy is distinct from that of beriberi, as it was much more sensitive to boiling. Though most were convinced that this evidence showed scurvy was a deficiency disease, Vitamin C would not be chemically isolated until 1928.
Funk went even further out on a limb. He asserted that Pellagra, a disease endemic to northern Italy, was also a deficiency disease. Pellagra was associated with starch-heavy diets based on corn. It wouldn’t be until two decades later, in 1937, that the associated vitamin would be discovered. Pellagra is caused by a deficiency of Niacin, also known as Vitamin B3.
In passing in the penultimate paragraph of his manuscript, Funk hypothesizes that Rickets, characterized by weakened bones and deformed legs, was also likely a deficiency disease. This hypothesis would also prove correct. Rickets is cured by vitamin D, a vitamin discovered in 1922 by McCollum. A year later, Harry Steenbock, another collaborator on the Single-Grain experiment at Wisconsin, found that Vitamin D could be synthesized by irradiating food with UV light and that this irradiated food cured rickets in mice.2
Though many now point to the serendipitous diet change in chicken as the “discovery” of vitamins, Funk’s assembly of 30 years of evidence and naming of a cause had more immediate impact. Funk’s theorizing flew in the face of germ theory and asserted something new. He completely revolutionized how we think about illness, as much as germ theory itself. The evidence had been piling up. People knew that treatments for these diseases involved dietary changes. The rodent studies assuredly pointed to particular necessary factors in food, but Funk was the first to put it all together and state it outright.
Once Funk formulated the concepts of vitamins and deficiency diseases, the rest of the scientific community jumped on board. They had a whole new way to think about what causes and cures illness. With sufficient dietary diversity, humankind was empowered to cure deficiency diseases plaguing large parts of the world.
This history of the discovery of Vitamin B in the Dutch colonies synthesizes Eijkman’s Nobel Prize address and the accounts of Carpenter, Combs and McClung, and Vandenbroucke. Combs and McClung’s text on vitamins also discusses Funk’s legacy in vitamins and his connection to McCollum and Davis. Griminger provides additional details about Funk’s biography.
Specifically, the vitamin whose absence causes beriberi is B1. Though they didn’t realize it at the time, nutritionists soon realized there were many water-soluble vitamins. We now have 12 named B vitamins, and all of them are water-soluble.
Steenbock would subsequently patent the method of irradiating milk to fortify it with Vitamin D. This patent would generate untold sums of money for the University of Wisconsin. It’s one of the earliest and most successful examples of Universities funding themselves through licensing their intellectual property.