Elizabeth AbrashBy 1914, Dr. Joseph Goldberger had spent fifteen years fighting epidemics of yellow fever, typhus, dengue fever, and typhoid fever. These infectious diseases swept through populations, spreading from person to person, through contaminated water, mosquitoes, fleas, and lice. The resulting epidemics were devastating – in 1905, 900 people in New Orleans died from yellow fever. Fortunately, the recent acceptance of germ theory, which states that microorganisms (like bacteria and viruses) can cause disease, meant that doctors and scientists were better positioned than ever to diagnose, combat, and prevent infectious diseases. Therefore, in 1914, as an experienced physician and bacteriologist, Dr. Goldberger was an obvious choice to investigate the devastating epidemic from an unknow n disease sweeping across the southern United States.
Eight years earlier, in 1906, Dr. George Searcy of the Bryce Hospital for Alabama Insane had reported 88 cases of patients suffering from an unusual disease that he identified as Pellagra or the disease of four D’s: dermatitis, diarrhea, dementia, and sometimes death. Dermatitis was the most characteristic symptom – patients would develop a rash that eventually progressed into dark, scaly bumps over the arms, legs, hands, face, and neck – any skin that was exposed to the sun. But patients also exhibited diarrhea and mental deficiencies, ranging from difficulty concentrating to delusions. After this initial report, pellagra continued to be diagnosed in prisons, orphanages, asylums, and the general population. Between 1907 and 1911, there were nearly 16,000 cases across eight southern states, and by 1912, South Carolina alone had reported 30,000 cases; 40% of people who developed pellagra died.
By the time that Dr. Goldberger began his investigation into pellagra, theories about the spread and origin of the disease abounded. Some believed the disease to be hereditary. But the foremost theory was that it, like the other epidemics across the country, was caused by an infectious microorganism. This theory was supported by the results of the Thompson-McFadden Pellagra Commission, a privately funded study that concluded “[pellagra’s] spread seemed most rapid when sanitary disposal of waste was poorest, and that the disease occurred almost exclusively in people who lived in or next to the house of another person with pellagra” – therefore, it was most likely infectious.
However, Dr. Goldberger had a different idea. Although he visited towns throughout the south, it was during his visits to orphanages and asylums that he made a key observation, which he noted in The Etiology of Pellagra.
“It is striking therefore that although many inmates develop pellagra after varying periods of institutional residence…nurses and attendants living under identical conditions appear uniformly immune. If pellagra be a communicable disease, why should there be this exemption of the nurses and attendants? To the writer this peculiar exemption or immunity is inexplicable on the assumption that pellagra is communicable.”
After fifteen years of experience, Dr. Goldberger knew that infectious diseases did not discriminate on the basis of class or job status. Instead, he suggested that the underlying cause of pellagra was dietary. He noted that some institutions provided drastically different meals to their nurses and inmates, and even at the institutions that seemed to provide the same meals, the nurses had “the privilege – which they exercise – of selecting the best and greatest variety for themselves”. He also argued that this distinction held true in the general population. Pellagra was known to be “essentially rural” and “associated with poverty.” To answer the question of why the rural poor were particularly susceptible, Dr. Goldberger pointed to a 1909 report from The Office of Experiment Stations, which found that “on the whole the very poor of cities have a more varied diet than the poor of rural sections.”
This was not the first time that pellagra had been linked to diet. Although pellagra was a new diagnosis in the United States, it had been endemic to southern Europe and the Mediterranean for nearly 200 years. Don Pedro Casal was the first to describe the disease in 1735, and the characteristic rash around the neck still carries his name – Casal’s necklace. Like the US officials two centuries later, Casal noted that the disease was associated with poverty. He also noted that the “pellegrins” ate mostly cornmeal. While corn (or maize), native to the Americas, had been introduced to Europe in 1493, it took a while for large-scale cultivation to take off. But by the mid-1600s, corn cultivation had spread, and cornmeal had become a major source of calories for poor people across the world. And where corn went, pellagra followed. As a result, many prevailing theories blamed spoiled corn for the disease, although no one was able to prove it.
Dr. Goldberger had a different idea – rather than a toxin in the corn, he proposed that people suffering from pellagra were lacking a vital nutrient. In September of 1914, Dr. Goldberger commenced his first pellagra experiment; he used federal funds to provide orphans and inmates across three institutions with varied meals that included more fresh food. Patients who were suffering from pellagra recovered, and no new cases occurred while the diet continued. In fact, some inmates improved so much that their dementia cleared, and they were released. For his next experiment, Goldberger took the opposite approach – he found eleven inmates at a prison without any pellagra cases and, in exchange for a pardon, put them on a limited diet similar to that in the rural south. Six of the prisoners developed pellagra.
Despite his resounding results, many Americans were not willing to accept Goldberger’s dietary explanation. On the one hand, Charles Davenport, founder of the Eugenics Record Office, was determined to show that pellagra was due to “constitutional, inheritable” traits. As a result of his efforts, many people believed that pellagra was due to “differences in hereditary susceptibility” rather than diet. On the other hand, Goldberger faced cultural resistance – Southerners didn’t appreciate a Jewish, New York doctor criticizing their way of life. Goldberger’s results were questioned, and he was accused of spreading propaganda about pellagra. The Memphis Commercial Appeal insisted that the South would deal with pellagra in a “manly and courageous way”, which apparently included refusing offers of free meat and condensed milk. It was easier for people to blame microorganisms for their problems rather than their diet.
Determined to prove that pellagra was not infectious, Dr. Goldberger followed a course of action that would be frowned upon (and forbidden) in today’s research atmosphere. He hosted “filth parties” where he actively tried to infect his guests and himself with pellagra. Dr. Goldberger was no stranger to infecting himself – in Philadelphia, he successfully identified the mite responsible for Schamberg’s disease by shoving his arm into questionable mattresses, contracting the disease, and extracting the mite. So, he was probably the most enthusiastic participant at his parties, where he and his guests injected and consumed the blood, skin scabs, urine, and stool of pellagra patients. The partygoers may have suffered from nausea, but none of them contracted pellagra. That same year, the Thomas-McFadden Commission reiterated their belief that pellagra was an “infectious disease caused by poor sanitation”. Not to be deterred, Dr. Goldberger, along with economist Edgar Sydenstricker, spent five years gathering data on pellagra, diet, and living conditions. They ultimately found an inverse correlation between income and pellagra – the poorer you were, the more likely you were to get pellagra.
There was another hurdle. Even for people who believed that pellagra was caused by diet, the proposed treatment – regular access to fresh food – was too expensive to gain much traction. So, Dr. Goldberger turned to lab experiments. After testing a variety of foods, Dr. Goldberger published a report in 1925 stating that dried brewers’ yeast was able to treat both a pellagra-like condition in dogs (black tongue) and pellagra in humans – 25 of his 26 human patients recovered. In 1927, his findings were put to another test. A flood from the Mississippi River destroyed crops and led to an outbreak of pellagra, which was successfully treated with brewers’ yeast for 3 cents per day.
For 11 years, from 1914-1925, Joseph Goldberger worked tirelessly to combat the devastating pellagra epidemic. Despite his evidence, self-experimentation, intensive study designs, and proof of treatment, Americans largely rejected his findings, and deaths from pellagra continued to rise, peaking in 1930 (Figure 1 at the link).
Dr. Goldberger died in 1929 before his findings were truly accepted and before identifying the missing nutrient that caused pellagra. But his research laid the groundwork for the discovery. In addition to brewers’ yeast, Dr. Goldberger had reported that liver extract was able to cure black tongue in dogs. In 1937, Dr. Conrad Elvehjem took that discovery further by purifying liver extract and testing each fraction as a treatment for black tongue. Ultimately, he identified a molecule that cured black tongue. At the time, it was known as nicotinic acid; today, we call it niacin or vitamin B3. In humans, niacin could “(a) cause fading of the fiery red lesions…(b) restore to normal disturbed gastrointestinal function, (c) restore to normal the mental function.”
Once consumed, cells convert niacin into its main active form, a coenzyme called NAD (nicotinic adenine dinucleotide). A coenzyme is a molecule that is required for certain proteins (enzymes) to perform cellular processes. NAD is a coenzyme in over 400 reactions – more than any other vitamin. Most of these reactions are involved in converting the energy from fat, carbohydrates, and protein into a form that cells can use. When a diet lacks enough niacin, the body struggles to convert food into energy. This impacts every part of the body, but it is most obvious in the areas that require the most energy – the skin (dermatitis), the gut (diarrhea), and the brain (dementia).
Many foods contain bioavailable niacin: animal products (meat, fish, and dairy) as well as nuts, legumes, and some whole grains. In other grains – like corn – the niacin is bound to other molecules so that it cannot be absorbed by cells. Foods that are high in the amino acid tryptophan, like turkey and milk, provide another avenue to niacin, because cells can convert tryptophan to niacin. Herein lies the answer to a question that must have puzzled epidemiologists.
Epidemics of pellagra spread across the world, from the United States, to Europe and Egypt and beyond – closely following the cultivation of corn. But the people of Central and South America, the original corn cultivators, rarely suffered from pellagra despite their corn-rich diet. This is because the traditional method of processing corn in these regions includes a step called nixtamalization, in which corn is soaked overnight in water that contains lime (the mineral, not the citrus). Nixtamalization removes the hard outer husks from kernels, improving the taste and texture of corn products. But it also makes nutrients in the corn more available. Some reports state that nixtamalization releases bound niacin, allowing it to be absorbed by the body. But experiments in cats, who cannot convert tryptophan to niacin, indicate that the increased availability of tryptophan after nixtamalization is responsible for preventing pellagra in Central and South America. If the process of nixtamalization had been exported along with corn, epidemics of pellagra may have been avoided completely.
Today, cases of pellagra are practically unheard of in the United States. Cases dropped dramatically after 1930 and by 1955, they were a problem largely relegated to the past. A number of factors influenced this change: crops diversified and led to a more varied diet in the rural south, refrigeration spread and allowed fresh food to be stored for longer, and laws were passed requiring commercially produced breads, cereal products, and baby formula to be fortified with bioavailable niacin. Despite the advances that many countries have made in preventing pellagra, outbreaks can still occur in non-industrial countries, particularly in emergency-affected populations, such as refugees. Still, much as germ theory positioned scientists and public health officials to combat infectious diseases, understanding the root cause of pellagra has allowed communities to prevent, cure, and even eliminate the disease. While politics prevented Dr. Goldberger from ending the US pellagra epidemic in his lifetime, his research ultimately went further by removing it from the American consciousness entirely.
Peer Editors: Rachel Sharp and Luvna Dhawka