From Factor P-P to Niacin: Goldberger's Legacy

Joseph Goldberger died of kidney cancer in Washington on 17 January 1929. By then he had shown, through diet trials in orphanages and an asylum, a prison-farm experiment, self-inoculation tests and a house-by-house survey of cotton-mill villages, that pellagra was a disease of diet and not of germs. He had also found that fresh meat, milk and, above all, cheap dried brewer’s yeast held something that prevented it, a substance he called factor “P-P” (pellagra-preventive). What he never learned was what that substance actually was.

This page follows the story after his death: how pellagra faded in the 1930s for reasons that had as much to do with cotton prices as with science, how a Wisconsin biochemist identified the P-P factor as nicotinic acid in 1937, how the amino acid tryptophan turned out to be the other half of the answer, how wartime enrichment of flour ended the American epidemic, and how historians and epidemiologists have weighed Goldberger’s work since. It closes with where pellagra is still found today and with niacin’s unexpected second career as a drug. The experiments themselves and the food tests of the 1920s are told on the wing’s other pages.

Table of Contents

  1. Pellagra’s Decline in the 1930s
  2. Elvehjem and Nicotinic Acid (1937)
  3. The First Nicotinic Acid Treatments
  4. Tryptophan, the Hidden Half of the Answer
  5. Enriched Flour and the End of Endemic Pellagra
  6. Goldberger as an Epidemiologist
  7. Poverty, Race and Gender in Historians’ Eyes
  8. Pellagra in the World Today
  9. Niacin’s Later Career in Medicine
  10. Goldberger’s Place in Nutrition History
  11. Key Research Papers
  12. Connections

1. Pellagra’s Decline in the 1930s

When Goldberger died, pellagra was still a mass disease of the American South. The historian Harry Marks puts the toll at no fewer than 100,000 deaths in the southern United States between 1900 and 1940, and at its peak the disease was killing thousands of people a year across the southern states. Goldberger had shown how to prevent it, but knowing the cure and delivering it were different problems. The neurologist and historian Douglas Lanska notes that the first prevention and treatment efforts proved inadequate because pellagra was tied to poverty: families living on cornmeal, fat pork and molasses could not simply buy milk and fresh meat, even after Goldberger and his colleagues showed that dried brewer’s yeast could cure or prevent the disease far more cheaply than a changed diet.

The turn, when it came, was economic as much as medical. In Lanska’s account, the Great Depression broke cotton as a viable cash crop. With cotton no longer worth planting on every acre, farmers diversified into other crops, gardens and livestock, and the monotonous diet that cotton tenancy had imposed began to loosen. Pellagra mortality fell abruptly in the early 1930s, before anyone knew the chemical name of the protective factor.

This is one of the quieter lessons of the pellagra story. Goldberger and his statistician colleague Edgar Sydenstricker had argued in 1920 that pellagra in the cotton-mill villages tracked family income and the local supply of fresh food. The 1930s decline is a large-scale version of that finding: when the economic structure that produced the “three Ms” diet (meat, meal and molasses) weakened, the disease weakened with it.

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2. Elvehjem and Nicotinic Acid (1937)

The breakthrough came from the University of Wisconsin, in the laboratory of the biochemist Conrad Arnold Elvehjem. Working with R. J. Madden, F. M. Strong and D. W. Woolley, Elvehjem concentrated liver extracts that cured black tongue in dogs and set out to purify the active substance. In 1937 the group announced in a short letter to the Journal of the American Chemical Society that nicotinic acid and its amide (nicotinamide) cured canine black tongue. The full paper, “The Isolation and Identification of the Anti-Black Tongue Factor”, followed in the Journal of Biological Chemistry in 1938.

A common shorthand says Elvehjem “discovered niacin”. That is not quite right. Nicotinic acid had been known to chemists for decades as a simple compound that could be made by oxidising nicotine, which is where its name comes from; it had even been isolated from rice polishings years earlier during the hunt for the anti-beriberi vitamin, without anyone recognising what it did. What Elvehjem’s group did was show that this already-known chemical was the anti-black-tongue factor, and so, by Goldberger’s chain of reasoning, the pellagra-preventive factor. In 2002 the Journal of Biological Chemistry marked the work in its “Classics” series, alongside Elvehjem’s earlier research showing copper to be an essential nutrient.

The dog that connected the two

The identification depended entirely on the animal model Goldberger had championed. In 1922 Goldberger’s colleague G. A. Wheeler, with Goldberger and Blackstock, had argued that the “Chittenden-Underhill” pellagra-like syndrome produced in dogs on restricted diets was the same as the black tongue known to veterinarians, and over the following years the PHS team used black tongue to test which foods carried factor P-P. Elvehjem’s group used the same dog disease as their assay: each fraction of liver extract was judged by whether it cured a dog. Without a reliable animal test, purifying a substance present in tiny amounts would have been close to impossible.

From “nicotinic acid” to “niacin”

Once the compound was going to be added to food, its chemical name became a problem: “nicotinic acid” sounded too much like nicotine. The name “niacin” (from nicotinic acid vitamin) was later adopted for the vitamin in food labelling, and today “niacin” or “vitamin B3” covers both nicotinic acid and nicotinamide. The site’s Vitamin B3 history page tells that naming story in more detail.

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3. The First Nicotinic Acid Treatments

Human trials followed within months. In 1938 the physician Tom Spies reported in the Journal of the American Medical Association on the use of nicotinic acid in the treatment of pellagra, one of several clinical reports from that period. The responses in individual patients were striking: the inflamed, sun-exposed skin, the sore red tongue, the diarrhoea and the mental confusion of pellagra could improve quickly once the missing factor was supplied.

Yet Lanska makes an important historical point: dramatic as these individual recoveries were, giving nicotinic acid to patients had relatively little impact on pellagra illness and death across the population. Treating a person who already had pellagra did nothing for the hundreds of thousands still eating the diet that caused it. The decisive change would come not through clinics but through the food supply.

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4. Tryptophan, the Hidden Half of the Answer

The identification of nicotinic acid solved one puzzle and opened another. Milk, a classic pellagra-preventive food in Goldberger’s trials, contains rather little niacin. Corn, the food most closely tied to pellagra, is not especially poor in niacin by simple chemical measurement. If niacin alone explained pellagra, these facts did not fit.

The answer came from Wisconsin again in the mid-1940s. Willard Krehl, working in Elvehjem’s department, was part of the group that found that the amino acid tryptophan could prevent niacin deficiency in animals fed corn-based diets. The body can convert tryptophan into niacin. Milk protein is rich in tryptophan, which explains its protective power; corn protein is notably poor in it. Krehl later recounted the discovery in a 1981 symposium paper on the effect of tryptophan on niacin deficiency.

In the 1950s Grace Goldsmith and her colleagues measured the niacin requirement of human volunteers on wheat and corn diets low in tryptophan, putting numbers on how much each source contributed. Out of this work came the idea of “niacin equivalents” still used in nutrition tables, which count both the niacin in food and the niacin the body can make from its tryptophan. The conversion is inefficient: nutrition tables count roughly 60 milligrams of dietary tryptophan as the equivalent of 1 milligram of niacin.

Goldberger was half right in 1922

This finding gave a curious twist to Goldberger’s own thinking. In 1922 he and W. F. Tanner had proposed that an amino-acid deficiency was probably the primary cause of pellagra. They later moved toward the idea of a distinct P-P factor, which turned out to be niacin. In Lanska’s summary, by the 1940s and 1950s pellagra was reformulated as a deficiency of niacin and its amino-acid precursor tryptophan. Both of Goldberger’s hypotheses had captured part of the truth.

Why lime-cooked corn protects

The other half of the corn puzzle lies in how corn is prepared. Much of the niacin in corn is chemically bound and poorly absorbed. The traditional Mesoamerican method of cooking corn in an alkaline lime solution, called nixtamalization, releases that bound niacin, which is why peoples who had eaten maize for thousands of years were not plagued by pellagra. The food scientists Suri and Tanumihardjo note that for niacin, processing of this kind is actually necessary for the nutrient to become available. The wing’s corn and yeast page tells this part of the story, and the site’s tryptophan and niacin synthesis page explains the biochemistry.

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5. Enriched Flour and the End of Endemic Pellagra

The step that finally ended pellagra as a mass disease in the United States was fortification. Once nicotinic acid could be manufactured cheaply, it could be added to the staple foods poor families already ate, with no change in habits required. During the Second World War, American flour and bread came to be enriched with B vitamins, niacin among them. Lanska concludes that vitamin fortification of foodstuffs during the war ultimately eradicated endemic pellagra in the United States.

The sequence matters. Goldberger had shown that pellagra could be prevented by diet, and his own 1923 report on institutional inmates concluded, in words quoted by the epidemiologist Alfredo Morabia, that “Pellagra may be completely prevented by diet.” But changing the diets of millions of tenant farmers and mill workers was beyond the reach of a small federal research unit. Enrichment achieved the same result by a different route: instead of changing what people ate, it changed what was in what they ate.

Upstream prevention

This is the point the epidemiologist John Frank draws out in a 2022 paper that re-reads the pellagra epidemic through the framework of the British epidemiologist Geoffrey Rose. Rose’s dictum, quoted by Frank, was “Seek the causes of (population) incidence, not of (individual) cases.” Frank uses the pellagra epidemic in the southeastern United States from 1900 to the 1940s to illustrate the full range of prevention, from treating sick individuals to reshaping the conditions that make a population sick, and argues that it still has much to teach about controlling modern non-communicable diseases. In this reading, nicotinic acid in the clinic was downstream care; cotton’s collapse, crop diversification and enriched flour were upstream prevention.

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6. Goldberger as an Epidemiologist

In 1994 Joann Elmore and Alvan Feinstein, both of Yale, published a paper in the Annals of Internal Medicine titled “Joseph Goldberger: an unsung hero of American clinical epidemiology.” They described how pellagra had been widely believed to be infectious, how severe “pellagraphobia” left victims and their families shunned, and how Goldberger’s research corrected the belief in an infectious cause and led to the elimination of pellagra epidemics in the United States.

What impresses epidemiologists is the range of methods Goldberger brought to a single question. Lanska summarises it: from 1914 to 1929 Goldberger completed well-designed epidemiologic investigations, tested theories with human experiments, and used an animal model, all strongly supporting a dietary explanation over the prevailing toxic and infectious theories. Observation (staff in institutions never caught pellagra from inmates), intervention (diet changes in orphanages and an asylum), experiment (the Rankin prison-farm diet and the transmission tests) and population survey (the cotton-mill villages) all pointed the same way.

Two investigations of the same villages

In 2014 Mooney, Knox and Morabia compared two investigations carried out in the same South Carolina cotton-mill country: the privately funded Thompson-McFadden Pellagra Commission, which concluded in 1912–1914 that pellagra was probably infectious, and Goldberger’s 1916 survey with Sydenstricker and Wheeler, which linked it to diet and income. Their paper uses the contrast to examine how study design and the questions asked shape the answer reached. Goldberger’s team collected detailed household diet records and income data, which let them see the dietary pattern the earlier work had not measured.

Morabia has also written on the orphanage and asylum trials as an early example of controlled prevention research, noting the comparison between wards that received the new diet and wards that did not. The wing’s experiments page describes these studies in full.

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7. Poverty, Race and Gender in Historians’ Eyes

Not every historian has written about Goldberger’s circle in heroic terms. The most pointed critique comes from Harry Marks, in a 2003 paper in the Journal of the History of Medicine and Allied Sciences on the epidemiology of Edgar Sydenstricker, Goldberger’s statistical partner. Marks begins with two facts: at least half of pellagra’s victims in the South were African-American, and more than two-thirds were women. Contemporary observers, he writes, paid little attention to these gender and racial differences in their analyses.

Marks argues that Goldberger and Sydenstricker located pellagra in the political economy of cotton monoculture, an analysis that was powerful but came at a price. In his reading, the methods Sydenstricker carried over from political economy, built around the household and its income, obscured the role of gender inequality within households, and the focus on economic underdevelopment led him to overlook the prominent place of African-Americans among pellagra’s victims. Marks concludes that research methods and traditions, no less than open ideology, helped maintain the subordinate social position of women and African-Americans in the South.

The Commission and the cost of delay

A second line of historical writing concerns the years before and around Goldberger’s arrival. Bryan and Mull, writing in 2015, reconstruct how the Surgeon General Rupert Blue and the British physician Fleming Sandwith had articulated a “vitamine” explanation of pellagra in 1912, drawing on Casimir Funk’s new vitamine idea, before Goldberger took up the problem. They argue that the infection theory, and the resistance to the dietary explanation drawn from the Thompson-McFadden Commission’s conclusion, delayed acceptance of the dietary cause, and in their view this cost thousands of lives. That judgement is theirs; Mooney and colleagues treat the Commission’s work more as a case study in how study design shapes conclusions.

Subjects and consent

Historians have also noted who the subjects of the pellagra research were: orphaned children, women in a state asylum, and prison inmates offered pardons in return for volunteering. These facts are part of the record and are described plainly on the experiments page.

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8. Pellagra in the World Today

Pellagra is now rare in wealthy countries, but it has not disappeared. Dermatologists still describe it by the “four Ds”: dermatitis, diarrhoea, dementia and, at the worst, death. A 2004 review by Hegyi, Schwartz and Hegyi and a 2011 review by Wan, Moat and Anstey both describe the characteristic rash: a darkened, symmetrical dermatitis on sun-exposed skin. Wan and colleagues call pellagra generally accepted to have been the first photosensitivity syndrome described, and note that the mechanism behind the light sensitivity of niacin deficiency has still not been worked out. They also note that niacin deficiency leading to pellagra continues to be a health problem in some countries.

Where it is still seen

South Africa: a later epidemic

A 2021 scoping review by Viljoen, Bipath and Tosh traced pellagra in South Africa from 1897 to 2019. It was first officially recorded there in 1906, and its prevalence peaked after it had been all but eradicated in the United States and Europe. As in the American South, it was associated with poverty and an over-dependence on maize, with alcohol misuse a possible contributing factor. Urinary studies in the 1960s and 1970s suggested widespread subclinical niacin deficiency, especially among Black South Africans disadvantaged under apartheid. Reports declined by the late 1980s and early 1990s and hardly any cases were reported by 2000, though the authors note that this does not rule out subclinical deficiency. The site’s pellagra page covers the disease itself.

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9. Niacin’s Later Career in Medicine

The vitamin that Goldberger hunted as factor P-P went on to a second life as a drug, at amounts far above those needed to prevent pellagra. In 1955 the Canadian researchers Rudolf Altschul, Abram Hoffer and J. D. Stephen reported in Archives of Biochemistry and Biophysics that nicotinic acid lowered serum cholesterol in human subjects. The cardiologist William C. Roberts, in a 2019 editorial in the American Journal of Cardiology that runs from pellagra and Goldberger to atherosclerosis, describes niacin as the first lipid-altering drug.

Hoffer, one of the 1955 authors, also became known for his use of niacin in psychiatry, which is described on the site’s Abram Hoffer page. The mental symptoms of pellagra, the “dementia” of the four Ds, had brought pellagrins into Southern asylums in Goldberger’s day, among them the Georgia State Sanitarium where he ran one of his diet trials.

From historical curiosity to therapeutic question

Writing in 2011, Wan and colleagues noted that niacin had been shown to lower blood pressure in hypertensive patients and to reduce cardiovascular events when combined with a statin, and that it had therefore moved from being of mainly historical interest as the treatment for pellagra to a compound with possible relevance to modern therapeutics. How well that promise held up became a question for later large outcome trials. The doses involved in these drug uses are a separate matter from the small amounts in food, and pharmacological amounts of nicotinic acid have well-described side effects such as flushing. The site’s Vitamin B3 page covers niacin in modern use.

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10. Goldberger’s Place in Nutrition History

Goldberger belongs to a small group of investigators who proved that a mass disease was caused by something missing from food. Christiaan Eijkman and Gerrit Grijns in Java traced beriberi to polished rice; Frederick Gowland Hopkins argued for “accessory food factors”; Edward Mellanby linked rickets to diet. Goldberger did the same for pellagra, but in an unusual setting: not a laboratory or a colonial garrison, but the orphanages, asylums, prison farms and mill villages of the American South, using the methods of a public health officer.

His achievement was to prove the dietary cause and identify the foods that prevented it, years before the chemistry caught up. Every later step depended on his groundwork: Elvehjem’s identification of nicotinic acid relied on the black-tongue dog model Goldberger’s team had established, the tryptophan work echoed his own 1922 amino-acid hypothesis, and wartime enrichment put into practice his conclusion that pellagra could be prevented by diet. The generation that followed told the story in their own histories, among them the pellagra clinician Virgil Sydenstricker in 1958 and W. H. Sebrell Jr. in 1981.

What the story shows

Goldberger died eight years too early to see factor P-P named. But the chain he began in 1914, from a disease blamed on germs to a vitamin added to every loaf of enriched bread, is one of the clearest examples in medical history of a disease ended by understanding what people ate. The life and career page tells the story of the man himself.

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Key Research Papers

  1. Lanska DJ. Chapter 30: historical aspects of the major neurological vitamin deficiency disorders: the water-soluble B vitamins. Handb Clin Neurol. 2010;95:445-76. PubMed PMID: 19892133
  2. Elvehjem CA, Madden RJ, Strong FM, Woolley DW. Relation of Nicotinic Acid and Nicotinic Acid Amide to Canine Black Tongue. Journal of the American Chemical Society. 1937;59(9):1767-1768. DOI: 10.1021/ja01288a509
  3. Elvehjem CA, Madden RJ, Strong FM, Woolley DW. The Isolation and Identification of the Anti-Black Tongue Factor. Journal of Biological Chemistry. 1938;123(1):137-149. DOI: 10.1016/s0021-9258(18)74164-1
  4. Simoni RD, Hill RL, Vaughan M. Copper as an essential nutrient and nicotinic acid as the anti-black tongue (pellagra) factor: the work of Conrad Arnold Elvehjem. J Biol Chem. 2002;277(34):e22. PubMed PMID: 12185207
  5. Spies TD. The Use of Nicotinic Acid in the Treatment of Pellagra. Journal of the American Medical Association. 1938;110(9):622. DOI: 10.1001/jama.1938.02790090004002
  6. Goldberger J, Wheeler GA, Lillie RD, Rogers LM. A Further Study of Butter, Fresh Beef, and Yeast as Pellagra Preventives, with Consideration of the Relation of Factor P-P of Pellagra (And Black Tongue of Dogs) to Vitamin B. Public Health Reports. 1926;41(8):297. DOI: 10.2307/4577789
  7. Krehl WA. Discovery of the effect of tryptophan on niacin deficiency. Fed Proc. 1981;40(5):1527-30. PubMed PMID: 7011848
  8. Goldsmith GA, Rosenthal HL, Gibbens J, Unglaub WG. Nutrition classics. The Jouranl of Nutrition Volume 56, Number 3, July 11, 1955, pages 371-386. Studies of niacin requirement in man. II. Requirement on wheat and corn diets low in tryptophan. Nutr Rev. 1975;33(10):303-5. PubMed PMID: 1105248
  9. Suri DJ, Tanumihardjo SA. Effects of Different Processing Methods on the Micronutrient and Phytochemical Contents of Maize: From A to Z. Compr Rev Food Sci Food Saf. 2016;15(5):912-926. PubMed PMID: 33401800
  10. Elmore JG, Feinstein AR. Joseph Goldberger: an unsung hero of American clinical epidemiology. Ann Intern Med. 1994;121(5):372-5. PubMed PMID: 8042827
  11. Frank JW. Prevention and Control Strategies for Non-Communicable Disease: Goldberger, Pellagra and Rose Revisited. Epidemiologia (Basel). 2022;3(2):191-198. PubMed PMID: 36417251
  12. Morabia A. Joseph Goldberger's research on the prevention of pellagra. J R Soc Med. 2008;101(11):566-8. PubMed PMID: 19029358
  13. Mooney SJ, Knox J, Morabia A. The Thompson-McFadden Commission and Joseph Goldberger: contrasting 2 historical investigations of pellagra in cotton mill villages in South Carolina. Am J Epidemiol. 2014;180(3):235-44. PubMed PMID: 24966221
  14. Marks HM. Epidemiologists explain pellagra: gender, race, and political economy in the work of Edgar Sydenstricker. J Hist Med Allied Sci. 2003;58(1):34-55. PubMed PMID: 12680009
  15. Bryan CS, Mull SR. Pellagra Pre-Goldberger: Rupert Blue, Fleming Sandwith, and The "Vitamine Hypothesis". Trans Am Clin Climatol Assoc. 2015;126:20-45. PubMed PMID: 26330657
  16. Hegyi J, Schwartz RA, Hegyi V. Pellagra: dermatitis, dementia, and diarrhea. Int J Dermatol. 2004;43(1):1-5. PubMed PMID: 14693013
  17. Wan P, Moat S, Anstey A. Pellagra: a review with emphasis on photosensitivity. Br J Dermatol. 2011;164(6):1188-200. PubMed PMID: 21128910
  18. Prabhu D, Dawe RS, Mponda K. Pellagra a review exploring causes and mechanisms, including isoniazid-induced pellagra. Photodermatol Photoimmunol Photomed. 2021;37(2):99-104. PubMed PMID: 33471377
  19. Viljoen M, Bipath P, Tosh C. Pellagra in South Africa from 1897 to 2019: a scoping review. Public Health Nutr. 2021;24(8):2062-2076. PubMed PMID: 33769244
  20. Altschul R, Hoffer A, Stephen JD. Influence of nicotinic acid on serum cholesterol in man. Archives of Biochemistry and Biophysics. 1955;54(2):558-559. DOI: 10.1016/0003-9861(55)90070-9
  21. Roberts WC. From the Editor Pellagra, Osler, Roberts, Goldberger, the Atherosclerotic Diet, Niacin, the Beginning of the Atherosclerotic Epidemic, and the First Lipid-Altering Drug. Am J Cardiol. 2019;123(4):697-700. PubMed PMID: 30563617
  22. Sydenstricker VP. The history of pellagra, its recognition as a disorder of nutrition and its conquest. Am J Clin Nutr. 1958;6(4):409-14. PubMed PMID: 13559167
  23. Sebrell WH Jr. History of pellagra. Fed Proc. 1981;40(5):1520-2. PubMed PMID: 7011846

PubMed Topic Searches

  1. Goldberger and pellagra
  2. Pellagra history
  3. Black tongue and nicotinic acid
  4. Niacin deficiency and pellagra
  5. Nixtamalization and niacin

Further Reading

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Connections