The Genetotrophic Concept of Disease

“Genetotrophic” is one of the words Roger J. Williams invented. He joined genetic (what you inherit) to trophic (to do with nourishment) to name an idea he spent the second half of his career defending: that some diseases arise when a person’s inherited, unusually high need for one or more nutrients is not met by an ordinary diet. In his view such a person is not “abnormal” in any dramatic way. He or she simply needs more of something than the average person, eats the average diet, and slowly becomes deficient in a way no textbook would predict.

This page follows the idea as Williams and his University of Texas co-workers stated it: the urine and saliva studies that convinced them every person has a distinctive body chemistry, the first statements of the concept in 1949 and 1950, the fuller version in his 1956 book Biochemical Individuality: The Basis for the Genetotrophic Concept, the animal experiments of the 1950s and 1960s, the diseases he proposed as candidates, and the practical advice he gave. Quotations from the 1956 book were checked against a scanned copy of the first edition; quotations from his later books come from the selection of his writings kept by the University of Texas Biochemical Institute.

Table of Contents

  1. What “Genetotrophic” Means
  2. The Metabolic-Pattern Studies That Led There
  3. The First Statements, 1949–1954
  4. Partial Deficiencies and Several-Fold Differences in Need
  5. The Genetotrophic Principle, 1956 and 1965
  6. Evidence from Rats, Chicks and Inbred Strains
  7. Vitamin C: Guinea Pigs and the Tongue Test
  8. Diseases He Proposed as Candidates
  9. Ketosteroids and Breast Cancer, 1968
  10. Relation to Orthomolecular Medicine
  11. His Practical Advice: Nutritional “Insurance”
  12. Key Research Papers
  13. Connections
  14. Featured Videos

1. What “Genetotrophic” Means

Williams liked making new words when the old ones would not do. The National Academy of Sciences memoir by Donald R. Davis, Marvin L. Hackert and Lester J. Reed lists “genetotrophic” beside his other coinages: pantothenic acid, folic acid, avidin, nutrilite, isotelic and propetology. The word puts two things together that medicine usually keeps apart. Genetics was about inheritance and inborn defects. Nutrition was about the foods and vitamins that every member of a species needs. Williams argued that the two meet in every person, because heredity sets how much of each nutrient an individual needs.

A genetotrophic disease, as he defined it, is one that develops when that genetically set need is unusually high for some nutrient and the diet does not supply it. Jeffrey Bland, writing in 2019 about Williams and Linus Pauling, summed up the definition this way: a disease that occurs in an individual when the diet fails to provide enough of one or more nutrients that this person needs at higher levels because of his or her unique genetic make-up.

Two features made the idea unusual. First, the “cause” is shared between heredity and environment: the gene creates the high need, the diet fails to meet it. Second, the cure, if there is one, is environmental. Williams pointed out in 1956 that readers might take him for a “hereditarian” because he stressed inheritance chapter after chapter, but that anyone who grasped the genetotrophic principle could equally call him an “environmentalist,” because of the great potential he saw in nutrition, which is purely an environmental factor.

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2. The Metabolic-Pattern Studies That Led There

The concept grew out of laboratory work at the Biochemical Institute in Austin in the late 1940s and early 1950s. Williams’s group, including L. Joe Berry, Ernest Beerstecher Jr., Helen Berry, Janet G. Reed and Lorene L. Rogers, used the new technique of paper chromatography to measure amino acids and other substances in the urine and saliva of volunteers, analyzing repeated samples from the same people. Much of this work was published in University of Texas Publication 5109 (1951), which Williams cited throughout Biochemical Individuality.

In the book’s chapter on “Excretion Patterns,” Williams described what they found:

Williams drew the lesson that these differences were inherited and real, not the product of food habits. He recalled that Sir Archibald Garrod, who described the “inborn errors of metabolism” in 1902, had already suggested that such rare disorders might be extreme examples of variations in chemical behavior present in everyone to a minor degree. Williams wrote that seriously testing Garrod’s hypothesis leads inevitably to the observation that the variations among “normal” individuals are major rather than minor.

In parallel, the group looked for “metabolic peculiarities” in alcoholics. In Biochemical Individuality Williams described a study that explored sixty items — urinary, salivary and blood constituents — in a small group of alcoholics and non-alcoholic controls, looking for anything that might be associated with proneness to alcoholism, and reported that several items appeared to differ significantly between the groups.

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3. The First Statements, 1949–1954

The word first appeared in print in 1949. In the Proceedings of the National Academy of Sciences that June, Williams, L. Joe Berry and Ernest Beerstecher published “Individual Metabolic Patterns, Alcoholism, Genetotrophic Diseases.” The title itself carries the chain of reasoning: individual metabolic patterns exist; alcoholism may be connected to them; and a new class of disease — genetotrophic — may explain the connection. The same authors published a longer paper in Archives of Biochemistry the same year, “Biochemical individuality; genetotrophic factors in the etiology of alcoholism.”

In February 1950 the three authors presented “The Concept of Genetotrophic Disease” to a medical audience in The Lancet, and Williams alone wrote a summary under almost the same title for Nutrition Reviews that September. A longer review in the Texas Reports on Biology and Medicine (1950) carried the title “Genetotrophic diseases; alcoholism,” and in 1954 Williams surveyed the subject again in the Annals of the New York Academy of Sciences under “The genetotrophic concept; nutritional deficiencies and alcoholism.”

Looking back in 1956, Williams explained what had convinced him. Rats fed the same diet and treated alike differed greatly in how much alcohol they chose to drink; the differences were genetically controlled; and the composition of the food changed the urge to drink. To explain all three facts together, he wrote, “genetotrophic ideas appeared to be the only reasonable interpretation.” Since then, he added, dozens of other facts had become explicable on the basis of the concept, and he knew of no observations that appeared to go counter to it.

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4. Partial Deficiencies and Several-Fold Differences in Need

The genetotrophic idea depends on a claim about size: that people’s needs for particular nutrients differ not by a few percent but several-fold. Williams devoted the long chapter “Individuality in Nutrition” in his 1956 book to collecting evidence for this, nutrient by nutrient — potassium, calcium, amino acids, vitamin B12, choline and others — drawn from his own laboratory and from the literature. He closed that chapter by summarizing its three central ideas:

“(1) each human individual has quantitatively a distinctive pattern of nutritional needs, (2) from individual to individual, specific needs may vary several fold, and (3) important deficiencies may exist which have not been discoverable clinically by observing acute outward symptoms.” — Biochemical Individuality, 1956, p. 162

The third point is the “partial deficiency” idea. Classic deficiency diseases — scurvy, beriberi, pellagra — are dramatic and were discovered because they are dramatic. Williams argued that milder, long-running shortfalls in individuals with higher-than-average needs could go unnoticed for years while weakening particular tissues. He described the mechanism in terms of “partial genetic blocks”: an inherited enzyme that works a little less efficiently, raising the amount of a nutrient needed to keep a reaction running. Such blocks, he reasoned, could occur anywhere in the body’s metabolism, so “any and every nutritional need” might be raised in some individual. He even suggested that substances not normally counted as essential, such as glutamine or arginine, might be essential for certain people.

He also stated the limits of his case. He acknowledged that nutrients interact, so needs are not simply additive, and he invited skeptics to test the claim: if careful study showed the variations to be smaller than he had indicated, he wrote, he would retreat from his position and admit that the principle was, to that extent, less important.

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5. The Genetotrophic Principle, 1956 and 1965

Chapter XI of Biochemical Individuality, “The Genetotrophic Approach,” gives the idea its most general form:

“The genetotrophic principle, as the author conceives it, is a very broad one encompassing the whole of biology. It may be stated as follows: Every individual organism that has a distinctive genetic background has distinctive nutritional needs which must be met for optimal wellbeing.” — Biochemical Individuality, 1956, p. 167

He then followed the principle across a lifetime. If a developing embryo has needs the mother’s environment cannot meet, its organs may fail to develop well; if a child’s needs are not fully met, growth and resistance to infection suffer; if an adult fails to meet his particular needs, the deficiency may contribute to many kinds of disease; and as a person ages, organs with inherited weak points may fail first because they carry unusually high needs that the diet does not supply. Williams put the practical stakes plainly:

“If the genetotrophic principle is valid and variation is as great as our evidence suggests, one of the chief frontiers of medical science in the decades to come will lie in the problem of finding out what specific needs are liable to go unmet, what consequences result from each deficiency, and how these needs can be met practically.” — Biochemical Individuality, 1956, p. 168

He illustrated the point with Walter de la Mare’s verse about Miss T — “whatever Miss T eats turns into Miss T” — and added his own corollary: whatever Miss T doesn’t eat doesn’t turn into Miss T. He also noted that the principle had probably acted for millions of years as a means of natural selection, since a mutation that imposed an extremely high need for a single nutrient would tend to be lethal.

Nine years later Williams and his long-time colleague Richard B. Pelton restated the idea in a short letter to Science titled “Individuality in Nutrition: The Genetotrophic Principle” (1965). The institute’s animal papers of the 1950s and 1960s, described next, carried “individuality” in their titles.

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6. Evidence from Rats, Chicks and Inbred Strains

Rats and alcohol. The first and, in Williams’s view, most fruitful line of experiments used rats given a free choice between water and alcohol. In Biochemical Individuality he reported that on ordinary stock diets the animals were highly individual — some drank heavily from the start, others would not touch alcohol — and that individuality could be almost eliminated by going to either dietary extreme. On a markedly deficient diet all the animals moved toward heavy drinking; on well-fortified diets supplemented particularly with vitamins, they turned away from alcohol. He wrote that in earlier experiments animals drinking at high levels had stopped practically entirely overnight when given vitamin supplements. Different colonies and inbred strains differed both in their tendency to drink and in how readily supplements changed it, which he took as direct evidence of inherited, quantitative differences in nutritional needs. Follow-up papers by Rogers, Pelton and Williams examined glutamine (1955) and amino acid supplements (1956).

Self-selection of food. Williams also cited findings that rats on deficient diets, given a choice, consumed more sugar than rats whose needs were better satisfied. He concluded that individual rats have quantitatively distinctive requirements; that deficiencies too mild to produce visible lesions are enough to impair the “wisdom of the body” in choosing food; and that rats need nutritional substances not yet recognized for every animal to choose well.

Chicks, 1955. With B. G. DeBusk, Williams reported “Overnight nutritional responses of chicks” in the Proceedings of the National Academy of Sciences (1955), one of a series of PNAS papers in which the institute studied how individual animals respond to changes in their diet.

Inbred animals, 1962. In “Individuality as exhibited by inbred animals: its implications for human behaviour,” Williams, Pelton and F. L. Siegel turned to animals bred to be as genetically alike as possible, and drew from the individuality those animals still showed implications for human behaviour.

Deficient diets, 1966. Williams and Pelton then published “Individuality in nutrition: effects of vitamin A-deficient and other deficient diets on experimental animals,” a title that names the kind of direct test of the genetotrophic principle he had invited in 1956: what happens to individual animals given the same deficient diet.

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7. Vitamin C: Guinea Pigs and the Tongue Test

Vitamin C was a natural test case because guinea pigs, like humans, cannot make it. In 1967 Williams and Gary Deason published “Individuality in vitamin C needs” in the Proceedings of the National Academy of Sciences. As summarized by the Linus Pauling Institute’s history blog, they divided more than 100 young male guinea pigs into groups receiving different daily amounts of ascorbic acid. Most animals fed none or very little developed signs of scurvy, yet two animals on only 1 mg per kilogram per day stayed healthy and gained weight, while seven animals given 8 to 32 mg per kilogram per day did poorly until their intake was raised to 64–128 mg per kilogram. Williams and Deason concluded that the animals’ requirements spread over a very wide range.

In 1973 Williams’s group tried to bring the question to people. In “Levels of optimal vitamin C intake in individuals as estimated by the lingual tests,” M. L. Yew, Y. Lo and Williams noted that the official recommended allowance for adults was then 55–60 mg a day, while there were strong suggestions that optimal intakes might be far higher and might vary greatly from person to person. They recruited 47 volunteers from University of Texas staff and students, had them avoid vitamin C supplements for three days, and applied a drop of a blue indicator dye (2,6-dichlorophenolindophenol) to the tongue after an overnight fast. The time the dye took to lose its color ranged from 8 to 65 seconds. Volunteers with long times were given graded vitamin C supplements — 500, 1,000 and 2,000 mg, and 3,000 and 4,000 mg if necessary — to see how much it took to shorten the time, as a rough estimate of each person’s individual need.

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8. Diseases He Proposed as Candidates

Alcoholism was the first and best-developed candidate; it has its own page in this series. Williams’s working hypothesis was that a person’s distinctive metabolism, rather than psychological factors alone, was probably crucial in deciding whether he or she would become alcoholic — that “alcohol does things to some individuals which it does not do to others.”

In the chapter “Implications for Medical and Dental Research” of Biochemical Individuality, Williams proposed a general three-step formula for any disease of obscure origin:

  1. Select a disease whose cause is obscure.
  2. Explore the known metabolic peculiarities, and look for new ones, that may be associated with the disease or with susceptibility to it.
  3. Seek to correct the metabolic failures by applying the genetotrophic principle in whatever way best suits the disease.

He worked through gout as an example. In one study his laboratory measured eleven blood constituents in eleven “normal” young men, drawing about five samples from each at weekly intervals; one man’s uric acid averaged 6.6 mg per cent and another’s 4.0. Williams suggested the first was more likely to develop gout, and wrote that if gout should respond to adding (or removing) a specific nutrient, it would belong in the category of genetotrophic disease. He discussed arthritis in the same chapter, proposing that where hormone treatment helps (as cortisone and ACTH did in rheumatoid arthritis), an alternative to giving the hormone is to supply the nutrients the body needs to make more of it.

He then listed further diseases that, in his words, needed to be attacked from the same point of view and held the same promise. The list in the 1956 book includes multiple sclerosis, hypertension, ulcers, diabetes, epilepsy, rheumatic heart disease, nephrosis, liver cirrhosis, congenital heart disease and other malformations that he thought probably involve nutritional deficiencies before birth, and even infectious diseases such as tuberculosis and poliomyelitis. He applied the same reasoning to dental caries.

Mental illness was the other major field. In “Implications for Advance in Psychiatry” Williams argued that biochemistry is basic to an understanding of mental disease, and that the brain’s metabolism, like every other tissue’s, is subject to biochemical individuality. With V. S. Machi he published “An analysis of interperson correlations among thirty psychotics” (1957), and the 1962 inbred-animal paper drew out implications for human behaviour. His 1960 paper “Etiological research in the light of the facts of individuality” set out the case for the whole approach to a research audience.

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9. Ketosteroids and Breast Cancer, 1968

Williams’s formula called for looking for metabolic peculiarities that might mark susceptibility to a disease years before it appeared. In 1956 he warned that a dozen healthy young men used as “normal controls” might each already carry metabolic peculiarities pointing toward a different later illness. The 1968 paper by R. M. Gutierrez and Williams, “Excretion of ketosteroids and proneness to breast cancer,” applied this search to cancer. Ketosteroids are breakdown products of steroid hormones excreted in the urine, and the paper examined whether the pattern of their excretion was connected with a woman’s proneness to breast cancer — the same strategy of reading an individual’s urinary chemistry for clues that his group had used for alcoholism and gout.

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10. Relation to Orthomolecular Medicine

In April 1968 Linus Pauling published “Orthomolecular psychiatry” in Science, proposing that mental disease might be treated by providing the optimum concentrations of substances normally present in the body. The two men knew each other well. The Linus Pauling Institute’s history blog records that Williams and Pauling began corresponding in 1936 about Williams’s pantothenic acid research, and that Williams became a founding fellow of the Academy of Orthomolecular Psychiatry in 1971. The National Academy of Sciences memoir lists Williams with Pauling, Albert Szent-Györgyi and Arthur M. Sackler among the founders of the Foundation for Nutritional Advancement.

Jeffrey Bland, in his 2019 history of personalized nutrition, places the two ideas in one line of development: Williams developing the concepts of the “genetotrophic origin of disease” and “biochemical individuality,” and Pauling advancing the personalized-nutrition concept in 1968 when he coined “orthomolecular,” meaning meeting each individual’s genetically determined nutrient needs in optimal concentrations. Bland also quotes Williams: “Nutrition is for real people. Statistical humans are of little interest.”

The fit between the ideas is close. Williams argued that individual needs vary several-fold and that ordinary diets can leave high-need individuals partially deficient; Pauling’s orthomolecular approach asked what the optimum amount was for a particular person, rather than the minimum that prevents classic deficiency in most people.

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11. His Practical Advice: Nutritional “Insurance”

Williams held that the ideal was a physician who knew a patient’s individual needs. Since few did, he gave readers two practical lines of defense.

The first was food quality. He wanted every meal to carry the full range of nutrients cells need — the “cellular nutrition” he wrote about in the 1959 paper “Biochemical individuality and cellular nutrition: prime factors in alcoholism” and in Nutrition Against Disease (1971). In the 1970s his laboratory compared foods by how well each could support animals on its own (“The nutritive value of single foods,” 1971; “The ‘trophic’ value of foods,” 1973), and his colleague Donald R. Davis later drew his “NutriCircle” diagrams of nutrient density for The Wonderful World Within You (1977).

The second was supplementation as insurance against an unmet individual need. In the Physicians’ Handbook of Nutritional Science (1975) he wrote:

“While I have never been in the vitamin business and have never derived profit from any vitamin or supplement formulation, I presently suggest the following vitamin formulation and mineral formulation to be used on a daily basis by those who need insurance. These formulations are subject to change when new information becomes available. No infallibility is claimed.” — Physicians’ Handbook of Nutritional Science, 1975, p. 75

He did not urge people to dose themselves blindly. In a 1982 foreword he agreed with “a vast segment of the medical profession that it is unfortunate for laymen to dose themselves with vitamins and minerals without professional advice,” and said it would be much better if physicians were well enough informed to advise patients on supplementing their diets. His complaint, repeated in Nutrition Against Disease, was that the experts had largely abandoned the field, so that the layman’s intuitions about nutrition, uninformed as they might be, were “often more justified than the physician’s neglect.”

In his final years he restated the whole program under a new name. In “Differential nutrition” (1986), written with Donald R. Davis, he called for an approach to human nutrition built from the start on individual differences — the genetotrophic concept carried into his tenth decade.

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Key Research Papers

  1. Williams RJ. Biochemical approach to individuality. Science. 1948;107:459. — PubMed PMID: 18938467
  2. Williams RJ, Berry LJ, Beerstecher E. Individual metabolic patterns, alcoholism, genetotrophic diseases. Proc Natl Acad Sci USA. 1949;35:265-71. — PubMed PMID: 16588890
  3. Williams RJ, Berry LJ, Beerstecher E Jr. Biochemical individuality; genetotrophic factors in the etiology of alcoholism. Arch Biochem. 1949;23:275-90. — PubMed PMID: 18136954
  4. Williams RJ, Beerstecher E Jr, Berry LJ. The concept of genetotrophic disease. Lancet. 1950;1:287-9. — PubMed PMID: 15405089
  5. Williams RJ. Concept of genetotrophic disease. Nutr Rev. 1950;8:257-60. — PubMed PMID: 14775937
  6. Williams RJ, Berry LJ, Beerstecher E Jr. Genetotrophic diseases; alcoholism. Tex Rep Biol Med. 1950;8:238-56. — PubMed PMID: 15418493
  7. Williams RJ. The genetotrophic concept; nutritional deficiencies and alcoholism. Ann N Y Acad Sci. 1954;57:794-811. — PubMed PMID: 13181310
  8. Williams RJ, Debusk BG. Overnight nutritional responses of chicks. Proc Natl Acad Sci USA. 1955;41:894-9. — PubMed PMID: 16589767
  9. Williams RJ, Pelton RB, Rogers LL. Dietary deficiencies in animals in relation to voluntary alcohol and sugar consumption. Q J Stud Alcohol. 1955;16:234-44. — PubMed PMID: 14385004
  10. Williams RJ, Machi VS. An analysis of interperson correlations among thirty psychotics. J Abnorm Psychol. 1957;55:50-7. — PubMed PMID: 13462660
  11. Williams RJ. Etiological research in the light of the facts of individuality. Tex Rep Biol Med. 1960;18:168-85. — PubMed PMID: 13844934
  12. Williams RJ, Pelton RB, Siegel FL. Individuality as exhibited by inbred animals: its implications for human behaviour. Proc Natl Acad Sci USA. 1962;48:1461-6. — PubMed PMID: 14007221
  13. Williams RJ, Pelton RB. Individuality in nutrition: the genetotrophic principle. Science. 1965;148:669. — PubMed PMID: 17801961
  14. Williams RJ, Pelton RB. Individuality in nutrition: effects of vitamin A-deficient and other deficient diets on experimental animals. Proc Natl Acad Sci USA. 1966;55:126-34. — PubMed PMID: 5220861
  15. Williams RJ, Deason G. Individuality in vitamin C needs. Proc Natl Acad Sci USA. 1967;57:1638-41. — PubMed PMID: 5231398
  16. Gutierrez RM, Williams RJ. Excretion of ketosteroids and proneness to breast cancer. Proc Natl Acad Sci USA. 1968;59:938-43. — PubMed PMID: 5238675
  17. Yew ML, Lo Y, Williams RJ. Levels of optimal vitamin C intake in individuals as estimated by the lingual tests. Proc Soc Exp Biol Med. 1973;144:626-7. — PubMed PMID: 4746937
  18. Williams RJ, Davis DR. Differential nutrition—a new orientation from which to approach the problems of human nutrition. Perspect Biol Med. 1986;29:199-202. — PubMed PMID: 3951955
  19. Bland JS. The evolution of personalized nutrition—from Addis, Pauling, and RJ Williams to the future. Integr Med (Encinitas). 2019;18(6):10-13. — PubMed PMID: 32549850

PubMed Topic Searches

  1. https://pubmed.ncbi.nlm.nih.gov/?term=genetotrophic
  2. https://pubmed.ncbi.nlm.nih.gov/?term=Williams+RJ%5Bau%5D+individuality+nutrition
  3. https://pubmed.ncbi.nlm.nih.gov/?term=biochemical+individuality+nutrient+requirements
  4. https://pubmed.ncbi.nlm.nih.gov/?term=individual+variation+vitamin+C+requirement

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Connections

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