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Department of Nutritional Sciences, University of California, Berkeley, CA 97420-3104
2To whom correspondence should be addressed. E-mail: kcarp{at}uclink.berkeley.edu.
In the early years of the 20th century, the number of researchers engaged in nutritional work expanded enormously. Space does not permit more than an introduction to the proliferation of literature on any specific topic and it has unfortunately not been possible to fully distribute the credit to several groups of researchers working on the same problem. Also I have probably not given a due share to those publishing in languages other than English. When a development has been presented in a series of papers, I have tried to cite a relatively recent one because it is easier for readers to work their way back through the literature than try to go forward.
| The vitamin era |
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Certainly "vitamins" (with the e omitted after it was realized that they could not all be amines) formed a new vein of knowledge waiting to be mined and were to be the major topic of nutritional research for the next 30 years. Looking for example, at the first two volumes of The Journal of Nutrition, published from 19281930, we see that more papers (some 40%) dealt with this general topic than any other. In 1933 Leslie Harris, who had been given the responsibility of reviewing the previous years work in the field, pointed out that nearly 1,000 papers had been published on vitamins with over 300 on vitamin D alone in just 12 months (6).
It is sometimes asked, "Who first had the idea of vitamins?" One can find tantalizing early quotations, but they were not followed up at the time. In 1804 Thomas Christie, a physician working in Sri Lanka, wrote, "The chief cause of beriberi is certainly a want of stimulating and nourishing diet ... . However, giving acid fruits, which I find of great value in scurvy has no effect in beriberi ... . I can suppose the difference to depend on some nice chemical combination" (7,8). In 1830 John Elliotson lecturing at a London teaching hospital said that, "scurvy is a purely chemical disease ... each part of the system is ready to perform all its functions, but one of the external things necessary for its doing so is taken away ... the remedy for this state is fresh food" (9). In 1842 George Budd also lecturing in London added, "Scurvy is only one of a number of diseases due to specific dietary deficiencies, another is rickets and a third is characterized by a peculiar ulceration of the cornea" (10,11). Gerrit Grijns pronouncement already quoted in "A Short History of Nutritional Science: Part 2 (18851912)," (2) was probably the first clear statement, based on his own work, of the existence of an organic nutrient required only in small amounts.
| Rats and mice fed purified diets |
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| The work of E. V. McCollum |
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| Searching the literature |
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Cornelis Pekelharing, whose work as the leader of the Beriberi Commission in Indonesia has been previously described (2), also reported that mice would not thrive on a simplified diet of casein, egg albumin, rice flour and minerals. He buried his brief announcement in a 1905 paper on a different subject, but made it clear that the mice were deficient in something that he could supply to them in whey (i.e., milk with the fat and casein removed). He added that he would say no more about it because he could not identify the missing factor. Indeed his work remained generally unknown until translated into English 20 years later (18) and McCollum was not aware of it. Strangely, Gowland Hopkins, Professor of Biochemistry at Cambridge University, said something very similar in the following year. Toward the end of an obscure published lecture we find, "No animal can live upon a mixture of pure protein, fat and carbohydrate, and even when the necessary inorganic material is carefully supplied the animal still cannot flourish... . In diseases such as rickets, and particularly in scurvy, we have had for long years knowledge of a dietetic factor; but, though we know how to benefit these conditions empirically, the real errors in the diet are to this day quite obscure. They are, however, certainly of the kind ... that I am considering." Many years later in his Nobel Prize speech, he said that he had based his remarks on studies he had made with mice in 19061907, but like Pekelharing had thought that they would not be taken seriously until he had identified the missing factor (19,20). He was probably the first to associate the deficiencies of a purified diet with human disease conditions.
It is interesting that McCollum had also failed to find any reference to the important work of Eijkman and Grijns in studying the disease produced by feeding chickens white rice and the latters conclusion that it was caused by deficiency of a relatively unstable water-soluble organic compound (2).
In 1909 a Swiss ophthalmologist, who had seen in another trial the mention of eye lesions appearing in rats fed a purified diet, repeated the experiment and identified the xerophthalmia and keratomalacia that he saw with conditions found in human subjects that had proved responsive to cod liver oil (21,22).
| McCollums first trials |
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| Factors "A" and "B" |
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By this time, Hopkins had argued that the two American groups had only been able to obtain growth with their diets because the casein and lactose were insufficiently purified from a water-soluble "growth factor" (26,27). McCollum and his colleagues looked into this and agreed, concluding that rats needed both a fat-soluble "Factor A" and a water-soluble "Factor B" that was identical to the antiberiberi factor deficiency which developed in chickens and pigeons fed white rice (28).
Here we see the beginning of the scheme for identifying vitamins by letters before their chemistry had been worked out. They then reported that leaves showed "Factor A" activity even though their ether extracts and also the plant oils that they had tested did not do so. It was also noticed that the deficiency of "Factor A" resulted in severe ophthalmia. This of course linked up with the clinical work previously described dealing with night blindness leading to xerophthalmia and its prevention with cod liver oil (2). We will return to the slow and complex progress in understanding "Factor A" in a later section.
| Rickets and vitamin D |
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As previously described, rickets had become a serious problem among young children in the large industrial cities of Western Europe and the northern United States (Fig. 1) (2). It was particularly serious in Glasgow, Scotlands largest city, whose medical school had an active group concerned with the problem. They reported in 1908 that puppies fed bread or oatmeal with whole milk would develop rickets if kept indoors, but not if taken for outdoor walks (29). From a study conducted in the citys slums, it was concluded that inadequate fresh air and exercise were "potent factors in determining the onset of rickets," and in a further trial with puppies it appeared that having an outside run was more important than the intake of milk fat (30).
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By this time, McCollum and his medical colleagues at Johns Hopkins had, as already mentioned, found that the more convenient rat could also be used to provide a model for rickets if its diet were severely imbalanced in ratio of calcium to phosphorus. They then found that cod liver oil would prevent the disease even after it had been aerated in a way that destroyed its antiophthalmic (factor A) value (35).
The next extraordinary finding, back in Wisconsin in 1924, was that not only did irradiation of rachitic rats with ultraviolet light have a curative effect, but so did irradiation of the diet from which they had developed the disease (36). Many groups tried to determine what factor might be activated in this way. It was quickly traced to "lipid," then to the sterol fraction and finally to ergosterol and, in 1931, the activated material itself now named "vitamin D" was crystallized (37). (The letter "C" had already been allocated to the antiscorbutic vitamin.)
With this new knowledge rickets ceased to be an intractable public health problem. It was later realized that there was more than one form of active vitamin, and that their relative activities depended on the species under consideration.
| Experimental scurvy |
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Harriette Chick and E. M. Hume, the first independent women scientists to be mentioned in this history, were soon able to demonstrate that cows milk had only a low antiscorbutic activity; guinea pigs receiving an "oats + milk" diet needed some 50 mL per day to remain healthy and if the milk went at all sour they would not touch it. It was essential therefore to monitor individual consumption in order to interpret the results. Scurvy consistently appeared with autoclaved milk that had apparently lost most of its vitamin C activity (39).
Because of suspicions that commercial lime juice was not an effective antiscorbutic, the same group now used guinea pigs to test this in what may have been the first bioassay for vitamin activity. They found that commercial lime juices had less than one tenth the activity of freshly squeezed lemon juice (Table 1) (40). The processing almost certainly included pumping through copper pipes and probably some form of sterilization. This of course confirmed that the Victorians had been correct to doubt that lime juice as they knew it was effective in preventing outbreaks of scurvy on long expeditions.
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In 1939 a surgeon at Harvard Medical School fed himself a diet containing no vitamin C, but supplements of all other vitamins. After 26 weeks he developed hemorrhages on his legs, a wound inflicted on his back failed to heal and he rapidly became exhausted. Upon dosing with ascorbic acid these problems quickly disappeared (44).
| Beriberi and vitamin B |
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The isolation of B1 was achieved in 1926 by Dutch scientists in Java using small "rice birds" fed on washed white rice supplemented with cod liver oil for their assays. Starting with nearly 700 pounds of rice polishings, they obtained 100 mg of crystals so potent that only 10 µg was needed to cure a deficient pigeon (45). The next problem was to determine the structure of the crystals of the chloride salt that had an empirical formula of C12H18Cl2N4OS. This was finally achieved and a biologically active compound synthesized in 1936 (46,47). It was named Thiamin(e) as "the vitamin containing sulfur (thios in, Greek)".
Meanwhile Rudolph Peters at Oxford was investigating the function of the vitamin. It was known that deficient subjects maintained unusually high levels of pyruvic or lactic acid in their blood after exercise, and his group obtained evidence that thiamin pyrophosphate served as a cofactor for the enzyme pyruvate decarboxylase. He introduced the term "biochemical lesion" to describe the effect of its deficiency (48). This was the first of a long series of findings that B-vitamins generally served as part of coenzymes concerned with different aspects of metabolism.
| Pellagra in the United States |
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Goldberger thought that an unbalanced diet was responsible and persuaded authorities in Mississippi to allow 12 prisoners to volunteer to eat for six months an experimental diet that might induce pellagra. In return the prisonerswould be released at the end of the periodif still alive! The diet had abundant corn and other cereals but no meat or dairy products. After five months, six of the men had developed dermatitis on the scrotum and in a few cases, on the back of their hands (53). Goldberger was satisfied that this was pellagra, but the volunteers immediately fled after obtaining their release and he could not demonstrate their condition to physicians who doubted whether he truly had produced the disease (54).
In another study in South Carolina mill villages, Goldbergers group found that pellagrous families had purchased a very similar pattern of foods to that of healthy families, but the latter nearly all kept a cow and were obtaining abundant milk (55).
They now tried to find an animal model with which they could assay the antipellagrous activity of different foods and extracts. Early work with monkeys and rats failed to elicit anything resembling the human disease. McCollum too had been finding that rats failed to show anything like pellagra when fed diets resembling those used in Goldbergers prison experiment and referring to the doubts as to whether pellagra had been produced there, he concluded that "probably ... pellagra is caused by an infectious agent" (55). So the man whose name is linked to the discovery of vitamins wanted at one point to erase both pellagra and scurvy from the list of deficiency diseases.
Goldbergers group persevered with searching for an animal model. Dogs given mixtures with mostly cornmeal and no meat or milk powder developed a condition called blacktongue, showing red lips with patches of necrosis, drooling and loss of appetite. The group considered this to be a model for pellagra after the dogs responded rapidly to yeast, and this proved equally valuable for pellagrins (57).
Dogs were then used to assay fractions obtained from yeast and liver. Finally in 1937 after nicotinic acid had been found to be a bacterial growth factor, both it and nicotinic amide were found in Wisconsin to be extremely potent in curing blacktongue, and also pellagrous patients in Alabama (58,59). This was the only example of a vitamin, an already familiar chemical, now being given the blander name of "niacin." This is not the end of the story; it will be continued in Part 4 of this series.
| Riboflavin |
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| Folic acid |
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In the same period workers interested in poultry nutrition had found that chicks fed purified diets containing all of the then known vitamins still grew slowly and developed a macrocytic anemia, and in 1944, that this could be prevented by giving them crystalline "vitamin Bc" isolated as a growth factor for certain bacteria (66). The same or a closely related compound had also been obtained from spinach and named "folic acid" because it had come from "foliage." These materials were also active in treating the experimental monkey anemia and it was hoped that they would be clinically effective in India when supplies became available (65).
The chemical identification and syntheses of these active compounds will be considered in Part 4.
| Other B vitamins |
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| The fat-soluble vitamins |
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In the first section of this history Part 3, we reviewed early work that led to the concept of "vitamin A" as a fat-soluble vitamin needed by young rats to support growth and to prevent the development of xerophthalmia. In Denmark during World War I, when fats were in short supply, an unintended experiment occurred in a childrens home. In one group of 16 children, 8 developed xerophthalmia, while no cases developed in a second group. The only difference in the diets of the two groups was that the second had received whole cream milk in the previous six months. Carl Bloch, the pediatrician in charge, then began to give cod liver oil to the affected group; their eye problems cleared up in eight days and they began to grow faster (72,73). Clearly, the work with rats had some practical relevance.
The problem now was to identify the vitamin, which appeared to exist in at least two forms: a highly colored form in leaves and carrots, and a colorless form in animal fat. Crystals of ß-carotene, a polyunsaturated hydrocarbon, were obtained from carrots and found to be active. The colorless factor was more difficult to obtain but the activity of extracts correlated with a characteristic color formation with antimony trichloride that could be differentiated from the color obtained with carotene. It was then found that giving carotene to rats depleted of vitamin A resulted in the reappearance of the color reaction of the "animal" factor in extracts from their livers (74). Thus carotene appeared to be a precursor of the final vitamin, and this was confirmed when the actual vitamin was finally isolated from fish liver oils in 1939 using centrifugal molecular stills, and its structure identified (75,76).
Synthesis proved particularly difficult. A major contributor wrote, "After so many years, victory has come and the romance of high hopes and bitter disappointment will in a few years simply be recorded in textbooks of organic chemistry in a few terse sentences" (76). Sad but realistic. The vitamin, now named "retinol," was an alcohol attached to a long unsaturated carbon chain linked in turn to a ß-ionone ring, and ß-carotene could be considered as two retinol molecules condensed through their alcohol groups.
Vitamins E and K.
In 1922 H. M. Evans and Katharine Bishop working at Berkeley found that a purified diet with vitamin supplements that supported good growth in female rats nevertheless failed to support normal reproduction; the embryos were being resorbed before the end of pregnancy (77). Lettuce was the first food found to prevent this problem, but then wheat and in particular, wheat germ oil. Cod liver oil seemed unexpectedly to increase the problem. The active factor was named "vitamin E" and following further investigations by many groups, it was isolated in 1935 and named "tocopherol" (from Greek terms signifying "the childbirth-producing alcohol"). Three years later the Swiss chemist Paul Karrer synthesized it by condensing phytyl bromide with trimethyl hydroquinone (78). He too received a Nobel Prize for his work on the chemistry of several vitamins.
During this period there was a change in thinking about the effects of a deficiency of vitamin E. In rats, males showed testicular degeneration, but it was realized that in pregnancy it was the fetus that failed to develop rather than the dam being at fault. It was also found that vitamin E deficiency in lambs and rabbits resulted in muscular degeneration rather than infertility; and in chicks it resulted in exudative diathesis and/or encephalomalacia, both related to disturbances in the vascular system (79).
Vitamin E became a popular treatment, backed by reports of early successes, for a number of clinical conditions including abortions, impotence and various forms of muscular dystrophy, but with more controlled testing, few if any of these claims could be confirmed (80).
Hemorrhaging in chicks, which responded to dosing with cabbage, was another disease that at one time was thought to possibly be caused by a deficiency of vitamin E. The Danish worker Henrik Dam reported in 1935 that it was the deficiency of a new fat-soluble vitamin, which he named "vitamin K" in recognition of its essential role in blood coagulation ("Koagulation" in Danish and German) (81). It was discovered to occur naturally in modified forms in many plants and to be produced by bacterial growth in stored animal products (82,83). The vitamin also cured the hemorrhaging of patients with obstructive jaundice who lacked bile to aid absorption of the vitamin and of cattle that had been eating sweet clover hay that contained an anti-vitamin (84).
Herman Almquist and a colleague at Berkeley could have published the discovery of vitamin K before Dam, but had to delay publication until a controversy on campus about the cause of the chick disease had been resolved and so missed a Nobel prize. By this period there were so many people at work on nutritional problems that such things were almost inevitable. Many years later Almquist was to write philosophically, "More often than not, a discovery is really born of a converging culmination of scientific leads ... to all of which many have contributed ... a stage has been set ... there are many who can do the job if they happen to be on the scene" (85).
| Essential fatty acids |
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| Proteins and amino acids |
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Chemical methods of amino acid analysis were slow and subject to interference (90). However, microbiological methods taking advantage of the complex requirements of lactobacilli were developed in the 1940s and allowed many more assays to be completed (91). From these it was possible to determine the "chemical score" of food proteins calculated as the lowest percentage value when the level of each essential amino acid was compared with that found in whole egg (taken as a provisional standard). These "scores" were then found in most cases to correlate well with the relative values of the same foods as determined in protein quality tests with young rats, based either on weight gain or nitrogen balance (92).
In 1930 William Rose, who had earlier been a graduate student with Mendel and attended Chittendens lectures, was a professor at the University of Illinois, Urbana campus. He and his group set out to develop amino acid mixtures that would support good growth in rats. They began with 19 known amino acids, but the animals failed to grow. With hindsight it is surprising that their list did not include methionine, discovered at Harvard in the 1920s as being required for the growth of certain bacteria (93). However, it was largely ignored by nutritionists for another decade, perhaps because they knew that rats receiving casein as their sole protein would grow faster if cystine were added to the diet, so that cystine appeared to be the sulfur-containing essential amino acid. Even with the inclusion of methionine, rats still failed to grow at Urbana unless they received in addition the mix of amino acids obtained from an acid-hydrolysate of casein.
Attempts to isolate an active factor from the hydrolysate proved very frustrating until it was realized that it was supplying two additional materials. With further careful fractionation, Madelyn Womack working with Rose, discovered that one was isoleucine (94). At that time there was no method for determining isoleucine separately from leucine. It was included in the original mix, but at a level well below what turned out to be its requirement.
The second factor was a previously unknown amino acid, which they identified as 2-amino-3-hydroxybutanoic acid and named threonine (95). When it was included in the amino acid mix the rats grew well so that this was a most important finding. Reviewers have referred to "the very high level of chemical competence and skill" with which these studies were conducted and, for example, to "fivefold crystallizations of tryptophan and histidine," even after analyses had shown them to be essentially pure (96).
Starting in 1942, Rose set out to extend the study to human adults. This involved preparing much larger quantities of amino acids, and then careful control of the energy intakes of volunteers and measurement of their nitrogen balance. All of this took time and the findings will be considered in Part 4.
Meanwhile, the availability of isotopes had allowed a new approach to studying the fate and distribution of nutrients in the body. In 1939 Rudolf Schoenheimer and his colleagues at Columbia University reported results from feeding rats for three days a physiological dose of l-leucine, doubly labeled with N15 and deuterium (replacing hydrogen in the side chain). They found that less than one third of the N15 had appeared in the urine, but that 57% was incorporated into body proteins, much of it in other amino acids with the exception of lysine (97). It was assumed that this was the consequence of transamination reactions.
Schoenheimer thought at this time of protein molecules opening to release one amino acid molecule at a time into the blood stream before reattaching a replacement. In any case, it appeared that most synthesis of body proteins must be coming from recycled amino acids rather than from newly digested dietary protein. As he was to write, "If the starting materials are available, all chemical reactions which the animal is capable of are carried out continually" and "The synthesis of amino acids, like that of fatty acids ... proceeds even when there is no obvious need for it" (98).
| Mineral elements |
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The development by 1929 of analytical procedures using emission spectroscopy allowed the detection of trace elements in foods. Thus, it was found that cows milk contained strontium and vanadium in addition to the previously detected iron, copper, zinc and manganese, as well as larger quantities of calcium, magnesium, potassium, sodium and phosphorus (97). Chlorine and iodine had been found using other procedures. There was no doubt in the minds of workers that the more abundant elements were essential, and studies now began on possible requirements for the trace elements" (100).
At Wisconsin copper had already been found to be required for the production of hemoglobin in rats fed purified diets (101). Then in 1931 a deficiency of copper was found to be responsible for a characteristic sickness occurring in cattle in parts of Florida (102). In the same year McCollums group reported results with young rats fed a purified diet designed to be as low as possible in manganese content. They grew normally, but the males were sterile with testicular degeneration, and the females would breed when mated with normal males, but were unable to suckle their young (103). Again, a few years later manganese deficiency was recognized at Cornell as being a practical problem, this time in intensive poultry production and responsible for "perosis" (a crippling deformity of the leg bones) in young birds (104).
Magnesium was known to be present in both bones and soft tissues of animals but it proved difficult to obtain a deficiency condition in rats. Finally, by feeding rats a diet that after careful purification contained only 1.8 µg/g of the element, McCollums group produced a characteristic condition of tetany (105). In contrast, grass-fed cattle would sometimes develop tetany that responded to dosing with magnesium salts even when the level in their blood appeared normal (106).
It also proved possible to produce zinc deficiency with a highly purified diet on which rats showed slow growth and loss of hair (107). However, no evidence of zinc deficiency being a practical problem was seen in the period under review. In contrast, serious problems affecting cattle and sheep in parts of Australia were recognized in 1937 as being due to cobalt deficiency without its having first been produced experimentally in laboratory animals (108). The special function of cobalt in ruminant nutrition would only be worked out in a later period.
The importance of iron in the prevention of microcytic anemia in human subjects was previously discussed (2). Interestingly, iron deficiency had been much less of a problem in traditional animal husbandry, in large part because animals had access to soil which is rich in iron. However, when sows began to be brought indoors in the 1920s for farrowing, the piglets had a higher death rate. This was found to be the result of anemia and workers in Scotland prevented it by adding iron salts to the sows feed (109). It was thought that the piglets obtained additional iron from contamination with her feed and feces rather than from any additional iron appearing in the sows milk and this was confirmed in Wisconsin (110).
In 1937 Robert McCance and Elsie Widdowson, working in London at that time, published a classic paper arguing that contrary to current opinion, humans had little or no ability to excrete iron, and that there must therefore be a mechanism that regulated its absorption according to need (111). This was confirmed by work with dogs using radioactive iron when it became available from the Berkeley cyclotron. It was interesting that absorption did not increase immediately after dogs had been bled to induce anemia, but only seven days later when body iron stores had been exhausted as a consequence of increased synthesis of red cells (112).
| Iodine |
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Old observations that the incidence of goiter did not seem to parallel the deficiency of iodine in local water and food supplies had made many enquirers believe that other factors must also be at work. In 1928 workers at Johns Hopkins discovered that rabbits fed mainly cabbage and being used for a study of infections had developed goiters (115). Deliberate studies with rats then showed that most Brassica plants and also unprocessed soybeans had goitrogenic activity that responded to higher intakes of iodide (114,115). However, feeding Brassica seeds resulted in goiters that were reversed with thyroxine but not with iodine (116).
In 1917 David Marine organized a large-scale trial of iodine supplementation of schoolgirls in an area of Ohio where the disease was endemic (119). The results of reexamination of these subjects six months after their first treatment are summarized in Table 3. Longer periods of treatment produced more complete freedom from the problem with no evidence of harm. After this iodized salt began to be produced in many parts of the world with government encouragement.
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| Fluorine |
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| Diet restriction and life span |
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Clive McCay had learned of this work while with Lafayette Mendel on a postdoctoral fellowship. Mendel had told him that a younger man was needed to pursue such long-term work. McCay, who had moved to a faculty position at Cornell in 1927, decided to take it on. He and his colleagues confirmed that, indeed, the life of rats, particularly males, could be greatly extended by restricting their diet for an initial year or even two years, though he commented that, "it seems little short of heresy to present data [supporting] the ancient theory that slow growth favors longevity" (124,125). However, they also had to report that when the heating failed in the animal room it was only the skinny ones that succumbed!
In addition to the advances in scientific knowledge in this period, there were important advances in its practical application. Distributing iodized salt, as already mentioned, significantly reduced the incidence of goiter. But there can be difficulties; for example, fortifying foods with iron salts may result in rancidity and destruction of vitamin A. Solving such technical problems can be as demanding as the original discoveries of nutrients, but is outside the scope of these articles as is the work of developing standards for the level of individual nutrients in adequate diets and also the evaluation of nutritional status in different population groups.
Those who had begun their careers in the 1930s looked back on it as "the golden age of nutrition," with its rapid discoveries of one nutrient after another. We are certainly indebted to them for their findings, but did they leave anything still to be discovered? That is what will have to be considered in Part 4.
| FOOTNOTES |
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Manuscript received 29 May 2003.
| LITERATURE CITED |
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1. Carpenter, K. J. (2003) A short history of nutritional science: Part 1 (17851885). J. Nutr. 133:638-645.
2. Carpenter, K. J. (2003) A short history of nutritional science: Part 2 (18851912). J. Nutr. 133:975-984.
3. Funk, C. (1912) The etiology of the deficiency diseases. J. State Med. 20:341-368.
4. Funk, C. (1922) The Vitamines 2nd ed. 1922 Williams & Wilkins Baltimore, MD.
5. Williams, R. R. & Spies, T. D. (1938) Vitamin B1 (Thiamin) and its Use in Medicine. 1938 Macmillan New York.
6. Harris, L. J. (1933) Vitamins. Annl. Rev. Biochem. 2:253-298.
7. Christie, T. (1804) Letter on beriberi. Hunter, W. eds. An Essay on the Diseases Incident to Indian Seamen 1804:77-87 Honorable E. India Co Calcutta. .
8. Carpenter, K. J. (2000) Beriberi, White Rice and Vitamin B 2000:26 University of California Press Berkeley.
9. Elliotson, J. (1831) Clinical lecture. Lancet. i:649-655.
10. Budd, G. (1842) Lectures on the disorders resulting from defective nutriment. London Med. Gaz. 2:632.
11. Carpenter, K. J. (1986) The History of Scurvy and Vitamin C. 1986:99-249 Cambridge University Press New York.
12. McCollum, E. V. & Davis, M. (1915) The nature of the dietary deficiencies of rice. J. Biol. Chem. 23:181-230.
13. Schneider, H. A. (1986) Rats, fats and history. Perspect. Biol. Med. 29:392-406.[Medline]
14. McCollum, E. V. (1964) From Kansas Farm Boy to Scientist 1964 Univ. of Kansas Press Lawrence, KS.
15. Hopkins, F. G. (1929) The earlier history of vitamin research. 1965, eds. Nobel Lectures: Physiology or Medicine 19221941 1929:214 Elsevier Amsterdam .
16. McCollum, E. V. (1909) Nuclein synthesis in the animal body. Am. J. Physiol. 25:120-141.
17. McCollum, E. V. (1957) A History of Nutrition 1957:203-212 Houghton Mifflin Boston, MA.
18. Van Leersum, E. H. (1926) The discovery of vitamins. Science 64:357-358.
19. Hopkins, F. G. (1929) :218 See cit. no. 13.
20. Carpenter, K. J. (2000) :101-103 See cit. no. 6.
21. Knapp, P. (1909) Experimenteller Beitrag zur Ernahrung von Ratten mit künstlicher Nahrung und zum Zusammenhang von Ernährungsstörungen mit Erkrankungen der Conjunctiva. Z. Exp. Pathol. Therap. 5:147-169.
22. Wolf, G. & Carpenter, K. J. (1997) Early research into the vitamins: the work of Wilhelm Stepp. J. Nutr. 127:1255-1259.
23. Osborne, T. & Mendel, L. B. (1911) Feeding experiments with isolated food substances. Carnegie Institution of Washington Publ. No 156.
24. McCollum, E. V. & Davis, M. (1914) Observations on the isolation of the substance in butter fat which exerts a stimulating effect on growth. J. Biol. Chem. 19:245-250.
25. Osborne, T. & Mendel, L. B. (1913) The influence of butter fat on growth. J. Biol. Chem. 16:423-437.
26. Hopkins, F. G. & Neville, A. (1913) A note concerning the influence of diets upon growth. Biochem. J. 7:97-99.[Medline]
27. Becker, S. L. (1983) Will milk make them grow?. Parascandola, J. Whorton, J. C. eds. Chemistry and Modern Society 1983:61-83 Am. Chem. Soc Washington, D.C. .
28. McCollum, E. V. & Simmonds, N. (1916) The relation of the unidentified dietary factors, the fat-soluble A, and water-soluble B, of the diet to the growth-promoting properties of milk. J. Biol. Chem. 27:33-43.
29. Findlay, L. (1908) The etiology of rickets: a clinical and experimental study. Brit. Med. J. ii:13-17.
30. Paton, D. & Watson, A. (1921) The aetiology of rickets: an experimental investigation. Br. J. Exp. Path. 2:75-85.
31. Mellanby, E. (1921) Experimental rickets. Med. Res. Council Spec. Rept. Ser. No. 61. .
32. Mellanby, E. (1950) A Story of Nutritional Research 1950:214 Williams & Wilkins Baltimore, MD.
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