In 1897 Eijkman1 published the observation that the disease beriberi was due to a one-sided diet of polished rice, and that if rice were not milled, but eaten with its pericarp, beriberi did not ensue. Eijkman2 also made the very valuable discovery that pigeons, when fed with polished rice, developed a polyneuritis analogous to that found in human beriberi, and that the addition of rice bran (rice polishings) to the diet prevented this condition.3

About this same time Rohmann4 found that if, instead of natural foods, purified materials, such as casein, egg-albumin, vitellin, potato starch, wheat starch, and oleomar-garin, together with the proper salts, were mixed and given to mice, their offspring were difficult to rear with this food and that no living young could be obtained from them.6 These experiments appeared difficult of interpretation.

In reality, the work of Eijkman and of Rohmann was the beginning of a scientific knowledge of the so-called "deficiency diseases." It now appears that a proper diet for growth or maintenance must contain not only protein, fat, carbohydrate, and salts, but also some substances existing in natural foods, in very minute quantities, which are absolutely essential to the harmonious fulfilment of the life processes. It should be added that Rohmann denies the necessity of these accessory substances.

1 Eijkman: "Virchow's Archiv," 1897, cxlix, 187.

2 Eijkman: Ibid., 1897, cxlviii, 523.

3 For useful reference consult Vedder, E. B.: "Beriberi," New York, 1913. 4 Rohmann: "Klinische therapeutische Wochenschrift," 1902, No. 40.

5 Consult Osborne and Mendel: Carnegie Institution, Publication 156, 1911; Rohmann: "Ueber kunstliche Ernahrung und Vitamine," Berlin, 1916.

Another pioneer in this field was Gowland Hopkins,1 who wrote in 1906, "No animal can live on a mixture of pure protein, fat, and carbohydrate, and even when the necessary inorganic material is carefully supplied the animal still cannot flourish. The animal is adjusted to live either on plant tissues or the tissues of other animals, and these contain countless substances other than proteins, carbohydrates, and fats. ... 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 scale errors in the diet are to this day quite obscure. . . . Scurvy and rickets are conditions so severe that they force themselves on our attention; but many other nutritive errors affect the health of individuals to a degree most important to themselves, and some of them depend upon unsuspected dietetic factors".

The study of the "accessory factors" of diet, a term used by Hopkins, has been in the hands and heads of some of the ablest physiologic chemists during the past ten years, and it is extremely difficult, perhaps impossible, to write of the subject and do even-handed justice toward the various contributors in the field. Hofmeister defines the unknown but beneficent factors alluded to here as "accessory food-stuffs," and Funk has called them "vitamins."2 Objection is made to the term "accessory" on the ground that it implies something non-essential, and to the term "vitamin" on the ground that there is no evidence that the substance or substances in question are amins, nor that they are more valuable to fife than other substances - epinephrin, for example. In acknowledgment of this insufficiency of information, McCol-lum3 suggests the provisional use of two terms, the "fat-soluble A" and the "water-soluble B," as representing the factors necessary for adequate growth. The "water-soluble B" cures beriberi and is regarded as identical with Funk's "vitamins".

1 Hopkins, F. G.: "Analyst," 1906, xxxi, 391.

2 Funk: "Ergebnisse der Physiologie," 1913, xiii, 126.

3 McCollum, E. V.: "Journal of Biological Chemistry," 1916, xxv, 105.

For the sake of simplicity, the word "vitamin" may be retained provisionally to express the group of as yet unidentified substances which cannot at present be classified with the familiar nutrients, proteins, fats, carbohydrates, inorganic salts, and water, upon which the harmonious behavior of the organism depends and which are ordinarily ingested in traces in the food. The term "food hormone" is probably a more rational expression of what the vitamins signify (see p. 378).

Interwoven with the experimental work upon the subject of the vitamins has been work upon the relative value of different proteins in nutrition. A diet may yield sufficient energy to maintain the organism and yet be a deficient dietary in that it lacks vitamins or contains insufficient salts or too little protein or protein of low nutritive value.

Stepp1 showed that when mice were fed with bread baked with a little milk this formed a complete diet, but if this diet were first extracted with alcohol and ether the animals all died. He2 further reported that the addition of salts or fat or lecithin or cholesterol to the extracted bread was without beneficial influence when it was given to mice. However, the addition of ether-alcohol extracts from skimmed milk, from egg-yolk, or from calf's brains to bread which had been extracted furnished a diet capable of supporting mice. In a later paper Stepp3 reported that ether extraction fails to remove the accessory substance necessary to life, whereas alcohol accomplishes this result; he therefore concludes that the significant substance is not a fat.

In 1912 Hoist and Frolich4 reported that if guinea-pigs were fed with a one-sided diet of white bread, or with polished rice or other milled grains, they invariably died, usually in about four weeks. They always showed loose teeth and usually hyperemic gums. Hemorrhages appeared, sometimes in the skin, but more usually at the knee-joints and at the cartilages of the ribs, and there were microscopic changes in the bone-marrow. All these phenomena are in entire accord with the manifestations of human scurvy. It is important to remember that it has never been demonstrated that any kind of unmilled grain will produce scurvy. Materials in the pericarp are, therefore, essential to health. As antidotes to foods which produce scurvy, fresh vegetables, dried peas, lime-juice, or fermented liquors (wines, beer) are antiscorbutic and cure human scurvy as well as the form artificially induced in animals. Drying or heating some of the effective substances to 110° reduces the antiscorbutic effect.

1 Stepp, W.: "Biochemische Zeitschrift," 1909, xxii, 452.

2 Stepp, W.: "Zeitschrift fur Biologie," 1911-12, lvii, 135. 3 Stepp, W.: Ibid., 1913, lxii, 405.

4 Hoist and Frolich: "Zeitschrift fur Hygiene," 1912, lxxii, 1.