by Isaac Asimov
A century later, in 1884, Admiral Kanehiro Takaki of the Japanese navy similarly introduced a broader diet into the rice monotony of his ships. The scourge of a disease known as beri-beri came to an end in the Japanese navy as a result.
In spite of occasional dietary victories of this kind (which no one could explain), nineteenth-century biologists refused to believe that a disease could be cured by diet, particularly after Pasteur’s germ theory of disease came into its own. In 1896, however, a Dutch physician named Christiaan Eijkman convinced them almost against his own will.
Eijkman was sent to the Dutch East Indies to investigate beri-beri, which was endemic in those regions (and which, even today, when medicine knows its cause and cure, still kills 100,000 people a year). Takaki had stopped beri-beri by dietary measures; but the West, apparently, placed no stock in what might have seemed merely the mystic lore of the Orient.
Supposing beri-beri to be a germ disease, Eijkman took along some chickens as experimental animals in which to establish the germ. A highly fortunate piece of skulduggery upset his plans. Without warning, most of his chickens came down with a paralytic disease from which some died; but after about four months, those still surviving regained their health. Eijkman, mystified by failing to find any germ responsible for the attack, finally investigated the chickens’ diet. He discovered that the person originally in charge of feeding the chickens had economized (and no doubt profited) by using scraps of leftover food, mostly polished rice, from the wards of the military hospital. It happened that after a few months a new cook had arrived and taken over the feeding of the chickens; he had put a stop to the petty graft and supplied the animals with the usual chicken feed, containing unhulled rice. It was then that the chickens had recovered.
Eijkman experimented. He put chickens on a polished-rice diet, and they fell sick. Back on the unhulled rice, they recovered. It was the first case of a deliberately produced dietary-deficiency disease. Eijkman decided that this polyneuritis that afflicted fowls was similar in symptoms to human beri-beri. Did human beings get beri-beri because they ate only polished rice?
For human consumption, rice was stripped of its hulls mainly so that it would keep better, for the rice germ removed with the hulls contains oils that go rancid easily. Eijkman and a co-worker, Gerrit Grijns, set out to see what it was in rice hulls that prevented beri-beri. They succeeded in dissolving the crucial factor out of the hulls with water, and found that it would pass through membranes that would not pass proteins. Evidently the substance in question must be a fairly small molecule. They could not, however, identify it.
Meanwhile other investigators were coming across other mysterious factors that seemed to be essential for life. In 1905, a Dutch nutritionist, Cornelis Adrianis Pekelharing, found that all his mice died within a month on an artificial diet that seemed ample as far as fats, carbohydrates, and proteins were concerned. But mice did fine when he added a few drops of milk to this diet. And in England, the biochemist Frederick Hopkins, who was demonstrating the importance of amino acids in the diet, carried out a series of experiments in which he, too, showed that something in the casein of milk would support growth if added to an artificial diet. This something was soluble in water. Even better than casein as the dietary supplement was a small amount of a yeast extract.
For their pioneer work in establishing that trace substances in the diet were essential to life, Eijkman and Hopkins shared the Nobel Prize in medicine and physiology in 1929.
ISOLATING VITAMINS
The next task was to isolate these vital trace factors in food. By 1912, three Japanese biochemists—Umetaro Suzuki, T. Shimamura, and S. Ohdake—had extracted from rice hulls a compound that was very potent in combating beri-beri. Doses of 5 to 10 milligrams sufficed to effect a cure in fowl. In the same year, the Polish-born biochemist Casimir Funk (then working in England and later to come to the United States) prepared the same compound from yeast.
Because the compound proved to be an amine (that is, one containing the amine group, NH2), Funk called it a vitamine, Latin for “life amine.” He made the guess that beri-beri, scurvy, pellagra, and rickets all arise from deficiencies of “vitamines.” Funk’s guess was correct as far as his identification of these diseases as dietary-deficiency diseases was concerned. But it turned out that not all “vitamines” were amines.
In 1913, two American biochemists, Elmer Vernon McCollum and Marguerite Davis, discovered another trace factor vital to health in butter and egg yolk. This one was soluble in fatty substances instead of water. McCollum called it fat-soluble A, to contrast it with water-soluble B, which was the name he applied to the antiberi-beri factor. In the absence of chemical information about the nature of the factors, this seemed fair enough, and it started the custom of naming them by letters. In 1920, the British biochemist Jack Cecil Drummond changed the names to vitamin A and vitamin B, dropping the final e of vitamine as a gesture toward taking amine out of the name. He also suggested that the antiscurvy factor was still a third such substance, which he named vitamin C.
Vitamin A was quickly identified as a food factor required to prevent the development of abnormal dryness of the membranes around the eye, called xerophthalmia, from Greek words meaning “dry eyes.” In 1920, McCollum and his associates found that a substance in cod-liver oil, which was effective in curing both xerophthalmia and a bone disease called rickets, could be so treated as to cure rickets only. They decided the antirickets factor must represent a fourth vitamin, which they named vitamin D. Vitamins D and A are fat-soluble; C and B are water-soluble.
By 1930, it had become clear that vitamin B was not a simple substance but a mixture of compounds with different properties. The food factor that cured beri-beri was named vitamin B1, a second factor was called vitamin B2, and so on. Some of the reports of new factors turned out to be false alarms, so that one does not hear of B3, B4, or B5 any longer. However, the numbers worked their way up to B14. The whole group of vitamins (all water-soluble) is frequently referred to as the B-vitamin complex.
New letters also were added. Of these, vitamins E and K (both fat-soluble) remain as veritable vitamins; but vitamin F turned out to be not a vitamin, and vitamin H turned out to be one of the B-vitamin complex.
Nowadays, with their chemistry identified, the letters of even the true vitamins are going by the board, and most of them are known by their chemical names, though the fat-soluble vitamins, for some reason, have held on to their letter designations more tenaciously than the water-soluble ones.
CHEMICAL COMPOSITION AND STRUCTURE
It was not easy to work out the chemical composition and structure of the vitamins, for these substances occur only in minute amounts. For instance, a ton of rice hulls contains only about 5 grams (a little less than one-fifth of an ounce) of vitamin B1. Not until 1926 did anyone extract enough of the reasonably pure vitamin to analyze it chemically. Two Dutch biochemists, Barend Coenraad Petrus Jansen and William Frederick Donath, worked up a composition for vitamin B, from a tiny sample, but it turned out to be wrong. In 1932, Ohdake tried again on a slightly larger sample and got it almost right. He was the first to detect a sulfur atom in a vitamin molecule.
Finally, in 1934, Robert Runnels Williams, then director of chemistry at the Bell Telephone Laboratories, climaxed twenty years of research by painstakingly separating vitamin B1 from tons of rice hulls until he had enough to work out a complete structural formula. The formula follows:
Since the most unexpected feature of the molecule was the atom of sulfur (theion in Greek), the vitamin was named thiamine.
Vitamin C was a different sort of problem. Citrus fruits furnish a comparatively rich source of this material, but one difficulty was finding an experimental animal that does not make its own vitamin C. Most mammals, aside from humans and the other primates, have retained the capacity to form this vitamin. Without a cheap and simple experimental animal that would develop scurvy, it was difficult to follow the location of vitamin C among the various
fractions into which the fruit juice was broken down chemically.
In 1918, the American biochemists B. Cohen and Lafayette Benedict Mendel solved this problem by discovering that guinea pigs cannot form the vitamin. In fact, guinea pigs develop scurvy much more easily than humans do. But another difficulty remained. Vitamin C was found to be very unstable (it is the most unstable of the vitamins), so it was easily lost in chemical procedures to isolate it. A number of research workers ardently pursued the vitamin without success.
As it happened, vitamin C was finally isolated by someone who was not particularly looking for it. In 1928, the Hungarian-bern biochemist Albert Szent-Cyorgi, then working in London in Hopkins’s laboratory and interested mainly in finding out how tissues make use of oxygen, isolated from cabbages a substance that helped transfer hydrogen atoms from one compound to another. Shortly afterward, Charles Glen King and his co-workers at the University of Pittsburgh, who were looking for vitamin C, prepared some of the substance from cabbages and found that it was strongly protective against scurvy. Furthermore, they found it identical with crystals they had obtained from lemon juice. King determined its structure in 1933, and it turned out to be a sugar molecule of six carbons, belonging to the L-series instead of the D-series:
It was named ascorbic acid (from Greek words meaning “no scurvy”).
As for vitamin A, the first hint about its structure came from the observation that the foods rich in vitamin A are often yellow or orange (butter, egg yolk, carrots, fish-liver oil, and so on). The substance largely responsible for this color was found to be a hydrocarbon named carotene; and in 1929, the British biochemist Thomas Moore demonstrated that rats fed on diets containing carotene stored vitamin A in the liver. The vitamin itself was not colored yellow, so the deduction was that though carotene is not itself vitamin A, the liver converts it into something that is vitamin A. (Carotene is now considered an example of a provitamin.)
In 1937, the American chemists Harry Nicholls Holmes and Ruth Elizabeth Corbet isolated vitamin A as crystals from fish-liver oil. It turned out to be a 20-carbon compound-half of the carotene molecule with a hydroxyl group added:
The chemists hunting for vitamin D found their best chemical clue by means of sunlight. As early as 1921, the McCollum group (who first demonstrated the existence of the vitamin) showed that rats do not develop rickets on a diet lacking vitamin D if they are exposed to sunlight. Biochemists guessed that the energy of sunlight converts some provitamin in the body into vitamin D. Since vitamin D is fat-soluble, they went searching for the provitamin in the fatty substances of food.
By breaking down fats into fractions and exposing each fragment separately to sunlight, they determined that the provitamin that sunlight converts into vitamin D is a steroid. What steroid? They tested cholesterol, the most common steroid of the body, and that was not it. Then, in 1926, the British biochemists Otto Rosenheim and T. A. Webster found that sunlight would convert a closely related sterol, ergosterol (so named from the fact that it was first isolated from ergot-infested rye), into vitamin D. The German chemist Adolf Windaus made this discovery independently at about the same time.
For this and other work in steroids, Windaus received the Nobel Prize in chemistry in 1928.
The difficulty in producing vitamin D from ergosterol rested on the fact that ergosterol does not occur in animals. Eventually the human provitamin was identified as 7-dehydrocholesterol, which differs from cholesterol only in having two hydrogen atoms fewer in its molecule. The vitamin D formed from it has this formula:
Vitamin D in one of its forms is called calciferol, from Latin words meaning “calcium-carrying,” because it is essential to the proper laying down of bone structure.
Not all the vitamins show their absence by producing an acute disease. In 1922, Herbert McLean Evans and K. J. Scott at the University of California implicated a vitamin as a cause of sterility in animals. Evans and his group did not succeed in isolating this one, vitamin E, until 1936. It was then given the name tocopherol (from Greek words meaning “to bear children”).
Unfortunately, whether human beings need vitamin E, or how much, is not yet known. Obviously, dietary experiments designed to bring about sterility cannot be tried on human subjects. And even in animals, the fact that they can be made sterile by withholding vitamin E does not necessarily mean that natural sterility arises in this way.
In the 1930s, the Danish biochemist Carl Peter Henrik Dam discovered by experiments on chickens that a vitamin is involved in the clotting of blood. He named it Koagulationsvitamine, and this was eventually shortened to vitamin K. Edward Doisy and his associates at St. Louis University then isolated vitamin K and determined its structure. Dam and Doisy shared the Nobel Prize in medicine and physiology in 1943.
Vitamin K is not a major vitamin or a nutritional problem. Normally a more than adequate supply of this vitamin is manufactured by the bacteria in the intestines. In fact, they make so much of it that the feces may be richer in vitamin K than the food is. Newborn infants are the most likely to run a danger of poor blood clotting and consequent hemorrhage because of vitamin-K deficiency. In the hygienic modern hospital, it takes infants three days to accumulate a reasonable supply of intestinal bacteria, and they are protected by injections of the vitamin into themselves directly or into the mother shortly before birth. In the old days, the infants picked up the bacteria almost at once; and though they might die of various infections and disease, they were at least safe from the dangers of hemorrhage.
In fact, one might wonder whether organisms could live at all in the complete absence of intestinal bacteria, or whether the symbiosis had not become too intimate to abandon. However, germ-free animals have been grown from birth under completely sterile conditions and have even been allowed to reproduce under such conditions. Mice have been carried through twelve generations in this fashion. Experiments of this sort have been conducted at the University of Notre Dame since 1928.
During the late 1930s and early 1940s, biochemists identified several additional B vitamins, which now go under the names of biotin, pantothenic acid, pyridoxine, folic acid, and cyanocobalamine. These vitamins are all made by intestinal bacteria; moreover, they are present so universally in foodstuffs that no cases of deficiency diseases have appeared. In fact, investigators have had to feed animals an artificial diet deliberately excluding them, and even to add antivitamins to neutralize those made by the intestinal bacteria, in order to see what the deficiency symptoms are. (Antivitamins are substances similar to the vitamin in structure. They immobilize the enzyme making use of the vitamin by means of competitive inhibition.)
VITAMIN THERAPY
The determination of the structure of each of the various vitamins was usually followed speedily (or even preceded) by synthesis of the vitamin. For instance, Williams and his group synthesized thiamine in 1937, three years after they had deduced its structure. The Polish-born Swiss biochemist Tadeus Reichstein and his group synthesized ascorbic acid in 1933, somewhat before the structure was completely determined by King. Vitamin A, for another example, was synthesized in 1936 (again somewhat before the structure was completely determined) by two different groups of chemists.
The use of synthetic vitamins has made it possible to fortify food (milk was first vitamin-fortified as early as 1924) and to prepare vitamin mixtures at reasonable prices and sell them over the drugstore counter. The need for vitamin pills varies with individual cases. Of all the vitamins, the one most likely to be deficient in supply is vitamin D. Young children in northern climates, where sunlight is weak in winter time, run the danger of rickets and may require irradiated foods or vitamin supplements. But the dosage of vitamin D (and of vitamin A) should be carefully controlled, because an overdose of these vitamins can be harmful. As for the B vitamins, anyone eating an ordinary, rounded diet does not need to take pills for them. The same is true of vitamin C, which in any case should not present a problem, for there are few people who do not enjoy orange juice or
who do not drink it regularly in these vitamin-conscious times.
On the whole, the wholesale use of vitamin pills, while redounding chiefly to the profit of drug houses, usually does people no harm and may be partly responsible for the fact that the current generation of Americans is taller and heavier than previous generations.
During the 1970s, schemes for megavitamin therapy were advanced. There were suggestions that minimum quantities of vitamins that were sufficient to stave off deficiency diseases were not necessarily enough for optimum working of the body or were not enough to stave off some other diseases. It was maintained, for instance, that large doses of some B vitamins might ameliorate schizophrenic conditions..
The most important exponent of megavitamin therapy is Linus Pauling who, in 1970, maintained that large daily doses of vitamin C would prevent colds and would have other beneficial effects on health. He has not convinced the medical profession generally; but the general public, which always accentuates the positive in connection with vitamins (especially since they are readily available and quite cheap), stripped the druggists’ shelves of vitamin C in their eagerness to gulp it down.
