DAM, [CARL PETER] HENRIK

(b. Copenhagen, Denmark, 21 February 1895; d. Copenhagen, 17 April 1976)

biochemistry.

Henrik Dam, son of Emil Dam, a pharmaceutical chemist, and Emilie Peterson, a teacher, was educated at the Copenhagen Polytechnic Institute. After graduating with the M.Sc. in chemistry (1920), he became an instructor in chemistry at the Royal School of Agriculture and Veterinary Medicine in Copenhagen (1920) and an instructor in biochemistry under Valdemar Henriques at the physiological laboratory of the University of Copenhagen (1923). On 15 July 1924 Dam married Inger Marie Martha Sophie Olsen. He studied microchemistry with Fritz Pregl in Graz, Austria (1925). In 1928 he was appointed assistant professor, and the following year promoted to associate professor, at the Institute of Biochemistry at the University of Copenhagen. Here he made his first observations that led by stages to the discovery of the blood-coagulation factor, vitamin K, and other bioquinones.

During the years 1932 and 1933 Dam worked at the laboratory of Rudolf Schoenheimer in Freiburg, Germany, thanks to a Rockefeller fellowship he obtained to further his studies of the metabolism of sterols. In 1933 he received the D.Sc. in biochemistry at the University of Copenhagen with a thesis entitled Nogle undersøgelser over sterinernes biologiske betydning (Some Investigations on the Biological Significance of the Sterols). Thenext year Dam worked with Paul Karrer in Zurich. He continued to hold his post as associate professor until his appointment as professor of biochemistry at the Polytechnic Institute in Copenhagen. This appointment, however, was in absentia, because since 1940 Dam was on a lecture tour to the United States and Canada under the auspices of the American-Scandinavian Foundation. The tour was planned before the occupation of Denmark by German troops in April 1940.

Dam spent the war years in the United States and returned to Denmark in June 1946. During this period he did research work at the Woods Hole Marine Biological Laboratories during the summer and autumn of 1941 and was a senior research associate at the Strong Memorial Hospital of the University of Rochester (1942–1945) and an associate member of the Rockefeller Institute for Medical Research in New York City (1945–1946). In the spring of 1949 Dam made a three month lecture tour of the United States and Canada that was arranged by the American-Scandinavian Foundation. His topic was the role of peroxidation in vitamin E deficiency.

Until his retirement in 1965 Dam was professor at the Polytechnic Institute in Copenhagen. In 1950 his chair was changed to that of biochemistry and nutrition. From 1956 to 1963 he also was head of the biochemical division of the Danish Fat Research Institute.

During the years 1928 to 1910 Dam studied the cholesterol metabolism of chicks at the Biochemical Institute of the University of Copenhagen. It was already known that rats, mice, and dogs can synthesize cholesterol, but some experiments seemed to show that chicks could not thrive on a sterolfree diet. Dam repeated experiments on cholesterol content of chicks that had been reported by John Addyman Gardner at the St. George’s Hospital Medical School at London in 1914. Dam used artificial, practically sterol-free diets consisting of casein, starch, marmite, salts, and paper (to supply indigestible matter) to which vitamins A and D were added. He found that chicks are able to synthesize cholesterol and to break it down. During his researches Dam observed that some of the chicks unexpectedly exhibited a marked bleeding tendency resembling that of scurvy. They displayed hemorrhages under the skin, in muscle, or in other tissues, and the blood coagulated more slowly than normally. Dam reported his findings in two articles in the German periodical Biochemische Zeitschrift (1929, 1930).

The observation of the hemorrhagic disease in chicks was also reported by William Douglas McFarlane and his associates William Richard Graham, Jr. and Frederik Richardson at the Ontario Agricultural College at Guelph, Canada (1931). During experiments to determine the need of chicks for fat-soluble vitamins, they related blood-clotting time to an ether-soluble substance in fish meal. The disease was also observed by Walther F. Holst and Everett R. Halbrook at the University of California at Berkeley (1933). They found that it could be prevented by fresh cabbage and drew the wrong conclusion that the protective factor in the cabbage was vitamin C.

After Dam returned from Freiburg to Copenhagen in the fall of 1933, he took up the research again. In June 1934 he published the detailed “Haemorrhages in Chicks Reared on Artificial Diets: A New Deficiency Disease,” Dam included gizzard erosions as a characteristic of the disease, but later it was found that the cause of this was unrelated to the blood-clotting factor. In his experiments Dam showed that parenteral injections of ascorbic acid (vitamin C) failed to prevent the disease, but that an addition of hempseed to the food prevented the bleeding. He came to the conclusion that the hemorrhagic disease in chicks was owing to the lack of a hitherto unrecognized deficiency factor in the diet occurring in seeds and cereals.

With his associate Fritz Schønheyder, Dam examined a number of animal organs and plant materials for their ability to protect against hemorrhagic disease. They found that the cause of hemorrhages could not be the lack or low content of cholesterol in the diet, nor the low amount of fat, nor a lack of vitamin C, but a dietary lack of antihemorrhagic vitamin. It appeared that green leaves and hog liver were among the most potent sources of this factor (1934). It was also found that the factor was fat soluble. In 1935 they characterized the antihemorrhagic factor as a new fat-soluble vitamin, which was not identifiable with vitamins A, D, or E, that had been found to be essential in trace quantities in the diet. Dam and Schønheyder designated it as vitamin K because K was the first letter of the Scandinavian and German word Koagulation (coagulation). The existence of this vitamin K was promptly confirmed by Herman James Almquist and Evan Ludvig Stokstad at the University of California (1935).

Dam and his associates next carried out studies in order to discover how the new vitamin acted on blood clotting, how it could be concentrated, and whether it played any part in other animals and in humans. They found the new nutrient to be present in large amounts in hog liver fat and also in a number of cereals, seeds, vegetables, fruits, animal organs, and fats.

In 1935 Schønheyder showed that blood plasma from normal chicks accelerated the clotting of the plasma from K-avitaminous chicks. It appeared that calcium, fibrinogen, and thromboplastin were not reduced in quantity in the K-avitaminous chicks. Dam, Schønheyder, and Erik Tage-Hansen (1936) were also able to explain the mechanism by which vitamin K produces its results they did experiments that greatly extended the knowledge of the nature of hemorrhagic disease. The amount of prothrombin, a substance formed in the liver, was below normal in the blood of birds fed diets deficient of vitamin K, The blood of chicks became depleted of prothrombin in about three weeks on vitamin K-deficient diets. Three days after feeding with vitamin K-rich preparations, the chicks’ prothrombin returned to normal, as did the clotting time of the blood. Deficiency of vitamin K leads to a lack of prothrombin and thus to a lack of thrombin, which forms fibrinogen in the blood. In consequence, fibrinogen cannot be formed into the fibrin necessary for the coagulation of the blood.

Immediately after the discovery of vitamin K, its chemical properties were studied mainly by Dam and his associates and by Almquist and his group. With Schønheyder, Johannes Glavind, Liese Lewis, and Tage-Hansen, Dam developed a method for the preparation of very strong concentrates from alfalfa (1938). Having improved the method further. Dam worked on isolating and characterizing vitamin K. This investigation, carried out in collaboration with Karrer, resulted in a joint publication from the Chemical Institute of the University of Zurich and the Biochemical Institute of the University of Copenhagen, “Isolierung des Vitamin K in hochgereinigter Form” (1939). Dam, Karrer, and their associates prepared pure vitamin K from dried plant materials, in particular from dried alfalfa, by means of fat solvents. It was concentrated by the removal of chlorophyll through selective adsorption, the removal of crystalline nonactive substances by chilling of an acetone solution of the remaining material, by fractional distillation at a pressure of 10^-3 millimeters mercury and a temperature of 115–140°C. Through this process the vitamin moved up the condenser and was finally purified by repeated chromatographic adsorption. The vitamin was obtained in the form of a light yellow oil. The elementary composition was found to be 82.2 percent carbon, 10.7 percent hydrogen, and 7.1 percent oxygen. The substance gave a characteristic color reaction with sodium ethylate and showed an adsorption spectrum in the ultraviolet region that pointed to a connection with 1, 4-quinone.

The pure vitamin K was isolated nearly simultaneously by Edward Adelbert Doisy’s group in the laboratory of biological chemistry at St. Louis University School of Medicine, by Louis Frederick Fieser’s group at the Conserve Memorial Laboratory at Harvard University, and by Almquist (1939). They succeeded in the elucidation of its constituents. It was established that the structure of vitamin K from green plants (vitamin K₁) was phylloquinone or 2-methyl-3-phytyl-1, 4-naphthoquinone. (Phytyl is the radical of the twenty-carbon alcohol phytol with four isoprene units.)

Doisy’s group also isolated a vitamin K by the putrefaction of ether-extracted fish meal, which chemically differs slightly from vitamin K as reported by Dam, Karrer, and associates. Its structure appears similar to vitamin K, but it has a side chain of seven isoprene units (vitamin K₂, menaquinone, or 2-methyl-3-polyprenyl-1, 4-naphthoquinone). The interest in the chemistry of vitamin K followed from the fact that the July 1939 issue of the Journal of the American Chemical Society contained six preliminary communications on vitamin K compounds, and the September 1939 issue, seven.

Dam made no investigations on the structure of vitamin K. He was mainly interested in experiments with vitamin K and vitamin K-active compounds using rats and rabbits as experimental animals. With Glavind (1938) he found that vitamins K are synthesized by plants and by certain microorganisms. The synthesis appears to be greatly influenced by sunlight. Peas grown in the dark contain only small amounts, while control plants raised in light contain considerably more. Coli bacteria synthesize vitamin K on an artificial medium that has only glucose, citrate, and asparagin as organic constituents (1941). Later Dam found vitamin K in the green alga Chorella vulgaris and in a lesser amount in some photosynthesizing bacteria (1944).

In studies on other vitamin K compounds, Dam, Glavind, and Karrer (1940) found that if vitamins K₁ and K₂ are converted into the diacetates of the corresponding hydroquinones, the activity is some-what reduced. Hydrogenation of the double bond in the phytyl group of vitamin K₁ results in a lowering of the activity and replacement of the methyl group. Vitamin K activity was also found in a number of simpler but related substances, such as 2-methyl-1, 4-naphthoquinone of menadione, and numerous esters of derived quinols. In 1949 Dam found that 5-methyl-4, 7-thionaptenequinone, an isostere of menadione, has about 3 percent of the vitamin K activity of menadione.

Dam further studied vitamin K not only with respect to its occurrence and biological function in animals and plants, but also with respect to its application in human medicine. In 1938 he and Glavind clinically demonstrated the usefulness of vitamin K for hemorrhagic diseases in man. The first hemorrhagic condition in man that was recognized as owing to lack of vitamin K was the cholemic bleeding tendency that poses a great danger in surgery on patients with obstructive jaundice. Suitable administration of vitamin K eliminates the risk of fatal bleeding, which was shown to be owing to insufficient absorption of vitamin K from the intestine in the absence of bile.

The most frequent form of the K-avitaminosis in man is that of the infant during the first few days of life. Dam, Tage-Hansen, and P. Plum studied neonatal bleeding disorders (1939). They found that this bleeding tendency can be prevented by the administration of vitamin K to the infant immediately after birth or by administration of an excess of vitamin K to the mother a suitable time before delivery. This type of bleeding tendency results from limitation of the passage of vitamin K from mother to fetus.

The mechanism of the coagulation of the blood was envisaged as a complex but ordered succession of processes. The coagulation of the blood is owing to the transformation of the protein fibrinogen into a close network of fibrin in whose meshes the blood corpuscles are caught. This transformation is caused by the action of the enzyme thrombin, which is derived from prothrombin with the aid of thromboplastin, a substance liberated from the injured cells. The lack of vitamin K was found to cause a drop in the prothrombin content, while a rapid increase occurred after the vitamin K had been added. Dam and Glavind (1940) showed that the effect of a given dose of vitamin K on the prothrombin level was quantitatively the same whether the disease was produced by a vitamin K—free diet or by choledochus ligature. Obviously vitamin K exerts a direct influence on the formation of the prothrombin, the precursor of the enzyme that is required for the coagulation. Therelation of vitamin K to the two components of prothrombin was studied by Dam in 1948.

In 1939 Dam was a recipient of the Christian Bohr Award in physiology for his discovery of vitamin K. In 1943 he was awarded the Nobel Prize in physiology or medicine for his discovery of vitamin K. The prize was shared with Doisy for his discovery of the chemical nature of vitamin K. On 27 October 1944, while war was still raging in Europe, the Caroline Institute in Stockholm made its decision about the Nobel Prizes in physiology or medicine for 1943 and 1944. Owing to the war conditions, it would have been impossible for the winners to come to Sweden. The American-Scandinavian Foundation was, therefore, asked to hold an awards ceremony at New York City in December 1944, at which the Swedish ambassador presented the prizes. On 12 December 1946, at Stockholm, Dam delivered his Nobel Prize Lecture, “The Discovery of Vitamin K, Its Biological Functions and Therapeutical Applications.”

From Dam’s studies in vitamin K arose the observation of some new symptoms in experimental animals, such as increased capillary permeability and coloration of adipose tissue, which turned out to be results of theingestion of certain fats in the absence of vitamin E. From 1937 Dam worked on vitamin E both in Copenhagen and in the United States. With Glavind he found that lack of vitamin E in chicks leads to a vascular disease causing alimentary exudative diathesis followed by increased capillary permeability and muscular dystrophy (1939). Lack of vitamin E will also cause encephalomalacia.In 1931 A. M. Pappenheimer and M. Goetsch had found that a high-fat, E-deficient diet caused the development in chicks of nutritional encephalomalacia, but in ducklings on the same dietary regimen muscular dystrophy resulted. Dam and Glavind (1939) found in chicks the development of exudative diathesis, characterized by the accumulation of plasma under the skin. The alimentary encephalomalacia, which was thought to be caused by lack of vitamin E, was shown in 1958 by Dam and his associates to be specifically dependent upon dietary fatty acids of the linoleic acid series concomitantly with the absence of vitamin E.

Other manifestations of vitamin E deficiency in chicks and rats were investigated with respect to their interrelationship to dietary fat and to the role of vitamin E as an antioxidant. In 1950 Dam, with l-L Granados and Erik Aaes-Jørgensen, reported that addition of sulfaguanidin to a diet with high cod-liver oil protected rats against peroxidation and yellow-brown coloration of the adipose tissue, but not against depigmentation of the incisors. They interpreted the influence on fat peroxidation as an in vivo autoxidant effect of sulfaguanidin and not as the result of the antibacterial action.

In the 1950’s Dam studied gallstones in his laboratory at Copenhagen. In hamsters he found that rearing on certain artificial diets induces formation of gallstones. When the diet is deficient in polyunsaturated fatty acids and carbohydrate is furnished as an easily absorbable sugar, cholesterol gallstones are formed abundantly. Other dietary combinations lead to the formation of amorphous pigmented gallstones.

After his retirement the main subjects treated by Dam were nutritional studies in relation to gallstone formation. During his scientific career Dam and his research school produced more than three hundred publications concerning vitamin K, vitamin E, and cholesterol. Dam wrote a number of review articles that are models of fairness and acumen as well as of deep scholarship. In collaboration with AaesJørgensen, Dam wrote two textbooks: Biokemi (1950) and Grundrids af biokemi og ernaering (1955). His accomplishments were honored with membership in the Danish Academy of Technical Sciences (1947) and the Royal Danish Academy of Sciences and Letters (1948), and election as foreign correspondent of the Académie Royale de Médecine de Belgique (1951) and as honorary fellow of the Royal Society of Edinburgh (1953). He was a fellow of the American Institute of Nutrition. In 1965 he received an honorary degree in sciences from St. Louis University.

BIBLIOGRAPHY

I. Original Works. Bibliographies of Dam’s writings are in S. Veibel, Kemien i Danmark, II. Dansk kemisk bibliograft 1800–1935 (Copenhagen, 1943), 119–122; and in Aarsberetninger for den Polyteknisk Laeranstalt 1945–1972 (Copenhagen).

His early writings include “Cholesterinstoffwechsel in Hühnereiern und Hünchen,” in Biochemische Zeitschrift, 215 (1929) 475–492; “Über die Cholesterinsynthese im Tierkörpern,” ibid., 220 (1930), 158–163; “A Deficiency Disease in Chicks Resembling Scurvy,” in Biochemical Journal, 28 (1934), 1355–1359. with Fritz Schønheyder; “Haemorrhages in Chicks Reared on Artificial Diets: A New Deficiency Disease,” in Nature, 133 (1934), 909–910; “The Antihaemorrhagic Vitamin of the Chick,” in Biochemical Journal, 29 (1935), 1273–1285; “The Occurrence and Chemical Nature of Vitamin K.” ibid., 30 (1936), 897–901, with Fritz Schonheyder; and “Studies on the Mode of Action of Vitamin K,” ibid., 1075–1079, with Frilz Schonheyder and Erik Tage-Hansen.

Later writings include “Anti-Encephalomalica Activity of de-α-Tocopherol,” in Nature, 142 (1938), 1157–1158, with Johannes Glavind, Ole Bernth, and Erik Hagens; “Vitamin K in Plant,” in Biochemical Journal, 32 (1938), 485–487, with J. Glavind and I. Svendson: “Clotting Power of Human and Mammalian Blood in Relation to Vitamin K.” in Acta medica scandinavica, 96 (1938) 108–128, with J. Glavind; “Vitamin K Lack in Normal and Sick Infants.” in Lancet (1939), 2. 1157–1161, with E. Tage-Hansen and P. Plum; “Alimentary Exudative Diathesis, a Consequence of E-Avitaminosis” in Nature, 143 (1939), 810–811, with Johannes Glavind; “Isolierung des Vitamin K in hochgereinigter Form,” in Helvetica chimica acta, 22 (1939), 310–313, with P. Karrer, A. Geiger, J. Glavind, W. Karrer, E. Rothschild, and H. Salomon; “Die biologische Aktivität der natürlichen K-Vitamine und einiger verwandter Verbindungen,” in Helvetica chimica acta, 23 (1940), 224–233, with Johannes Glavind and Paul Karrer; “Bildung von Vitamin K in Colibakterien auf synthetischem Substrat,” in Die Naturwissenschaften, 29 (1941), 287–288, with J. Glavind, S. Orla-Jensen. and A. D. OrlaJensen; “Vitamin K in Unicellular Photosynthesizing Organisms,” in American Journal of Botany, 31 (1944), 492–493; “Dicumarol Poisoning and Vitamin K Deficiency in Relation to Quick’s Concept of the Composition of Pro thrombin,” in Nature, 161 (1948), 1010–1011; “Observations on Experimental Dental Caries. Effect of Certain Quinones with, and without Vitamin K Activity,” in Acta pathologica et microbiologica scandinavica, 26 (1949), 597–602, with H. Granados and J. Glavind; and “Influence of Sulphaguanidin on Certain Symptoms of Vitamin E Deficiency in Rats,” in Experientia, 6 (1950), 150–152, with H. Granados and E. Aaes-Jørgensen.

Dam wrote a number of review articles, including “Vitamin K, Its Chemistry and Physiology,” in Advances in Enzymology and Related Subjects, 2 (1942), 285–324; “Vitamin K,” in Vitamins and Hormones. Advances in Research and Application, VI (New York, 1948), 27–53; “Fat-soluble Vitamins,” in Annual Review of Biochemistry, 20 (1951), 265–304; “The Biochemistry of Fat-soluble Vitamins,” in R. T. Holman, W. O. Lundberg, and T. Malkin, eds., Progress in the Chemistry of Fats and Other Lipids, ill (London and New York, 1955), 153 212; and “The Determination of Vitamin K,” in Paul Gÿorgy and W. N. Pearson, eds., The Vitamins, Chemistry, Physiology, Pathology, Methods, 2nd ed., VI (New York, 1967), 245–260.

Dam’s Nobel Lecture is in Nobel Lectures: Physiology or Medicine, 1942–1962 (Amsterdam, London, and New York, 1964), 8–24.

II. Secondary Literature. Current Biography 1949 (New York, 1950), 135–136; “Henrik Dam,” in McGraw-Hill Modern Men of Science (New York, 1966), 125–126; R. A. Morton, “Obituary,” in Nature, 261 (1976), 621; E. Rancke-Madsen. “Carl Peter Henrik Dam,” in Dansk biografisk leksikon, III (Gyldendal, 1979), 556; and H. H. Ussing, “Henrik Dam. 21. februar 1895–17. april 1977,” in Oversigt over det K. danske videnskabernes selskabs forhandlinger (1976–1977), 98–103.

H. A. M. Snelders