SIGNIFICANCE OF FOREIGN CONTRIBUTIONS TO PRESENT KNOWLEDGE IN THE FIELD OF ARTHRITIS AND METABOLIC DISEASES

The National Institute of Arthritis and Metabolic Diseases, having its origin in several of the oldest research laboratories of the Public Health Service, has maintained interest and activity in a large number of disease areas of medicine. This broad interest is reflected in the title of NIAMD's immediate antecedent, the Experimental Biology and Medicine Institute. The disease areas of present principal concern are the following: diabetes mellitus, arthritis and related rheumatic or collagen diseases, diseases of nutrition and metabolism, diseases of the endocrine glands (thyroid, parathyroid, adrenal), diseases of the blood, and disorders of the gastrointestinal tract.

A majority of the outstanding scientific contributions and accomplishments in these fields up through the nineteenth century came from European physicians, chemists, and physiologists. With the development of the Hopkins system of medical education in 1890, however, and the gradually improving training of young American physicians in scientific methods of medical research, American contributions steadily increased and are now predominant in the expanding attack on disease. Also during the past fifty years, American chemists and biologists have more frequently produced fundamental advances of value to medicine, although an impressive number of important contributions continue to come from foreign scientists.

DIABETES

Scientific definition and understanding of the complex disorder of carbohydrate metabolism known as diabetes mellitus began during the 17th century in England when Dr. Robert Willis, friend of Isaac Newton and Christopher Wren, first reported the sweet taste of the urine of diabetic patients and thereby differentiated diabetes mellitus, "sugar diabetes," from diabetes insipidus, or "water diabetes." Patients with the latter disease also pass large volumes of urine, but do so as the result of a specific lesion in the posterior lobe of the pituitary gland, and their urine does not contain sugar.

In mid-19th century Claude Bernard of Paris discovered glycogen, the principal storage form of sugars (in the liver and in muscle), and recognized this material as a source of the sugar of the blood. Within the past few years in NIAMD laboratories, Drs. DeWitt and Marjorie Stetten have added greatly to our knowledge of the forms and mechanisms of storage and release of glycogen.

During the hey-day of descriptive medicine, Adolf Kussmaul, a German, in 1874 not only delineated the classic breathing of the patient in diabetic coma, but related the forceful respirations to the body's need to extrude toxic acidic substances produced during severe alteration of the processes of burning and storage of sugar.

An extremely important landmark in diabetic progress was reached in 1890 when definite association between the pancreas and diabetes was shown by the Germans, Oskar Minkowski and Joseph von Mehring. They found that when the pancreas was removed from dogs, permanent diabetes resulted, corresponding to a severe form of this disease in man. Another German, Paul Langerhans, studied the microanatomy of the pancreas and recognized the small islets of tissue now named after him. Several investigators by the first decade of the 20th century obtained evidence suggesting the islets to be the sites of insulin production. A vigorous race to isolate insulin ensued, which was won in 1921 by the Canadians Sir Frederick Banting and Charles Best.

Use of insulin in the treatment of diabetes followed rapidly upon the development, largely by American pharmaceutical firms, of methods for its industrial production. Insulin was obtained as a pure crystalline protein by an American, John Abel, at Johns Hopkins in 1926. English workers at Cambridge, Sanger and his associates, then established its chemical structure, the first protein for which a complete chemical formula could be written. As an important means of reaching more rapidly the day of better and simpler control and ultimate understanding of diabetes, investigators are now engaged in the rigorous work of determining the precise spatial and bonding configurations of insulin structure which are responsible for its action on sugar in the body.

Coincident with the effort to isolate insulin and evaluate its action, extensive studies have been made of the fundamental processes of metabolism by which glucose is utilized in the body controlled by the catalysts known as enzymes. The contributions of Warburg and Meyerhof in Germany (from 1920 on) have been pre-eminent in formulation of these important metabolic pathways, as have also the studies of Carl and Gerty Cori, Austrians working in this country. Extension of basic carbohydrate metabolism studies has been an important part of NIAMD's activities in this field.

Another extremely important aspect of diabetic research, particularly during the past 30 years, has been the physiological approach. Physiological studies endeavor to elucidate the regulation of carbohydrate and fat metabolism by the complex interplay between the secretions of the anterior pituitary, the adrenal cortical hormones, and in some instances the hormone of the adrenal medulla. Foremost in these at once competitive and collaborative endeavors have been Bernardo Houssay of Argentina, F. G. Young of England, and in this country, C. N. H. Long (English), W. C. Stadie, Richard de Bodo (Hungarian) and Rachmiel Levine; the latter is particularly noteworthy because of his elucidation (1950) of the primary mechanism by which the hormone insulin exerts its action (by increasing the permeability of membranes to various sugars). The investigations of these several scientists have in various ways contributed greatly toward understanding of the disturbance in hormonal balance thought to exist in diabetes.

THE RHEUMATIC DISEASES

The rheumatic diseases comprise a number of clinical disorders of the joints and connective tissues of the body. Rheumatoid arthritis, rheumatic fever, osteoarthritis, gout, spondylitis, disseminated lupus

erythematosus, polyarteritis, and scleroderma are the principal members of this group. These disabling afflictions are among the oldest of known diseases; prehistoric skeletons disinterred in Egypt, for example, have shown some of the deformities of rheumatoid arthritis. In ancient Greek times the physician Alexander of Tralles (525-605 A. D.) prescribed colchicine for gout, and this drug is still the sovereign therapeutic agent for this disease.

Up to the beginning of the 20th century, principal advances were made in the difficult task of unraveling the complex clinical characteristics of these various diseases. English physicians showed the greatest aptitude in this respect, as Thomas Sydenham in 1676 gave the first full description of acute rheumatic fever and in 1683 distinguished between it and gout. David Pitcairn (1788) was the first to associate rheumatism with the heart, and Scudamore in 1827 asserted that the true pathology of chronic rheumatism was an inflammation of the white fibrous tissues of the body (ligaments and tendons) and not the fleshy parts of muscle. A most important step in gout was the recognition in 1848 by A. B. Garrod that the tophi of this disease consist of uric acid crystals and his demonstration by means of a thread that the blood of gouty patients contains an excess of uric acid. This English physician also coined the term "rheumatoid arthritis," and his son, A. E. Garrod, in 1907 distinguished correctly and clearly between rheumatoid arthritis and osteoarthritis. The first accurate description of spondylitis, on the other hand, was the early (17th century) contribution of an Irishman, Bernard Connor. The distinctive microscopic lesion in heart muscle which identifies rheumatic heart disease was made by a German, Aschoff, in 1904. Among the less common collagen diseases, lupus erythematosus was recognized in 1872 as a systemic disease and not simply a skin disorder by Kaposi, an Austrian, and the complications within various organs of the body were described by Osler, a Canadian, a few years later (1895) while at Hopkins. The means of making a virtually specific pathologic confirmation of a clinical diagnosis was provided in 1935 by Baehr and Klemperer (American and German) who described "wire loop" kidney lesions. An American, Hargraves, in 1948 made an important contribution to clinical laboratory diagnosis by discovering a distinctive cell in the circulating blood.

Clinical and pathologic descriptions of polyarteritis go back nearly 200 years, but the Germans, Rokitansky (1852) and Kussmaul (1866), are given credit for the most appropriate delineations of the distinctive arterial lesions of this disease. The suggestion that polyarteritis is due to an allergic or hypersensitivity phenomenon was suggested by a German, Gruber, in 1925, but classical demonstration that the typical lesions could be experimentally produced by a hypersensivity reaction was made by the American pathologist, Rich, in 1942. The disease, scleroderma, was apparently earliest described during the 17th and 18th centuries by Italian and Dutch physicians. Recognition that the hardening process of this disorder was not limited to the skin was made variously by an Englishman, Finlay, in 1891, who noted fibrosis of the lungs, by Ehrman, an Austrian, in 1903, who found thickening of the esophagus, and by an American, Rake, who in 1931 noted involvement of the intestine.

The past 20 years has seen an intensification of interest in the rheumatic diseases and the application of varied and sophisticated research techniques. These latter have been directed toward fundamental studies of connective tissue structure and metabolism, the relationship of infectious agents, investigation of hypersensitivity mechanisms, and study of the influence of endocrine hormones. In rheumatic fever more definite progress has been made than in the other connective tissue diseases. The suppressive action of salicylates on acute attacks was noted at least as early as the nineteenth century by various European physicians; involvement of the hemolytic streptococcus was suspected by German investigators at the end of the last century, but laboratory evidence for its close association was obtained by Coburn (1931) and other Americans; the prophylactic value of antibiotics on the recurrence of the disease has been observed (Thomas, Coburn, and other Americans, 1939); and the therapeutic efficacy of adrenal cortical steroids realized (Hench and others, 1949). The most stimulating recent contribution in the field has been the striking effect of cortisone (Hench and Kendall, 1948, Mayo Clinic) on the acute symptoms of rheumatoid arthritis. American pharmaceutical firms are now industriously synthesizing various modifications of the adrenal cortical steroid molecule (being tested clinically and in animals in various American medical centers) in the effort to obtain a more effective, less toxic therapeutic agent. Other important developments in rheumatoid arthritis during this century have been the introduction of gold salt therapy in 1927 by Lande and Pick (Germans) and in 1929 by Forestier (French); a significant advance in serological testing for the disease by Waaler, a Norwegian, in 1940, who first employed sensitized sheep cells for agglutination; and definition of vasculitis as the important pathogenetic lesion in the subcutaneous nodule (1953, Sokoloff, an American now at NIAMD, NIH).

NUTRITION AND METABOLISM

The science of nutrition and metabolism owes its inception and early development mainly to contributions during the 18th and 19th centuries, first from the English and French and later from the Germans. Discovery of oxygen, the "fire air" or air of life is generally attributed to the Englishman, Priestley, who was in communication with Lavoisier and Seguin in Paris. The latter investigators in approximately 1790 made a key experiment (both the heat and the carbon dioxide produced by a guinea pig in a given time were found equivalent to the heat and the carbon dioxide produced by burning a specific quantity of carbon) which demonstrated the significance of the respiratory process in relation to the utilization of food for energy. Extension of these studies to man with further understanding of the metabolic processes by which food is burned in oxygen to yield energy for life and growth were carried out by the French, Regnault and Reiset, and by the Germans, Liebig (divided foods into proteins, fat, and carbohydrates), Bidder and Schmidt (established basal metabolism), Pettenkofer, Voit, and Rubner (demonstrated physical law of conservation of energy in the animal body). Respiratory metabolism studies were then largely carried forward in this country, by Atwater, Benedict, Lusk, and Dubois, mainly during the first 30 years of this century, and are now with modern dynamic tech

niques being pushed forward again in a very few centers, including NIAMD in NIH.

Knowledge of the metabolism of proteins was advanced particularly by the German, Emil Fischer, who at the end of the 19th century devised quantitative methods for isolating amino acids and showed specificity of enzyme action, and by Folin (Swedish, 1912) and VanSlyke (American, 1913) who studied the breakdown' metabolic processes of proteins. In 1937, the American, W. C. Rose, demonstrated the thesis that there are 10 amino acids essential for the building of body protein. Advances in carbohydrate metabolism owe much to the Germans, Fischer, Embden, and Meyerhof, at the turn of the century (pathways of metabolism), to the Englishman Cathcart (1909, protein-sparing action) and to others mentioned in the diabetes section. Studies of the metabolism of fat have been principally conducted since 1900. Liebig (German) showed fat synthesis from carbohydrates; Lebedev (1882, Russian) found that dietary fats could be deposited in the body; Knoop (1905, German) determined the chief process of breakdown, or catabolism; and Lusk (1922, American) studied fat synthesis from protein.

The importance of the accessory dietary substances now known as vitamins first began to be appreciated with the discovery in 1747 by the British naval surgeon Lind that citrus fruits were effective preventives of scurvy. Isolation and identification of vitamin C, however, the factor whose absence is responsible for this disease, was not made until 1932 when it was crystallized by Americans, Waugh and C. G. King (the latter at present a member of NIAMD's National Advisory Council). First experimental evidence that accessory food factors were essential, representing the true beginning of vitamin research, came from Lunin in the Swiss laboratory of Bunge who in 1884 showed that there was a growth factor in natural milk not present in synthetic milk. The chemical constitution of this factor, vitamin A, was finally determined in 1933 by Karrer of Switzerland, although much of the early work leading to this achievement was carried out at Yale and Wisconsin Universities, and crystallization was achieved by an American, Holmes, in 1934. In the treatment of rickets, a Russian, Schabad, in 1909, was apparently the first to appreciate cod liver oil as being more important than minerals; isolation of an anti-rachitic substance named vitamin D was made in 1920 by both British and American workers, the preparation of a highly concentrated substance being made by Zucker, an American, in 1921. Recognition of beri-beri as a dietary disease was made (1883) by a Japanese naval medical officer, Takaki. Vitamin B, or thiamine, which cures beri-beri, was first crystallized in 1926 by Jansen and Donath in Amsterdam, but earlier the preparation of an impure concentrate in 1911 by Casimir Funk, a Pole working in London, prompted him to coin the term "vitamin" for those dietary factors which we now recognize as being required in very small amounts. Lohman and Schuster (Germans) showed that thiamine is a co-factor for an important enzyme system involved in the metabolism of carbohydrate.

Other members of the "vitamin B complex" have been even more difficult to track down. The recognition of niacin as a cure for pellagra stems from the work of Goldberger (American, U. S. Public Health Service, 1925), who showed that the disease is not infectious