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Marrack, John Richardson

MARRACK, JOHN RICHARDSON

(b. Clevedon, Somerset, England, 26 November 1886; d. Houston, Texas, 13 June 1976)

immunology, Chemical pathology, nutrition.

Marrack, the second son of the three sons and one daughter of John Read Marrack, a mathematics teacher, and of Mary Saunders, was educated at Blundell’s School in Tiverton, Devon. The school left a lasting impression on him, for it was there that his interest in the chemistry of biological phenomena began—sparked, so he said, when he heard of Friedrich Wöhler’s synthesis of urea. He decided to study medicine in order to make a living from this interest. Marrack went up to St. John’s College, Cambridge, on a mathematics scholarship and took a first in part I of the natural sciences tripos and a second in part II. He went on to the London Hospital Medical College as a Price Scholar for the clinical part of his studies.

A tough and vigorous man, Marrack played rugby for the hospital for about ten years, and represented it in wrestling and boxing. He was runner-up in the interhospital competition as a middleweight in 1910 and won the welterweight championship in 1912, holding it for the next seven years. His boxing came in handy when, at about the age of fifty, he was attacked by a gang that, it was said, had to be taken to the hospital in an ambulance. Throughout his life he loved cycling and walking.

Marrack completed his medical studies at Cambridge in 1912 with an M.A. and an M.D. Postgraduate honors included the John Lucas Walker Studentship, which supported his first research project, on rheumatoid arthritis, a disease from which his father had suffered. He also held the Beit Memorial Fellowship for Medical Research, which enabled him to work in the laboratories of the Cambridge Research Hospital (now the Strangeways Laboratory).

Marrack Joined the Royal Army Medical Corps during World War I, serving as battalion medical officer and bearer officer. He suffered a fractured femur at Ypres, was twice mentioned in dispatches, and was awarded the Distinguished Service Order and the Military Cross. In 1917 he transferred to work on the military uses of poison gases, and he ended the war in charge of a mobile pathology laboratory specializing in gas warfare.

After the war Marrack returned to Cambridge as lecturer in chemical pathology, but soon resigned to accept a post at London Hospital Medical College as lecturer and chemical pathologist. He was appointed professor in 1934. Marrack remained at the Hale Clinical Laboratories of London Hospital until his retirement in 1952.

In 1913 Marrack married Bertha Ada Fitzgerald Whiddington, whom he divorced in 1921; they had one son. His second marriage, in 1922, was to Alice May Swaffield Milward. Their three sons followed their father into medicine, starting, as he had done, from the London Hospital.

Marrack’s first years as lecturer were taken up with teaching and organizing routine services for the hospital. At the same time he collaborated with hospital clinicians and with the hospital’s morbid anatomist, Dorothy Russell, on problems such as the chemical changes in nephritis. His superior, Philip Noel Panton, director of the hospital’s laboratories, was the author of a textbook of clinical pathology that had appeared in 1913, and it was among Marrack’s duties to help him update it for successive editions. For the historian of immunology, the chapter “Immunity” of the (fourth) 1939 edition is a neat compendium of practical immunology or serology of the period. “Panton & Marrack,” as it was known, gives details of vaccines for localized infections using Staphvlococci and Gonococci, chronic nasal discharge, and even Robert Koch’s tuberculin preparation. Koch’s treatment is usually supposed by historians to have been discredited about 1900, soon after its introduction; Panton & Marrack says in 1939 that its use is “declining.” Much space is given to technical details of the Wassermann and Kahn tests for syphilis and their interpretation. Indeed, the word serology was often used to mean just those tests.

Clinical pathology in the early part of the century, under the voluntary hospital system, suffered from a lack of status and funding compared with clinical medicine. The London Hospital was unusually lucky in that it had been given an anonymous gift of £50,000 for medical research. Marrack therefore had the opportunity to do research as well as teaching and routine work. After some preliminary work on the physical chemistry of proteins, he began the series of papers on the antigen-antibody reaction that was to be his main interest.

The immunochemistry of the first half of the twentieth century derived from the practical problems with the assay of the diphtheria antiserum, introduced into medical practice in 1894. Much of the work centered on the reaction of diphtheria toxin and antitoxin. Conflicting views of this reaction had been proposed by Paul Ehrlich and by Jules Bordet around the turn of the century. Ehrlich’s theory claimed that the reaction was a purely chemical one, and Bordet’s that it was a physical adsorption of one component upon the other. Physical adsorption meant that the reaction was one of those typical of colloid chemistry, dependent on surface phenomena rather than on the chemical nature of the reactants. Bordet himself, and also Svante Arrhenius and Thorvald Madsen, later suggested a reversible acid-base neutralization as a model for the reaction. The work of Karl Landsteiner started from an opposition to Ehrlich’s point of view. By 1918 he had found evidence that antigenic specificity depends on the charge outline of an antigen, thus implicating both surface phenomena and the chemical nature of the antigen.

Marrack’s work on immunochemistry began in the late 1920’s, and focused on the antigen-antibody reaction and its interpretation. His first series of experiments showed that the precipitate formed by diphtheria toxin and antitoxin is mostly antitoxin, and that the antitoxin is composed of serum globulin. Quantitative tests showed that increasing amounts of antigen resulted in an increase in the proportion of antigen in the complexes. Similar findings were made by Michael Heidelberger and Frank Kendall in New York. In 1934 Marrack summed up existing knowledge of the problem in The Chemistry of Antigens and Antibodies. Here he proposed a new model for the reaction, that of a crystal lattice, the relationship between antigen and antibody being like that between the molecules in a crystal. They were linked not by true chemical valencies, as Ehrlich’s theory had it, but by the short-range forces that surround a molecule, the same forces that determine the specific selection of molecules built into a crystal. The reaction was less specific than crystal formation, however, because the fit had to cover only a small depression and not a whole molecule. Marrack suggested that if the antibody, like the antigen, had more than one binding site, the antigen-antibody complexes would bind together in the form of a lattice. The theory accounted for immune precipitation in that the polar groups of the globulin, on which its solubility depended, attracted each other instead of water, and so allowed the formation of an aggregate that came out of solution. Heidelberger and Kendall followed this up with a more fully worked out quantitative version of the lattice concept, summarized in a review of 1939.

Marrack continued to work on the antigen-antibody reaction, designing experiments with various junior collaborators to answer questions on the conditions affecting the precipitin reaction and the phenomena, such as that known as zoning, connected with it, which he explained by means of the lattice theory. His year of greatest productivity was 1938, when four of his substantial papers appeared in British Journal of Experimental Pathology, and he published the second edition of Antigens and Antibodies as well as a review.

Marrack’s suggestion that there were two binding sites on precipitating antibodies received support in 1940 when A.M. Pappenheimer found a non precipitating antibody that nevertheless bound to its antigen. He called this “incomplete” antibody. Based upon the lattice theory, Pappenheimer, and Heidelberger and Kendall, proposed that this type of antibody was probably monovalent. Marrack himself resisted this interpretation. He preferred, he said, to make no assumptions about valency, but to regard antibodies of different types as having different biological functions. He continued to feel that the failure to precipitate was caused by the antigen-antibody complex’s not having lost its attraction for water. As Marrack wrote in 1951, the incomplete antibodies remained a nuisance in practice and no more than an academic interest in theory, until the early 1940’s, when they were shown to be produced by immunization to the Rhesus blood groups, and to be responsible for Erythroblastosis foetalis, hemolytic disease of the newborn. The relation of incompleteness to the nature of the antibody and to its biological function began to be resolved in the 1960’s, when Rodney Porter’s models elucidated the chain structure of the globulin molecule. Incomplete antibody was not monovalent; it had two binding sites.

The 1930’s was a period of political activism for Marrack. He belonged to the well-known group of left-wing scientists that included Lancelot Hogben, J. B. S. Haldane, J. D. Bernal, and J. G. Crowther. At first a Liberal, he joined the Communist party in the early 1930’s at about the same time that many of his colleagues and friends became Marxists, but he resigned in 1937 over a question of policy’ just before Haldane became a member. Even after the break, he remained a close friend of Harry Pollitt, the party secretary. During the Spanish Civil War he was secretary of the Spanish Medical Aid Committee and was with the International Brigade at the siege of Barcelona.

Marrack also became concerned with food and welfare, at a time when nutrition and food supply were matters of growing interest in scientific and political circles. Reports on nutrition were brought out by both the Medical Research Council and the British Medical Association. The scientists of the left, including Marrack, began to agitate for a national food distribution policy. He was in touch with the Cambridge group led by L. J. Harris, whose program of nutrition surveys, started in the early 1930’s, used Marrack’s expertise as a chemical pathologist in the design of urine tests that would detect the partial nutritional deficiency the group felt was very common among the less well-off. Along with Hogben, Marrack began in the mid 1930’s to prepare in a practical way for food shortages in what they both felt was the coming war against fascism. He and his family dug up their large garden to grow vegetables.

The outbreak of World War II made state control of food distribution an urgent necessity in Britain. Marrack’s Food and Planning (1942) discusses not only the dietary requirements but also the history of food planning and the nutrition of populations during World War I in Britain and Europe, and it proposes postwar “planning for plenty,” a phrase that echoes Hogben’s “planning for an age of plenty.” Marrack argued for state control of food production and distribution under the direction of a supranational authority. In 1943 he was appointed director of the Bureau of Nutrition surveys, and he continued to work along these lines for some years after the war. His contributions in this field were aimed at organizing and explaining the data on food requirements from a policy making point of view.

Marrack’s immunochemistry work was interrupted during World War II—again his knowledge of gas warfare was called upon—but in 1950 he resumed his work on the physicochemical parameters of the antigen–antibody reaction with young collaborators.

In 1958, at the age of seventy–two, Marrack undertook the founding editorship of Immunology, the official organ of the British Society for Immunology; he resigned five years later. When he retired, the new editor shared some of his editorial functions among a group of editorial advisers, experts in different fields. His last paper, the fruit of a visiting professorship at the University of Texas M. D. Anderson Hospital and Tumor Institute in Houston, published in 1972, concerned the application of a new physical method to the problem of the formation of the antigen–antibody complex.

In 1971, at the First International Congress of Immunology, Marrack was one of five senior workers to receive a Distinguished Service Award. His citation read: “For revolutionary ideas that have become commonplace in his lifetime, and for pioneering work in the physicochemical interpretation of antigen–antibody interactions.” Marrack’s work, however, was not really revolutionary. His thinking remained within the perimeter marked out by Landsteiner’s conception of the physicochemical nature of specificity. His experimental work was well regarded and often cited, but it was perhaps his reviews that had most influence on the field. Antigens and Antibodies was an organized account of a new and complex subject, difficult to grasp from the primary literature. It was the introduction to the field for many who later became leading immunologists, thereby contributing to the acceptance of Landsteiner’s view on the nature of specificity. Marrack noted in a 1942 review that immunochemistry was changing. In the years between the wars, it had been concerned mainly with the relation of specificity to chemical structure, and the nature of the antigen-antibody reaction. In 1942 he saw that it had begun to focus more on protein chemistry and the nature of the antibody molecule. Marrack changed with the time: some of his papers of the 1950’s and 1960’s did deal with molecular fragments. But Antigens and Antibodies had appeared at just the right moment to summarize the thinking of its era. Up to now, little of that thinking has been superseded:fifty years after its last edition, it still is often cited.

BIBLIOGRAPHY

I. Original Works. Marrack published nearly ninety articles and three books. The most important book was The Chemistry of Antigens and Antibodies (London, 1934; 2nd ed., 1938). His main papers include “The Composition of Diphtheria Toxin–Antitoxin Floccules,” in Proceedings of the Royal Society, B106 (1930), 1–19, with Frank C. Smith; “Diphtheria Toxin–Antitoxin Floccules,” in British Journal of Experimental Pathology, 11 (1930), 492–494, with Frank C. Smith; “Quantitative Aspects of Immunity Reactions: The Precipitin Reaction,” ibid., 12 (1931), 30-35, with Frank C. Smith; “Quantitative Aspects of Immunity Reactions: The Combination of Antibodies with Simple Haptens,” ibid., 13 (1932), 394–402, with Frank C. Smith; and “Derived Antigens as a Means of Studying the Relation of Specific Combination to Chemical Structure,” in Proceedings of the Royal Medical Society, 27 (1934), 1063–1065, with Frank C. Smith. In 1938 he produced “Cross-reactions of Vegetable Gums with Type 11 Anti-Pneumococcus Serum,” in Bristish Journeal of Experimental Pathology, 19 (1938), 53–65, with Blanche R. Carpenter; “Immunological Behaviour of Fractions of Serum Globulin,” ibid 171–178, with Dora A Duff; “Surface Films of Antigens and Antibodies. I. The Effect of Spreading on a Water Surface on the Specific Properties of Pneumococcal (TypeII) Antibody and Horse Serum Globulin,” ibid 393–396, with J. F. Danielli and Mary Danielli; “Effects of Increased Salt Concentration on the Amount of Precipitate Formed by Antisera with Specific Precipitant,” ibid., 424–433, with Helga F. Hollering; and “Immunochemistry and Its Relation to Enzymes,” in Ergebnisse der Enzymeforschung, 7 (1938), 281–300.

Marrack also wrote a number of shorter reviews on subjects connected with the antigen-antibody reaction. They include “Immunochemistry,” in Annual Review of Biochemistry, 11 (1942), 629–658; “The Biological Significance of Complete and Incomplete Antibodies,” in International Archives of Allergy and Immunology, 2 (1951), 264–273; “Forty Years of immunochemistry,” ibid., 5 (1954), 192–197; and “Structure of Antigen-Antibody Aggregates and Complement Fixation,” in Annual Review of Microbiology, 9 (1955), 369–386.

Marrack’s work on nutrition includes “A National Food Policy,” in Labour Monthly, 20 (1938), 502–507; Food in Wartime: Free Basic Ration-or Higher Wages, “in Medicine Today & Tomorrow, 2 (1940), 2–9 Food and Planning (London, 1942; 2nd ed., 1944); “Modern Views on Diet,” in Practitioner, 151 (1943), 277–290; “Standards for Food Requirements,” ibid., 155 (1945), 129–153; and “Laboratory Investigations into the State of Nurition,” part of “Proceedings of the Nutrition Society: Forty-fifth Scientific Meeting: Results of Recent Investigations of NutritionalStatus in Great Britain,” in British Journal of Nutrition, 2 (1948), 147–158.

Most of Marrack’s papers, which include an unfinished manuscript on the history and philosophy of immunology are in the possession of his son, Dr. David Marrack, 420 Mulberry Lane, Bellaire, Texas 77401.

II. Secondary Literature. No study of Marrack’s work has yet appeared, nor is there a full bibliography in print. His lattice theory is discussed in Debra J. Bibel Milestones in Immunology: A Historical Exploration (Madison, Wis., 1988), 91–94, with an excerpt from Antigens and Antibodies. Obituaries and short biographical articles include Rosa Augustin, “Editorial; Professor J. R. Marrack, M.D., D.S.O., M.C.,” in Immunology, 6 (1963), 1–2 J. H. Humphrey, “Obituary,” in Nature, 263 (1976), 535; F.C.O.V and E.R.H., “professorMarrack,” in London Hospital Gazette, 55 (1952), 153–154; and R.G.W(hite), “Jogn Richardson Marrack,” in Lancet (1976), ii, 378

Pauline M. H. Mazumdar

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