(450 OSWALD THEODORE AVERY October 21, 1877—-February 20, 1955 BY A. R. DOCHEZ SWALD THEODORE AVERY was born in Halifax, Nova Scotia, on O October 21, 1877. He came to the United States with his family at an early age, settling in New York City, where he spent all of his active scientific life. He was a man of great simplicity and singleness of purpose, endowed with unusual powers of concentration on those matters of science which aroused his curiosity; and the interest they evoked endured throughout his life. He was by nature somewhat reticent and seldom permitted the ordinary distractions of life to divert him from those scientific problems in which he was so com- pletely immersed. The long list of his achievements which grew in importance to the very end of his life is testimony of his capacity for logical and progressive thinking and for using and developing for his purposes his own techniques and those of other sciences, par- ticularly those of biochemistry. Avery was graduated with an A.B. degree from Colgate Uni- versity in 1goo, and received his M. D. degree from the College of Physicians and Surgeons of Columbia University in 1904. After graduation from medical school, Avery spent a few years in the prac- tice of clinical medicine, which supplied him with some amusing stories but did not attract him sufficiently for him to make his career in that field. He subsequently joined and cooperated with Benjamin White, Director of the Hoagland Laboratory in Brooklyn, where he became Associate Director of the Division of Bacteriology. Thus he instinctively selected the subject to which he was to devote his life 32 BIOGRAPHICAL MEMOIRS work and in which he was later to become famous. While here ne began to familiarize himsett with me activites ot onan Spee ia and their relationship to infectious . Th < Fr The very beginning led him in the direction of anarytica! thinking and of the investigation of the sue of ama The chara ro i k attracted the interest of Dr. Rutus Vole, | Hospital of the Rockefeller Institute, who invited him to become member of that organization, with which he became associates 1913. Here he found satisfaction and happiness an the en Hon which he needed for the full development “ as growing vst in i . He continued as a member 0 Ror er otal until his retirement in 1948 and, rine ane voted among other bacteriological and immunological subjects, en himself in large part to the study of a single microorga my the pneumococcus, the cause of lobar pneumonia, until more was pwn about that organism than about almost uy nen ‘e e of Avery’s work was large and its brea re enon for bacteriology in general and related fields were of ignificance. Pring the time when Avery was progressively developing be knowledge of the pneumococcus, he promoted and engage im with the assistance of his colleagues, a number of important ar ons of general bacteriological interest, using the phenmocacss ant a tain other microorganisms for this purpose. With K. . Der y be determined the optimum and limiting hydrogen ton rane for the growth of the pneumococcus and showed that the ° * nved concentrations for the growth of bacterial races are pr ‘ y * definite and characteristic as those for enzyme action. Wit - Cullen he showed that the final hydrogen ion oe reach “jn the growth of a hemolytic streptococcus differed ween tains of human and bovine origin as to the ultimate end Point an ™ onstration constituted a simple and rapid method for the i omen - tion of human and bovine types of streptococcus hemolytic. sof some interest that in the studies of the different types of pneumoc ’ OSWALD THEODORE AVERY 33 cus all the fermentable carbohydrates used gave identical results in the rate of reaction change and in the final hydrogen ion concentra- tion reached. Avery participated with Theodor Thjotta and H. J. Morgan in a number of studies on bacterial nutrition. It had been shown that the microorganism hemophilus influenzae, a strictly hemoglobinophilic organism, will grow in hemoglobin free medium consisting of plain broth enriched by sterile suspensions or extracts of mucoid bacteria. This observation was extended by a study of the growth require- ments of the so-called hemophilic bacilli of which H. influenzae served as a type. The growth stimulating action of extracts of yeast and of vegetable cells, and the importance of blood as a source of growth accessory substances were studied. The growth of H. influ- enzae depends upon two distinct and separable substances. Both are present in blood, but neither alone suffices for growth. One is a vita- min-like substance extractable from red blood cells, yeast, and vege- table cells, and is relatively heat labile; and the other is an iron-con- taining substance which is heat stable and is present in red blood cells. Both occur in plant as well as in animal tissue, so that sterile raw potato serves as a substitude for blood in the cultivation of H. influenza. Further studies showed that plant tissue also has a growth accelerating action on other microorganisms such as pneumococcus, streptococcus hemolyticus, and streptococcus viridans. It also facili- tates the growth of anaerobic bacteria under aerobic conditions, since it furnishes certain necessary growth accessory substances and pro- vides an oxidizing-reducing system whose action destroys toxic per- oxides of bacterial origin. In a series of studies in cooperation with J. M. Neill, Avery pre- sented the results of an examination of the nature of the oxidation- reduction systems of sterile extracts of pneumococcus. These active systems consist of two components: (1) a thermo-labile constituent of the pneumococcus cell which is not removed by washing; (2) thermo-stable substances which are lacking in washed cells and which are not necessarily of pneumococcus origin, since they may be 34 BIOGRAPHICAL MEMOIRS supplied by muscle infusion and yeast extract. The character of these reactions is determined by the presence or absence of molecular oxygen. In the presence of molecular oxygen, active extracts were shown to exhibit the following activities: consumption of molecular oxygen, formation of peroxide, oxidation of hemoglobin, and oxida- tion and destruction of the hemolysin and intracellular enzymes contained in pneumococcus extracts. All of these oxidations are ex- amples of “oxygen activation,” whereby substances themselves not reactive with molecular oxygen are easily oxidized by agents formed during the oxidation of other substances. Analysis of these processes shows that the active systems consist of two components, one of which is thermo-labile, the other thermo-stable. By themselves the thermo-stable substances react slowly with molecular oxygen to form oxidizing agents, and in the absence of molecular oxygen they establish conditions under which methemoglobin and other sub- stances are slowly reduced. In the presence of the thermo-labile component, the reactions of oxidation and reduction are markedly ac- celerated. This latter component is wholly nonreactive with molecu- lar oxygen, possesses no reducing power, and seems to be catalytic in nature. When present together, these substances constitute systems responsible for many of the biological oxidations and reductions of the living cell. Avery in collaboration with G. E. Cullen made an interesting study of the intracellular enzymes of pneumococcus and, as a result, suggested their relationship to the metabolic activity of the cell. The demonstration of the intracellular agents was affected by breaking down the cell structure by suitable means and making extracts which were tested for enzymatic activity. In this way, active cell-free agents were obtained which hydrolyzed intact protein to some extent and which hydrolyzed peptones with striking avidity. An active esterase was also isolated as were such carbohydrate-splitting enzymes as in- vertase, amylase, and inulinase. On the other hand, fermentation of dextrose could not be demonstrated. These studies indicated that the enzymes described were not secretory products of the pneumococcus OSWALD THEODORE AVERY 35 but were of the nature of endo-enzymes, since their activity could be demonstrated only when cell disintegration had occurred. At the time when Avery- joined the staff of the Hospital of the Rockefeller Institute, the study of the pneumococcus and its relation- ship to lobar pneumonia had been in progress for about three years As a result of this study, pneumococci had been separated by ee of immunological reactions into two different groups by Dochez and Gillespie. The first group consisted of Types I, II, and III, which could be sharply differentiated from one another by serological tests and were found only in association with severe examples of lobar pneumonia or in the mouths of individuals in close contact with such cases of pneumonia. The other group consisted of strains as- sociated with lobar pneumonia in a much smaller percentage of in- stances, and was of greater serological diversity. These latter strains resembled the varying types of pneumococcus found in the mouths of healthy normal individuals. On his arrival, Avery joined in the study of the immunological classification of pneumococci and added to this classification several new serological types. As the study passed to other hands, many new immunological types were discovered. On the whole, the original Types I, II, and III remained fairly constant in from 60 to 80 percent of cases as the causative agents of the severe and highly fatal instances of lobar pneumonia. The results of these studies brought about a more exact knowledge of the character of pneumococcus infection of the lung, and shed a considerable amount of new light on the etiology and epidemiology of lobar pneumonia. In 1917 Dochez and Avery reported the elaboration of a specific soluble substance by the pneumococcus during its growth in culture medium. This substance was identical immunologically with the type of pneumococcus growing in the culture and was present in large amounts at a time when little or no cell disintegration had taken place. The substance consequently did not represent dead dissolved bacterial protein, but was due to the elaboration and passage into solution of a substance which was the product of the life activity of the pneumococcus cell. That it was not an intracellular substance 36 BIOGRAPHICAL MEMOIRS liberated at the death and disintegration of the pneurmococeus was proven by the fact that it was already present in considera © a a tities at a time when no intracellular hemolysin was presen i me culture medium. The intracellular hemolysin is liberated on y on ne death and disintegration of the cell, and the curve of peme ysin die not begin to rise until a time when ue curve of the soluble su ttained its maximum elevation. nee ene of a soluble substance by the pneumococcus on growth in vitro suggested the probability that an analogous su stance would be formed on growth of the organism in the anima body, and because of the readiness with which the su sane pa - into solution it was expected that there would be no di cu y in demonstrating it in the body fluids of animals experimenta i fected with pneumococcus and in those of human beings su ering from lobar pneumonia. This was found to be the case, since * Pe cific precipitin reaction with antipneumococcus um ane ae ing to the type of organism with which the animal or uman eins was infected was easily demonstrated in the blood ‘eum an ne during the period of infection. The discovery of this substance was 0 | great importance to Avery's subsequent study of the pneumorocce , since it served as the point of departure for much of his succeeding aren soe onward, Avery, Heidelberger, and their associates une dertook a chemical study of the soluble specific apres " | Avery believed were an important key to the whole nu ject ot © immunological specificity of bacteria. Papers were published s ow ing that the soluble specific substances of the pneumococcus were polysaccharides, the first instance in which carbohydrates were : nowen to be involved in immune reactions. The soluble Substances oO i Il and Type III pneumococci were found to be nitrogen ree carbo- hydrates, the former made up mainly of glucose, an th “ atter om posed of aldobionic acid units. The Type I polysacchari e was nitr gen-containing, and made up in part of galactouronic acid. 1 Differences in bacterial specificity were related by Avery an OSWALD THEODORE AVERY 37 Ld Heidelberger to characteristic chemical differences in the substances responsible; where these substances were similar, cross-reactivities were found to occur, and accounted chemically for the observed spec- ificities. A whole new field of bacteriology, immunology, and chemistry was opened up. Many puzzling and confused observations in bacteriology and immunology were thus clarified and systematized on a rational chemical basis. At least a part of the virulence, specific- ity, and behavior of many important bacteria is referable to a specific polysaccharide and in the encapsulated microorganism this is the major factor. Here, then, is one of the principal foundation stones of the science of immunochemistry, which is rapidly including an ever-widening study of artificial and natural antigens. Meanwhile, in the hands of Avery and his co-workers, knowledge of the specific characters of the pneumococci and the manner in which these are acquired had been moving to a new pinnacle of achievement. The culmination of this knowledge and of the studies conducted by Avery and his co-workers, Dawson, Alloway, MacLeod, McCarty, Taylor, and Hotchkiss, came with the announcement, in 1944, that the fundamental constituent of the transforming agent of pneumococcus Type III is a polymerized desoxyribonucleic acid. That the transformation of one type of pneumococcus into a pneu- mococcus of another type could occur in vivo was first demonstrated by Griffith in 1928. Studies on the mechanism of experimental trans- formation of pneumococcal types were carried out in Avery’s labora- tory from 1928 to 1948. The transforming substance was extracted from heat-killed pneu- mococci or from living cells caused to undergo lysis. Sodium citrate, which inhibits the inactivating effect of pneumococcal desoxyribonu- clease, was used in the lysing process in the later procedures. After deproteinization, the desoxyribonucleic acid was further purified, so that an exceedingly minute quantity, 0.0015 microgram per milliliter, was capable in vitro of inducing transformation of susceptible cells under proper cultural conditions. Evidence that the transforming agent is a nucleic acid of the desoxyribose type was obtained by 38 BIOGRAPHICAL MEMOIRS chemical, enzymatic, serologic, and physico-chemical studies of highly purified material. Elementary analysis showed that the ma- terial closely resembles authentic preparations of desoxyribonucleic acid of animal origin. Serological procedures with anti-pneumococcal sera of appropriate type failed to reveal the presence of capsular or somatic polysaccharides or of pneumococcus protein in the trans- forming material, each of which would easily have been demon- strated by such tests. Amino acids were obtained on hydrolysis in so small an amount that not more than 0.2 percent of protein could be present. Later studies showed that glycine from the degradation of adenine was ap- parently the only amino acid present in the hydrolysate, so that the possibility that a specific protein or nucleoprotein, rather than the nucleic acid itself, was responsible for the transforming activity seemed to have been excluded decisively. Highly purified preparations of the transforming agent obtained from pneumococcus Type II] made possible for the first time the in- duction of a predictable and permanent alteration in a heritable character of the living cell by means of a chemically defined substance of known nature. In other words, a specific mutation was induced as a result of specific treatment, an achievement which had long, eluded biologists. The broad implications of the discovery of the na- ture of the transforming agent became apparent when it was demon- strated in Avery’s laboratory that desoxyribonucleic acids, separated from a number of other types of pheumococci, possess predictable transforming activity relative to a specific cell character. Confirma- tory evidence supporting Avery’s interpretation of the transforma, tion phenomenon was later obtained in other laboratories with both pneumococcus and other microorganisms. As a result of these studies of Avery and his associates, it became apparent that certain polymerized desoxyribonucleic acids are con- cerned with the heredity of microbial cells in much the same fashion that genes are concerned with the hereditary characteristics of higher organisms. OSWALD THEODORE AVERY 39 The impact of these findings upon prevailing concepts of investi- gators in cytology, genetics, and virology, already aware that desoxy- ribonucleic acid is a prominent constituent of nuclei, chromosomes, and viruses, was of great importance. It was now learned that this constituent is the one functionally operative in transmitting the manifold biologic capacities and potentialities of the germ plasm. This, in turn, indicated to biochemists that nucleic acids are capable of innumerable variations in composition and structure. Both of these concepts have received considerable support, and it has become . increasingly evident that they play an important part in the orient- ing of investigations in the several fields concerned with cellular de- velopment and differentiation. At the time the above investigation was being presented, from its beginning to its successful conclusion in 1948, Avery and certain of his associates engaged in a number of collateral studies related to the immunological significance of carbohydrates, both those of bacterial origin and certain more common sugars. As a result of these studies ‘an antigenic relationship was shown to exist between the polysac- charides and pneumococcus and those of certain types of Bacillus Friedlander and of a number of plant gums, such as gum acacia. Following this, a study of the specificity of certain azo-protein anti- gens containing simple saccharides of known chemical constitution was undertaken with W. F. Goebel. This study showed unequivo- cally that the specificity of carbohydrates was determined by their chemical constitution and that differences in structure, no matter how slight, were invariably reflected in the specificity of the anti- bodies which such antigens evoked. As an example, the specific poly- saccharide of Pneumococcus Type T is characterized by the presence of a highly labile acetyl group. Gentle removal of this group de- prives this polysaccharide of its antigenicity in certain animals and alters its over-all serological specificity as well. A species-specific carbohydrate distinct from the capsular polysac- charide was isolated from the somatic component of pneumococci. This substance was designated as Fraction C. It subsequently became 40 BIOGRAPHICAL MEMOIRS of considerable interest, since it gave rise to a precipitating antibody in the serum of patients suffering from pneumonia, which was pres- ent only during the acute phase of the disease and disappeared dur- ing convalescence. The antibody is not specific for pneumonia, but also occurs during the acute phase of a number of infections, such as rheumatic fever, and in conditions associated with tissue degenera- tion. Its presence or absence is now regularly used as a measure of the activity of the clinical condition under study. During this time Avery in collaboration with René Dubos investi- gated the action of a bacterial enzyme which decomposed the poly- saccharide of Pneumococcus Type III, both in vitro and in vivo. This enzyme, when injected in conjunction with virulent Type Il pneumococcus, was capable of protecting mice, rabbits, and monkeys against experimental infection because of its capacity of stripping the virulent cell of its protective capsular coat. This constituted one of the very early demonstrations of antibiotic action against patho- genic microorganisms, a procedure which has since become of great importance in the cure of numerous infectious diseases. Avery also participated with Dochez and Lancefield in an im- munological classification and antigenic analysis of the hemolytic streptococcus. This study proved that this organism is not a unit type, as was previously supposed, but consists of a number of types which can be definitely identified serologically. Subsequent development and employment of the techniques used resulted in the establish- ment of the hemolytic streptococcus as the causative agent of scarlet fever, acute rheumatic fever, and hemorrhagic nephritis, all of which diseases may now be brought within the range of prevention or cure by antibiotic agents effective against the hemolytic streptococcus. Avery, by his studies of the chemical basis for the differences be- tween the several types of pneumococcus and the importance of car- bohydrates in determining the antigenic specificity of bacterial and synthetic antigens, became one of the founders of the modern science of immunochemistry, a science which has rapidly come to include an ever-widening range of studies of artificial and natural antigens. OSWALD PHEODORE AVERY 41 During both the First and the Second World Wars, Avery placed his scientific knowledge and skill at the disposal of the United States Government, serving on various committees concerned with the con- trol of a number of important infectious diseases which are prevalent among troops under conditions of warfare. During his active career he received a number of honorary degrees: Sc.D., Colgate University 1921; L.L.D., McGill University, 1935: Sc.D., New York University, 1947; and Sc.D., Rutgers University 1953. In addition, he was awarded a number of other honors and prizes, among them the Paul Ehrlich Gold Medal and the Copley Medal of the Royal Society of London. He was elected to the National Academy of Sciences in 1933 and was also a foreign member of the Royal Society of London. Dr. Avery was a true scientist with an insatiable curiosity and a powerful and unremitting urge to discover the innermost mecha- nisms of the biological facts that came under his observation. His ap- ' proach to the solution of a problem was characterized by a logical simplicity of thought and a perfection of technical procedure, com- bined with a complete objectivity that guaranteed the soundness of his deductions. Most of Avery’s associations were with his colleagues by whom he was greatly revered and who have preserved for him a timeless affection. He was a truly lovable person, humble, disinter- ested, and generous. The inspiring and friendly quality of his leader- ship is conspicuously represented by his many former associates who _ Now occupy distinguished positions in medicine in the United States and elsewhere, so that his light still burns in many places of learning and research. BIOGRAPHICAL MEMOIRS KEY TO ABBREVIATIONS 42 Ann. Int. Med.= Annals of Internal Medicine Arch. Int. Med.= Archives of Internal Medicine Arch. Pediat. = Archives of Pediatrics Centr. Bakt.—Zentralblat fir Bakteriologie J.A.M.A.= Journal of the American Medical Association J. Exp. Med. = Journal of Experimental Medicine J. Infect. Dis.= Journal of Infectious Diseases J. Med. Res. == Journal of Medical Research Proc. Soc. Exp. Biol. Med.=Proceedings of the Society for Experimental Bi- ology and Medicine Trans. Assn. Am. Phys. cians — Transactions of the Association of American Physi- BIBLIOGRAPHY : “, 1909 With B. White. The Treponema Pallidum; Observations on its Occur- rence and Demonstration in Syphilitic Lesions. Arch, Int. Med., 3:41. 1910 With N. B. Potter. Opsonins and Vaccine Therapy. (In: Hare, Modern Treatment, Philadelphia and New York, 1:515.) With B. White. Observations on Certain Lactic Acid Bacteria of the So-called Bulgaricus Type. Centr. Bakt., Abt. II, 25:161. With L. C. Ager. A Case of Influenza Meningitis. Arch. Pediat., 32:284. With B. White. Concerning the Bacteremic Theory of Tuberculosis. J. Med. Res., 23:95. 1912 With B. White. The Action of Certain Products Obtained from the Tu- Bacillus. A. Cleavage Products of Tuberculo-protein Obtained by bercle Communication I. The Poisonous Substance. the Method of Vaughan. J. Med. Res., 26:317. 1913 With H. W. Lyall. Concerning Secondary Infection in Pulmonary Tuber- culosis. J. Med. Res., 28:11. With B. White. Some Immunity Reactions of Edestin. III. The Biological Reactions of the Vegetable Proteins. J. Infect. Dis., 13:103. o SWALD THEODORE AVERY 43 1914 With C. E. North and B. Whi i . : te. A Septic S : . Cortland and Homer, New York, J. life iL Dis, ie Epidemic in 1915 With A. R. Dochez. Varieties of P . rene Pneumonia. J. Exp. Med., 4, and Their Relation to e Distribution of the Imm B «oe Cy, oo, . wi J. Exp. Med., 21 133. odies Occurring in Anti-pneumococcus ith A. R, Dochez. The Occurrence i , of C : . Types of Pneumococcus. J. Exp, Med, mae of Disease-producing A Further Stud he Biologi ye Med, 29:804 y on the Biologic Classification of Pneumococci. J. Exp. . 1916 With A. R. Dochez. Antiblastic Immunity. J. Exp. Med 23:61 1917 With H. T. Chickering, R. Cole, and A. R. Dochez. Acute Lobar Pneu- monia: Prevention and Serum Treat wan, Institute for Medical Research No. i i taiaiae ith A. R. Dochez. Soluble Substance f ; . Pneumococ Origin i Bled ani Se ce of cus Origin in the a ne During Lobar Pneumonia. Proc. Soc. Exp. Biol. Med., With A. R. Dochez. The Elaborati . . ration of Specific Solub] Pneumococcus During G . Tage mtance, By Phys pote g Growth. J. Exp. Med., 26:477; Trans, Assn, Am. 1918 Determination of Types of Pneumococcus in Lobar Pneumonia: A Rapid Cultural Method. J.A.M.A., 70:17. With K. G. Dernby. The Opti . . ptimum Hyd i Growth of Pneumococcus. J. Exp. Med, rate. Concentration for the A Selective Medium f . wx 050. m for B. Influenzae. Oleate-hemoglobin Agar. J.A.M.A., 1919 i E. Cullen. The Use of the Final Hydrogen Ion Concentration in ifferentiation of Streptococcus Haemolyticus of Human and Bovine Types. J. Exp. Med., 29:215. 44 BIOGRAPHICAL MEMOIRS . . f field. Studies on the Biology o ith A. R. Dochez and R. C. Lancehe. W ereptacorcus. I. Antigenic Relationships Between Strains of Strepto coccus Haemolyticus. J. Exp. Med., 30:179. 1920 With G. E. Cullen. Studies on the Enzymes of Pneumococcus. I. Proteo- ic E es. J. Exp. Med., 32:547- i we ee Gallen. Studies on the Enzymes of Pneumococcus. Il. Lipo ic Enzymes: Esterase. J. Exp. Med., 32:57!- Wik G. E Callen. Studies on the Enzymes of Pneumococcus iil. tee hydrate-splitting Enzymes: Invertase, Amylase, and Inulase. ). . Med., 32:583. 1921 With T. Thjotta. Studies on Bacterial Nutrition. Te ore Med. 97 ' ili ill ed., 34:97- in the Cultivation of Hemophilic Bacilli. J. Exp. Mec’, Wah. Thjotta, Studies on Bacterial Nutrition. Ill. Plant Tisste as a Source of Growth Accessory Substances in the Cultivation of bact . J. Exp. Med., 34:455- 7 Wane hota, Growth Accessory Substances in the Nutrition of Bac i Soc. Exp. Biol. Med., 18:197. Wal th | Morgan, The Effect of the Accessory Substances of Plant Tis- sue Upon Growth of Bacteria. Proc. Soc. Exp. Biol. Med,, 19:113. 1923 - With M. Heidelberger. Soluble Specific Substance of Pneumococcus. J. d., 38:73. a Walt M. Hetlelberger. Immunological Relationship of Cell Constitu us, J. Exp. Med., 38:81. wil M Heidelberger, The Specific Soluble Substance of Pneumococcus. . Soc. Exp. Biol. Med., 20:434- a - With M Heidelberger. Immunological Relationships of Cell Constitu ents of Pneumococcus. Proc. Soc. Exp. Biol. Med., 20:435- IV. Bae With G. E. Cullen. Studies on the Enzymes of Pneumococcus. IV. iolytic E e. J. Exp. Med., 38:199- ' with BJ Morgan. ‘seudees on Bacterial Nutrition. IV. Effect of oe Tissue Upon Growth of Pneumococcus and Streptococcus. J. Exp. Med. 38::207. OSWALD THEODORE AVERY 45 1924 With H. J. Morgan. The Occurrence of Peroxide in, Cultures of Pneu- mococcus. J. Exp. Med., 39:275. With H. J. Morgan. Studies on Bacterial Nutrition. V. The Effect of Plant Tissue Upon Growth of Anaerobic Bacilli. J. Exp. Med., 39:289. With H. J. Morgan. Growth-inhibitory Substance in Pneumococcus Cul- tures. J. Exp. Med., 39:335. With J. M. Neill. Studies on Oxidation and Reduction by Pneumococcus. I. Production of Peroxide by Anaerobic Cultures of Pneumococcus on Exposure to Air Under Conditions Not Permitting Active Growth. J. Exp. Med., 39:347. With J. M. Neill. Studies on Oxidation and Reduction by Pneumococcus. Il. The Production of Peroxide by Sterile Extracts of Pneumococcus. J. Exp. Med., 39:357. With J. M. Neill. Studies on Oxidation and Reduction by Pneumococcus. III. Reduction of Methylene Blue by Sterile Extracts of Pneumococcus. J. Exp. Med., 39:543. With J. M. Neill. Studies on Oxidation and Reduction by Pneumococcus. IV. Oxidation of Hemotoxin in Sterile Extracts of Pneumococcus. J. Exp. Med., 39:745. With J. M. Neill. Studies on Oxidation and Reduction by Pneumococcus. V. The Destruction of Oxyhemoglobin by Sterile Extracts of Pneumo- coccus, J. Exp. Med., 39:757. With M. Heidelberger. The Soluble Specific Substance of Pneumococcus. J. Exp. Med., 4o:301. With J. M. Neill. Studies on Oxidation and Reduction by Pneumococcus. ‘VI. The Oxidation of Enzymes in Sterile Extracts of Pneumococcus. J. Exp. Med., 40:40s. With J. M. Neill. Studies on Oxidation and Reduction by Pneumococcus. VII. Enzyme Activity of Sterile Filtrates of Aerobic and Anaerobic Cultures of Pneumococcus. J. Exp. Med., 40:423. 1925 With J. M. Neill. Studies on Oxidation and Reduction by Pneumococcus. VIII. Nature of Oxidation-reduction Systems in Sterile Pneumococcus Extracts. J. Exp. Med., 41:285. With H. J. Morgan. Immunological Reactions of Isolated Carbohydrate and Protein of Pneumococcus. J. Exp. Med., 42:347. 46 BIOGRAPHICAL MEMOIRS With J. M. Neill. The Antigenic Properties of Solutions of Pneumococcus. J. Exp. Med., 42:355- With M. Heidelberger. Immunological Relationships of Cell Constituents of Pneumococcus. J. Exp. Med., 42:367. With M. Heidelberger and W. F. Goebel. The Soluble Specific Substance | of a Strain of Friedlander Bacillus. Proc. Soc. Exp. Biol. Med, 23:1. With M. Heidelberger and W. F. Goebel. Immunological Behavior of the “f” Strain of Friedlander Bacillus and Its Soluble Specific Substance. Proc. Soc. Exp. Biol. Med., 23:2. With M. Heidelberger and W. F. Goebel. The Soluble Specific Substance of a Strain of Friedlander’s Bacillus. J. Exp. Med,., 42:701. With M. Heidelberger and W. F. Goebel. The Soluble Specific Substance of Friedlander’s Bacillus. Chemical and Immunological Relationships of Pneumococcus Type II and a Strain of Friedlander’s Bacillus. J. Exp. Med., 42:709. With M. Heidelberger and W. G. Goebel. The Soluble Specific Substance of Pneumococcus. J. Exp. Med. 42:727- 1927 With W. F. Goebel. The Soluble Substance of Friedlander’s Bacillus. III. On the Isolation and Properties of the Specific Carbohydrates from Types A and C Friedlander Bacillus. J. Exp. Med., 46:601. 1929 With W. S. Tillett. Anaphylaxis with the Type- of Pneumococcus. J. Exp. Med. 49:251- With W. F. Goebel. A Study of Pneumococc 49 :267. With M. Heidelberger and W. F. Goebel. A “Soluble Specific Substance” Derived from Gum Arabic. J. Exp. Med., 49 :847- With W. F. Goebel. Chemo-immunological Studies on Conjugated Carbo- hydrate-proteins. I. The Synthesis of p-aminophenol B-glucoside, p-ami- nophenol B-galactoside, Exp. Med., 50:521. specific Carbohydrates us Autolysis. J. Exp. Med. With W. F. Goebel. Chemo-immunological Studies on Conjugated Carbo- logical Specificity of Synthetic Sugar- hydrate-proteins. IJ. Immuno protein Antigens. J. Exp. Med., 50:533- and Their Coupling with Serum Globylin. J. w ee ee OSWALD THEODORE AVERY 47 wae W. S, Tillett and W. F. Goebel. Chemo-immunological Studies on onjugated Carbohydrate-proteins. III. Active and Passive Anaphylaxis with Synthetic Sugar-proteins. J. Exp. Med., 50:551. 1930 Wath Writ and W. F. Goebel. Chemical and Immunological Prop- ofa “enact . ae pecies-specific Carbohydrate of Pneumococci. J. Exp. Med., With R. Dubos. The Specifi i i . pecific Action of a Bacterial E cocci of Type III. Science, 72:151. B SBayme on Mmeume. 1931 With R. Dubos. The Specifi i i . pecific Action of a Bacterial Pneumococci. Trans. Assn. Am. Phys., ob. enzyme on Type TI With R. Dubos. Decomposition of the Capsular Polysaccharide of Pneu- woes Type UI by a Bacterial Enzyme. J. Exp. Med., 54:51 _ R. Dubos. The Protective Action of a Specific Enzyme Against w, ype III Pneumococcus Infection in Mice, J. Exp. Med, 54:73 _ i hydiate concn Creme immunological Studies on Conjugated Car- -proteins. IV. The Synthesis of the p-aminobenzyl Eth the Soluble Specific Substance of Type II Pneumococcus and It C . pling with Protein. J. Exp. Med., 54:43. — wie wv F. Goebel. Chemo-immunological Studies on Conjugated Car- is y rate proveins, V. The Immunological Specificity of an Antigen repare by Combining the Capsular Polysaccharide of Type II Pn mococcus with Foreign Protein. J. Exp. Med., 54:437. ~ 1932 wih Ww F. poe and F, H. Babers. Chemo-immunological Studies on oe Carbohydrate-proteins. VI. The Synthesis of p-aminophenol wt weoside and Its Coupling With Protein. J. Exp. Med., 55 6. i . F. Goebel and F. H. Babers. Chemo-i ical Studi Conjusnted. Cached bers. o-immunological Studies on ydrate-proteins. VII. Immunological Specificit pnigens Prepared by Combining a- and b-glucosides of Gluco oT oh roteins. J. Exp. Med., 55:769. = The Role of Specific Carbohyd i i munity. Ane Tan Mak ry rates in Pneumococcus Infection and Im- 48 BIOGRAPHICAL MEMOIRS With K. Goodner and R. Dubos. The Action of a Specific Enzyme Upon the Dermal Infection of Rabbits with Type III Pneumococcus. J. Exp. Med., 55:393- 1933 Chemo-Immunologische Untersuchungen an Pneumokokken-Infektion und -Immunitat. Naturwissenschaften, 21:777. With W. F. Goebel. Chemo-immunological Studies on Soluble Specific Substance of Pneumococcus. I. The Isolation and Properties of Acetyl Polysaccharide of Pneumococcus Type I. J. Exp. Med., 58:731. 1934 With W. F. Goebel and F. H. Babers. Chemo-immunological Studies on Conjugated Carbohydrate Proteins. VIII. The Influence of the Acetyl Group on the Specificity of Hexoside-protein Antigens. J. Exp. Med., 60:85. With W. E. Goebel and F, H. Babers. Chemo-immunological Studies on Conjugated Carbohydrate Proteins. IX. The Specificity of Antigens Prepared by Combining the p-aminophenol Glycosides of Disaccha- rides with Protein. J. Exp. Med., 60:599. With T. Francis, E. E. Terrell, na fh Dubos. Experimental Type II Pneumococcus Pneumonia in Monkeys. II. Treatment with an Enzyme Which Decomposes the Specific Capsular Polysaccharide of Pneumo- coccus Type III. J. Exp. Med., 59:641. 1941 With T. J. Abernethy. The Occurrence During Acute Infections of a Pro- , tein Not Normally Present in the Blood. I. Distribution of the Re- active Protein in Patients’ Sera and the Effect of Calcium on the Floc- culation Reaction with C-polysaccharide of Pneumococcus. J. Exp. Med., 73°173+ With C. M. MacLeod. The Occurrence During Acute Infections of a Protein Not Normally Present in the Blood. II. Isolation and Properties of the Reactive Protein. J. Exp. Med., 73:183. With C. M. MacLeod. The Occurrence During Acute Infections of a Protein Not Normally Present in the Blood. II]. Immunological Prop- erties of the C-reactive Protein and its Differentiation from Normal Blood Proteins. J. Exp. Med., 73:191. OSWALD THEODORE AVERY 49 . 1944 wie Senco’ and M mecCarty. Studies on the Chemical Nature nce Inducing Transformation of Pneumococcal T Induction of Transformation by a Desoxyribonucleic Acid F raction Is . lated from Pneumococcus Type III. J. Exp. Med. 793137 ~ 1946 With M. McCarty. Studies on the Chemical Nature of the Substance In- ducing Transformation of Pneumococcal Types. II. Effect of Desoxy- ribonuclease on the Biological Activi ; J. Exp, Med, 83:86. ogical Activity of the Transforming Substance. with M. McCarty. Studies on the Chemical Nature of the Substance In- ucing Transformation of Pneumococcal Types. II. An I J Method for the Isolation of the Transforming Substance and Its Ay plication to Pneumococcus Types II, II, and VI. J. Exp. Med., 8 " e rental marty and in E, pve. Biochemical Studies of Envivon- ‘actors Essential in Transformation of Cold Spring Harbor Symposia on Quantitative sree wes