From Physician to Researcher: Early Laboratory Career and World War I, 1904-1919

Oswald T. Avery's early career was not marked by any major scientific accomplishment, but many still recognized his intelligence and potential as a researcher. One of these was Benjamin White, who offered the young doctor a position at the Hoagland Laboratory in Brooklyn in 1907. After several unfulfilling years in private practice, Avery was eager to accept his appointment as the Associate Director of the Division of Bacteriology. At the Hoagland, he honed the analytical and research skills which would characterize his career at the Rockefeller Institute. Often working together, White and Avery published several papers on various problems of bacteriology and immunity. After White developed tuberculosis, Avery became acutely interested in studying blood cultures from patients in the active phase of this disease. His research resulted in several papers, one of which caught the attention of Rufus Cole, then director of the Hospital of the Rockefeller Institute for Medical Research, who offered Avery a position in 1913.

When Cole became director of the Hospital in 1908, he determined that its primary goal should be the development of a therapeutic serum for lobar pneumonia (affecting the whole lobe of the lung), which was characterized by sudden onset, chills, high fever, rapid course, and rapid decline. Termed the "captain of the men of death" by noted clinician William Osler, pneumonia was among the leading causes of death at the time, killing over 50,000 annually in the United States. The most common form, pneumococcal pneumonia, is a bacterial infection of the lungs spread by coughing, sneezing, or close contact. Development of a serum was complicated by the recognition by Fred Neufeld at the Robert Koch Institute in Berlin of distinct types of pneumococcus, which would require specific corresponding antibodies. At the Rockefeller Institute, Alphonse R. Dochez was given the task of comparing the distribution of pneumococcal types in New York with those found by Neufeld. Dochez reported in 1913 that they could be divided into the three main types (designated I, II, and III) found by Neufeld, and a fourth group (type IV) that consisted of "poorly characterized subtypes" that did not fit into the first three main groups. Therapeutic trials of a serum held at the Rockefeller Hospital soon resulted in positive results for type I lobar pneumonia, although it would be several years before a truly effective serum would be fully developed.

When Avery joined the Hospital staff in 1913, he was charged with the tasks of processing the serum and determining its effectiveness by measuring anti-pneumococcal activity. Also responsible for much of the diagnostic work for pneumonia at the Hospital, he quickly mastered his duties and developed a rapid culture method for determining the pneumococcal types recovered from patients. Avery quickly recognized that although the newly developed therapeutic sera did not kill pneumococci, they did retard pneumococcal growth in a culture medium. In an article published in 1916, he and Dochez reported their finding that anti-pneumococcal serum inhibited several digestive properties of the pneumococcus involved in the formation of amino acids, as well as retarding the fermentation of several carbohydrates. This, they believed, suggested that resistance to pneumococci results from inhibition of specific pneumococcal enzymes (proteins that act as catalysts for chemical reactions in the cell) by the serum. Although their observations were relatively limited, they developed from them an innovative metabolic understanding of immunity, which they termed "antiblastic immunity" (In the article, they explain that they chose the term "in order to indicate that the forces at work are antagonistic to the growth activities of the organism." The word "antiblastic" was derived from the Greek word "blastos," meaning growth, or budding.) Avery and Dochez hypothesized that pneumococci could not multiply in vivo (within a living organism) if the bacteria could not utilize certain constituents of an infected person by means of enzymes located at the surfaces of their cells. They demonstrated that the addition of anti-pneumococcal serum to a broth culture of pneumococci inhibited some enzymatic activities and thus retarded bacterial growth. Avery and Dochez's theory of antiblastic immunity offered an explanation of resistance to infection--that is, the arresting of the development of the infectious agent by inhibiting its enzymes--which differed completely from the conventional understanding of protective antibodies. If the theory were correct, they argued, "considerable light would be thrown on the obscure mechanisms by which parasitic bacteria establish themselves in animal tissues, and on the forces mobilized by the animal body in opposition to such invasion."

Other researchers--even some at the Hospital--such as Francis Blake, M. A. Barber, and Cole, had their doubts about what they termed "so-called" antiblastic immunity. Avery and Dochez's colleagues argued that under the conditions the two researchers had used, anti-pneumococcal serum could retard the growth of pneumococci and depress enzymatic activity, but it was likely that these effects were the result of the agglutination, or clumping, of the organisms due to the presence of specific antibodies, not the inhibition of their enzymes. Although they continued to work on antiblastic immunity for several more months, neither Avery nor Dochez published anything to refute this criticism. In fact, they never referred to antiblastic immunity again in either scientific journals or the annual reports to the Hospital. Although Avery usually doggedly pursued his inquiries until he reached a satisfactory conclusion, he abandoned antiblastic immunity after he and Dochez submitted their findings to the Hospital's Board of Directors in 1916. The antagonism to their hypothesis of antiblastic immunity also made Avery more deliberate in all future public assertions on the theoretical implications of his research.

Following the entry of the Untied States into the First World War in 1917, Avery's laboratory work at the Hospital was disrupted for most of the next two years. He joined the U.S. Army Medical Corps in 1917 and was designated a private because he could not be commissioned as an officer as he was born in Canada and still a British subject. Due to his service, however, Avery eventually qualified for citizenship, and was commissioned as a captain prior to the war's conclusion. For much of the war, he conducted research on the emerging global influenza epidemic and taught courses to Army medical officers on diagnosing acute respiratory diseases. His lectures to officers constituted the last formal teaching experience of his life. However, these lectures were the antecedents to the compelling accounts of the then current state of pneumococcus research that he presented years later to young researchers in his laboratory. His colleagues at the Rockefeller Hospital affectionately referred to them as the "Red Seal Records," after a popular brand of musical recordings. During the war, Avery published several papers on the bacteriology of influenza bacilli and hemolytic streptococci. Almost as soon as the war and influenza epidemic ended, however, Avery returned to his metabolic studies of pneumonia.