Avery, Oswald Theodore (1877-1955) (World of Microbiology and Immunology)
Canadian-born American immunologist
Oswald Avery was one of the founding fathers of immunochemistry (the study of the chemical aspects of immunology) and a major contributor to the scientific evolution of microbiology. His studies of the Pneumococcus virus (causing acute pneumonia) led to further classification of the virus into many distinct types and the eventual identification of the chemical differences among various pneumococci viral strains. His work on capsular polysaccharides and their role in determining immunological specificity and virulence in pneumococci led directly to the development of diagnostic tests to demonstrate circulating antibody. These studies also contributed to the development of therapeutic sera used to treat the pneumonia virus. Among his most original contributions to immunology was the identification of complex carbohydrates as playing an important role in many immunological processes. Avery's greatest impact on science, however, was his discovery that deoxyribonucleic acid (DNA) is the molecular basis for passing on genetic information in biological self-replication. This discovery forced geneticists of that time to reevaluate their emphasis on the protein as the major means of transmitting hereditary information. This new focus on DNA led to James Watson and Francis Crick's model of DNA in 1952 and an eventual revolution in understanding the mechanisms of heredity at the molecular level.
Avery was born Halifax, Nova Scotia, to Joseph Francis and Elizabeth Crowdy Avery. His father was a native of England and a clergyman in the Baptist church, with which Avery was to maintain a lifelong affiliation. In 1887 the Avery family immigrated to the United States and settled in New York City, where Avery was to spend nearly sixty-one years of his life. A private man, he guarded his personal life, even from his colleagues, and seldom spoke of his past. He stressed that research should be the primary basis of evaluation for a scientific life, extending his disregard for personal matters to the point that he once refused to include details of a colleague's personal life in an obituary. Avery's argument was that knowledge of matters outside of the laboratory have no bearing on the understanding of a scientist's accomplishments. As a result, Avery, who never married, managed to keep his own personal affairs out of the public eye.
Avery graduated with a B.A. degree from Colgate University in 1900, and he received his M.D. degree from Columbia University's College of Physicians and Surgeons in 1904. He then went into the clinical practice of general surgery for three years, soon turned to research, then became associate director of the bacteriology division at the Hoagland Laboratory in Brooklyn. Although his time at the laboratory enabled him to study species of bacteria and their relationship to infectious diseases, and was a precursor to his interest in immunology, much of his work was spent carrying out what he considered to be routine investigations. Eventually Rufus Cole, director of the Rockefeller Institute hospital, became acquainted with Avery's research, which included work of general bacteriological interest, such as determining the optimum and limiting hydrogen-ion concentration for Pneumococcus growth, developing a simple and rapid method for differentiating human and bovine Streptococcus hemolyticus, and studying bacterial nutrition. Impressed with Avery's analytical capabilities, Cole asked Avery to join the institute hospital in 1913, where Avery spent the remainder of his career.
At the institute Avery teamed up with A. Raymond Dochez in the study of the pneumococci (pneumonia) viruses, an area that was to take up a large part of his research efforts over the next several decades. Although Dochez eventually was to leave the institute, he and Avery maintained a lifelong scientific collaboration. During their early time together at the Rockefeller Institute, the two scientists further classified types of pneumococci found in patients and carriers, an effort that led to a better understanding of Pneumococcus lung infection and of the causes, incidence, and distribution of lobar pneumonia. During the course of these immunological classification studies, Avery and Dochez discovered specific soluble substances of Pneumococcus during growth in a cultured medium. Their subsequent identification of these substances in the blood and urine of lobar pneumonia patients showed that the substances were the result of a true metabolic process and not merely a result of disintegration during cell death.
Avery was convinced that the soluble specific substances present in pneumococci were somehow related to the immunological specificity of bacteria. In 1922, working with Michael Heidelberger and others at Rockefeller, Avery began to focus his studies on the chemical nature of these substances and eventually identified polysaccharides (complex carbohydrates) as the soluble specific substances of Pneumococcus. As a result, Avery and colleagues were the first to show that carbohydrates were involved in immune reactions. His laboratory at Rockefeller went on to demonstrate that these substances, which come from the cell wall (specifically the capsular envelopes of the bacteria), can be differentiated into several different serological types by virtue of the various chemical compositions depending on the type of Pneumococcus. For example, the polysaccharide in type 1 pneumococci contains nitrogen and is partly composed of galacturonic acid. Both types 2 and 3 pneumococci contain nitrogen-free carbohydrates as their soluble substances, but the carbohydrates in type 2 are made up mainly of glucose and those of type 3 are composed of aldobionic acid units. Avery and Heidelberger went on to show that these various chemical substances account for bacterial specificity. This work opened up a new era in biochemical research, particularly in establishing the immunologic identity of the cell.
In addition to clarifying and systemizing efforts in bacteriology and immunology, Avery's work laid the foundation for modern immunological investigations in the area of antigens (parts of proteins and carbohydrates) as essential molecular markers that stimulate and, in large part, determine the success of immunological responses. Avery and his colleagues had found that specific anti-infection antibodies worked by neutralizing the bacterial capsular polysaccharide's ability to interfere with phagocytosis (the production of immune cells that recognize and attack foreign material). Eventually Avery's discoveries led scientists to develop immunizations that worked by preventing an antigenic response from the capsular material. Avery also oversaw studies that showed similar immunological responses in Klebsiella pneumonia and Hemophilus influenza. These studies resulted in highly specific diagnostic tests and preparation of immunizing antigens and therapeutic sera. The culmination of Avery's work in this area was a paper he coauthored with Colin Munro MacLeod and Maclyn McCarty in 1944 entitled "Studies on the Chemical Nature of the Substance Inducing Transformation of Pneumococcal Types. Induction of Transformation by a Desoxyribonucleic Fraction Isolated from Pneumococcus Type III." In their article, which appeared in the Journal of Experimental Medicine, the scientists provided conclusive data that DNA is the molecular basis for transmitting genetic information in biological self-replication.
In 1931 Avery's focus turned to transformation in bacteria, building on the studies of microbiologist Frederick Griffith showing that viruses could transfer virulence. In 1928 Griffith first showed that heat-killed virulent pneumococci could make a nonvirulent strain become virulent (produce disease). In 1932 Griffith announced that he had manipulated immunological specificity in pneumococci. At that time Avery was on leave suffering from Grave's disease. He initially denounced Griffith's claim and cited inadequate experimental controls. But in 1931, after returning to work, Avery began to study transmissible hereditary changes in immunological specificity, which were confirmed by several scientists. His subsequent investigations produced one of the great milestones in biology.
In 1933 Avery's associate, James Alloway, had isolated a crude solution of the transforming agent. Immediately the laboratory's focus turned to purifying this material. Working with type-3 capsulated Pneumococcus, Avery eventually succeeded in isolating a highly purified solution of the transforming agent that could pass on the capsular polysaccharides's hereditary information to noncapsulated strains. As a result the noncapsulated strains could now produce capsular polysaccharides, a trait continued in following generations. The substance responsible for the transfer of genetic information was DNA. These studies also were the first to alter hereditary material for treatment purposes.
Avery, however, remained cautious about the implications of the discovery, suspecting that yet another chemical component of DNA could be responsible for the phenomenon. But further work by McCarty and Moses Kunitz confirmed the findings. While some scientists, such as Peter Brian Medawar, hailed Avery's discovery as the first step out of the "dark ages" of genetics, others refused to give up the long-held notion that the protein was the basis of physical inheritance. The subsequent modeling of the DNA molecule by James Watson and Francis Crick led to an understanding of how DNA replicates, and demonstration of DNA's presence in all animals produced clear evidence of its essential role in heredity.
See also Antibody-antigen, biochemical and molecular reactions; Antibody and antigen; Antibody formation and kinetics; History of immunology; Immunogenetics; Immunologic therapies