Oswald Theodore Avery

Avery (1877?-1955) was one of the founding fathers of immunochemistry and a major contributor to the scientific evolution of microbiology.

Oswald Theodore 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 on October 21, 1877 (one source says 1887), in 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 believed 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 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 but soon turned to research and 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. Avery spent the remainder of his career there.

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 which 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 is nitrogen-containing and 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 stunned the scientific world when he announced that he had manipulated immunological specificity in pneumococci. At the 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 on 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' 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.

Avery also continued to work on other antigenic aspects of carbohydrates and the immune system. He was the first to create antibody-based treatments that were successful in protecting laboratory animals from infection, essentially by removing the protective capsular coat of the virulent cell. Collaborating with Dochez, he immunologically classified hemolytic (destructive to blood cells) streptococcus and identified many of the specific antigens at work. These efforts revealed that hemolytic streptococcus had many serological types. Eventually hemolytic streptococcus was identified as the infectious agent in scarlet and acute rheumatic fever and hemorrhagic nephritis (kidney disease). Avery's work was the foundation for the eventual discovery of effective antibiotics for hemolytic streptococcus.

Despite the fact that Avery guarded his personal life, some information is known about his interests outside of science. A musician, he played cornet with the New York Conservatory of Music Orchestra and organized his own band. He also painted water colors. An independent Republican, he was a commissioned captain in the U.S. Army Medical Corps during World War I, assigned to the Institute for Medical Research. He served on various advisory committees during World War II, including the U.S. Army Board for the Study and Control of Epidemic Disease.

A highly reserved individual, Avery preferred to be remembered by his scientific accomplishments. He was fondly remembered by many of his colleagues and former students and clearly recognized for his efforts in helping to solve the puzzle of heredity. His honors were many, including several honorary degrees, the Paul Ehrlich Gold Medal, and the Copley Medal of the Royal Society of London. He also was a member of the National Academy of Sciences and foreign member of the Royal Society of London. He continued to conduct research in laboratories at the Rockefeller Institute Hospital for several years after his retirement. Eventually, he moved to Nashville, Tennessee, in 1947. He died there on February 20, 1955.

Further Reading

Biographical Memoirs of Fellows of the Royal Society, Royal Society (London), Volume 2, 1956, pp. 34-47.

Dochez, A. R., "Oswald Theodore Avery," in Biographical Memoirs, Volume 32, National Academy of Sciences, 1958, pp. 31-48.

Gillispie, Charles Coulston, editor, Dictionary of Scientific Biography, Volume 1, Scribner's, 1970, pp. 342-343.

Magner, Lois N., A History of the Life Sciences, Marcel Dekker, 1979, pp. 452-454.

McGraw-Hill Modern Men of Science, McGraw-Hill, 1966, pp. 15-17. □

Avery, Oswald Theodore (1877-1955)

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

Oswald Theodore Avery

1877-1955

Canadian-American Bacteriologist and Physician

DNA's role in genetics and heredity was one of the focal points of biological inquiry in the second half of the twentieth century, but through most of the first half of the century there was little interest in this molecule. The person who changed all that was Oswald T. Avery. In 1944, he and his coworkers published evidence that DNA carried genetic information in bacteria, and this research first brought attention to this paper launched a renewed interest and research into DNA.

Avery was born in 1877 in Halifax, in the Canadian Province of Nova Scotia, and several years later, his family emigrated to the United States. Avery graduated from Colgate University in 1900 and then went to medical school at Columbia University College of Physicians and Surgeons in New York, graduating in 1904. After a brief period of medical practice and research at the Hoagland Laboratory in Brooklyn, Avery moved to the Rockefeller Institute for Medical Research in 1913. He spent the rest of his career there, retiring in 1948 to Tennessee, where he died in 1955.

At Rockefeller, almost all of Avery's research was on pneumococcus, the bacterium that causes pneumonia, which at the turn of the century was a leading cause of death. By the time Avery was doing his work, several different types of pneumococcus had been identified. In 1917 Avery and Alphonse Dochez (1882-1964) found that these differences were due to substances on the surface of the bacteria, which also appeared in the blood of patients. Six years later, working with Michael Heidelberger (1888-1991), Avery identified these substances as polysaccharides, sugar molecules linked together. The different pneumococcus types produced polysaccharides with different combinations of sugars. A patient's immune system reacted against the bacteria's polysaccharides, which explained why immunity was specific for each pneumococcus type. This discovery was the first indication that the immune system could respond to polysaccharides; until this time it was assumed that only proteins could stimulate such a response.

In Britain, Fred Griffith (1877-1941) researched another difference among pneumococci strains: those with the polysaccharide coat formed large smooth colonies (the S form) when grown on agar gel, while those that lacked the coat formed rough-looking colonies and were incapable of causing infection (the R form). Griffith discovered that when live type II pneumococci of the R form were mixed with dead type I of the S form, and this mixture was injected into mice, the mice died of pneumonia, but of the type I kind. In other words, something—some chemical information—from the dead S-form bacteria had been transferred to the live R-form bacteria, allowing them to make the type I polysaccharide.

While Avery was skeptical of this result, biologists in his lab were able to reproduce it, and so he then set out to identify the substance responsible for the transformation of one type of pneumococcus bacterium into another. This effort began in 1928 and eventually involved the assistance of two collaborators, Colin MacLeod (1909-1972) and Maclyn McCarty (1911-). The results weren't published until 1944 because it proved difficult to achieve reproducible results. But finally they were able to show convincingly that what Avery called the "transforming factor" was DNA. Biologists long knew that DNA, along with protein, made up chromosomes, the cellular structures that appeared to carry genetic information. But the assumption had been that protein, with its 20 different building blocks, was the likely genetic material, and that DNA, with only 4 different building blocks, simply served as a structural foundation. Avery's work called this assumption into question, and while it took several years for his findings to be widely accepted, his research did spur others to at last look more closely at DNA. Among these researchers were James Watson (1928- ) and Francis Crick (1916- ), who worked out the structure of DNA in 1953. This discovery led to the tremendous level of interest in the molecular basis of genetics that characterized biology in the second half of the twentieth century.

MAURA C. FLANNERY

Avery, Oswald Theodore (1877–1955) Canadian bacteriologist who worked at the Rockefeller Institute Hospital in New York (1913–48), where he and his colleagues Maclyn McCarty and Colin Macleod identified DNA as the hereditary material in the cells of pneumococcus bacteria. It had previously been thought that protein was the hereditary material; Avery's work was an important step in leading Watson and Crick to the discovery of the true chemical basis of heredity.