Alfred Nisonoff
Encyclopedia
Alfred Nisonoff was a 20th century chemist who helped to experimentally determine the molecular structure of the antibody
, and, as a result, made major contributions to the field of immunology
. Nisonoff’s monograph, “The Antibody Molecule,” was the most important and in-depth paper on the antibody during his time.
Biographical Information
Alfred Nisonoff’s parents immigrated from Hungary
and Russia
to New York
as teenagers. He was born in Corona, Queens
on January 26, 1923. His parents moved the family to South River, New Jersey
where they operated a butcher shop and a grocery store throughout Alfred’s childhood.
Education
As a child, Alfred Nisonoff was an extremely well educated person. At the age of 6 he was in the third grade, and went on to graduate from high school at the age of 15. After graduation, he received a state scholarship to attend college and enrolled in Rutgers University
, within less than 50 miles of his home. Nisonoff’s interest in chemistry began when he was introduced to a home laboratory of a high-school friend. From this experience, Nisonoff made the decision to major in chemistry at Rutgers. 1
In 1942, at age 19, Nisonoff graduated from Rutgers with a chemistry degree, and went to work for the U.S. Rubber company in Detroit, Michigan
. He was assigned to determine a way to adhere nylon cords to rubber airline tires in order to add strength to the tires, previously manufactured using cotton cords. In passing through the factory, he stopped to watch a process in which nylon cords were used in strengthening self-sealing gas tanks made of rubber, and adapted this same process to the problem that faced him in strengthening the airplane tires. This type of analytical and creative thinking would prove to be useful in his future research on the structure of the antibody. 1
In Detroit, Alfred Nisonoff met Sarah Weismann, his future wife. In 1943, Nisonoff joined the U.S. Navy to help in the war effort. He missed the battle of Okinawa by only a month due to engine problems with his ship. 2 He served until the end of the war in 1945, and was finally discharged in July, 1946. He then took the opportunity to pursue graduate research in biochemistry in September 1946, with Frederick W. Barnes at Johns Hopkins University
through funds provided by the G.I. Bill. He received his M.A. in 1948 and his Ph.D. in 1951. His research with Barnes was on the enzymatic mechanism of transamination. 1
Research Work
Alfred Nisonoff was introduced to the subject of antibodies while studying at the Roswell Park Memorial Institute in Buffalo with a man named David Pressman. David Pressman was working in one of Linus Pauling’s
groups exploring the antigenic specificity of antibodies against haptenic determinants. This research took advantage of the technique of quantitative hapten inhibition, originally developed by Karl Landsteiner. While conducting these experiments in Pressman’s lab, Nisonoff contributed to an important paper explaining an idea that eventually led to important conclusions about the structure of the antibody molecule. In this early paper he demonstrated that the antibody molecule has two combining sites with the same specificity for an antigenic determinant. This helped to disprove the “instructional theories” of antibody formation. 2
Alfred Nisonoff’s most important work started when he began the enzymatic cleavage of rabbit antibodies to better determine the structure that contributed to their specificity in disease. He was continuing the work of Rodney Porter who had performed the enzymatic cleavage of antibodies with the enzyme papain. When Nisonoff used a different enzyme, pepsin, to digest the antibodies, he discovered that the enzymes cleave the proteins at different sites on opposite sides of the disulfide bridge connecting the two heavy chains of rabbit IgG. This led to the conclusion that papain cleaves on the amino-terminal side of the disulfide bond, and pepsin cleaves on the carboxyl-terminal side. Nisonoff’s work also contributed to the identification of the F(ab’)2 fragment of the antibody molecule, which is the single bivalent fragment that is produced after pepsin cleavage. Later, it was found that this fragment is responsible for antigen interaction and agglutination and precipitation reactions. 1
Nisonoff’s experiment led to many conclusions about the structure of the antibody. It was determined that the two antigen binding sites of the antibody are located opposite the Fc fragment, the part of the antibody responsible for binding to receptor cells. Through the further work of his colleagues, with the help of Nisonoff’s previous work, the full structure of the antibody molecule as well as its amino acid composition were determined. 1
Alfred Nisonoff’s work continued to concentrate on efforts to determine how the structure of the antibody reflects its function and specificity as an immunological tool. In 1975, Alfred Nisonoff, John Hopper, and Susan Spring published the monograph The Antibody Molecule. This piece reviewed the comprehensive information available at the time on the structure and function of the B-cell receptor. 1
Nisonoff focused the remainder of his career in a variety of positions within the immunology community, including work for the Department of Biological Chemistry in Chicago and the National Institutes of Health
(NIH). The research work of Alfred Nisonoff in determining the structure and functions of small proteins called antibodies, made major steps towards our modern understanding of the immune system. Without his work we may still be years behind our current understanding of the antibody molecule. Alfred Nisonoff died on March 12, 2001. 1
References
1“In Memorium: Alfred Nisonoff (1923−2001).” Nature Magazine. 2001.
2Steiner, Lisa A., Knight, Katherine L., and Capra, J. Donald. “Alfred Nisonoff; January 26, 1923-March 12, 2001.”
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
, and, as a result, made major contributions to the field of immunology
Immunology
Immunology is a broad branch of biomedical science that covers the study of all aspects of the immune system in all organisms. It deals with the physiological functioning of the immune system in states of both health and diseases; malfunctions of the immune system in immunological disorders ; the...
. Nisonoff’s monograph, “The Antibody Molecule,” was the most important and in-depth paper on the antibody during his time.
Biographical Information
Alfred Nisonoff’s parents immigrated from Hungary
Hungary
Hungary , officially the Republic of Hungary , is a landlocked country in Central Europe. It is situated in the Carpathian Basin and is bordered by Slovakia to the north, Ukraine and Romania to the east, Serbia and Croatia to the south, Slovenia to the southwest and Austria to the west. The...
and Russia
Russia
Russia or , officially known as both Russia and the Russian Federation , is a country in northern Eurasia. It is a federal semi-presidential republic, comprising 83 federal subjects...
to New York
New York
New York is a state in the Northeastern region of the United States. It is the nation's third most populous state. New York is bordered by New Jersey and Pennsylvania to the south, and by Connecticut, Massachusetts and Vermont to the east...
as teenagers. He was born in Corona, Queens
Corona, Queens
Corona is a densely-populated neighborhood in the former Township of Newtown in the borough of Queens in New York City, New York, United States...
on January 26, 1923. His parents moved the family to South River, New Jersey
South River, New Jersey
South River is a Borough in Middlesex County, New Jersey, United States. As of the United States 2000 Census, the borough population was 15,322....
where they operated a butcher shop and a grocery store throughout Alfred’s childhood.
Education
As a child, Alfred Nisonoff was an extremely well educated person. At the age of 6 he was in the third grade, and went on to graduate from high school at the age of 15. After graduation, he received a state scholarship to attend college and enrolled in Rutgers University
Rutgers University
Rutgers, The State University of New Jersey , is the largest institution for higher education in New Jersey, United States. It was originally chartered as Queen's College in 1766. It is the eighth-oldest college in the United States and one of the nine Colonial colleges founded before the American...
, within less than 50 miles of his home. Nisonoff’s interest in chemistry began when he was introduced to a home laboratory of a high-school friend. From this experience, Nisonoff made the decision to major in chemistry at Rutgers. 1
In 1942, at age 19, Nisonoff graduated from Rutgers with a chemistry degree, and went to work for the U.S. Rubber company in Detroit, Michigan
Detroit, Michigan
Detroit is the major city among the primary cultural, financial, and transportation centers in the Metro Detroit area, a region of 5.2 million people. As the seat of Wayne County, the city of Detroit is the largest city in the U.S. state of Michigan and serves as a major port on the Detroit River...
. He was assigned to determine a way to adhere nylon cords to rubber airline tires in order to add strength to the tires, previously manufactured using cotton cords. In passing through the factory, he stopped to watch a process in which nylon cords were used in strengthening self-sealing gas tanks made of rubber, and adapted this same process to the problem that faced him in strengthening the airplane tires. This type of analytical and creative thinking would prove to be useful in his future research on the structure of the antibody. 1
In Detroit, Alfred Nisonoff met Sarah Weismann, his future wife. In 1943, Nisonoff joined the U.S. Navy to help in the war effort. He missed the battle of Okinawa by only a month due to engine problems with his ship. 2 He served until the end of the war in 1945, and was finally discharged in July, 1946. He then took the opportunity to pursue graduate research in biochemistry in September 1946, with Frederick W. Barnes at Johns Hopkins University
Johns Hopkins University
The Johns Hopkins University, commonly referred to as Johns Hopkins, JHU, or simply Hopkins, is a private research university based in Baltimore, Maryland, United States...
through funds provided by the G.I. Bill. He received his M.A. in 1948 and his Ph.D. in 1951. His research with Barnes was on the enzymatic mechanism of transamination. 1
Research Work
Alfred Nisonoff was introduced to the subject of antibodies while studying at the Roswell Park Memorial Institute in Buffalo with a man named David Pressman. David Pressman was working in one of Linus Pauling’s
Linus Pauling
Linus Carl Pauling was an American chemist, biochemist, peace activist, author, and educator. He was one of the most influential chemists in history and ranks among the most important scientists of the 20th century...
groups exploring the antigenic specificity of antibodies against haptenic determinants. This research took advantage of the technique of quantitative hapten inhibition, originally developed by Karl Landsteiner. While conducting these experiments in Pressman’s lab, Nisonoff contributed to an important paper explaining an idea that eventually led to important conclusions about the structure of the antibody molecule. In this early paper he demonstrated that the antibody molecule has two combining sites with the same specificity for an antigenic determinant. This helped to disprove the “instructional theories” of antibody formation. 2
Alfred Nisonoff’s most important work started when he began the enzymatic cleavage of rabbit antibodies to better determine the structure that contributed to their specificity in disease. He was continuing the work of Rodney Porter who had performed the enzymatic cleavage of antibodies with the enzyme papain. When Nisonoff used a different enzyme, pepsin, to digest the antibodies, he discovered that the enzymes cleave the proteins at different sites on opposite sides of the disulfide bridge connecting the two heavy chains of rabbit IgG. This led to the conclusion that papain cleaves on the amino-terminal side of the disulfide bond, and pepsin cleaves on the carboxyl-terminal side. Nisonoff’s work also contributed to the identification of the F(ab’)2 fragment of the antibody molecule, which is the single bivalent fragment that is produced after pepsin cleavage. Later, it was found that this fragment is responsible for antigen interaction and agglutination and precipitation reactions. 1
Nisonoff’s experiment led to many conclusions about the structure of the antibody. It was determined that the two antigen binding sites of the antibody are located opposite the Fc fragment, the part of the antibody responsible for binding to receptor cells. Through the further work of his colleagues, with the help of Nisonoff’s previous work, the full structure of the antibody molecule as well as its amino acid composition were determined. 1
Alfred Nisonoff’s work continued to concentrate on efforts to determine how the structure of the antibody reflects its function and specificity as an immunological tool. In 1975, Alfred Nisonoff, John Hopper, and Susan Spring published the monograph The Antibody Molecule. This piece reviewed the comprehensive information available at the time on the structure and function of the B-cell receptor. 1
Nisonoff focused the remainder of his career in a variety of positions within the immunology community, including work for the Department of Biological Chemistry in Chicago and the National Institutes of Health
National Institutes of Health
The National Institutes of Health are an agency of the United States Department of Health and Human Services and are the primary agency of the United States government responsible for biomedical and health-related research. Its science and engineering counterpart is the National Science Foundation...
(NIH). The research work of Alfred Nisonoff in determining the structure and functions of small proteins called antibodies, made major steps towards our modern understanding of the immune system. Without his work we may still be years behind our current understanding of the antibody molecule. Alfred Nisonoff died on March 12, 2001. 1
References
1“In Memorium: Alfred Nisonoff (1923−2001).” Nature Magazine. 2001.
2Steiner, Lisa A., Knight, Katherine L., and Capra, J. Donald. “Alfred Nisonoff; January 26, 1923-March 12, 2001.”