A Brief History of Antibodies

The acquisition of immunity to a disease that a patient has already encountered has been documented for many centuries. Arguably some of the earliest work in the field that has now become known as immunology was performed in the period around 1714-1717. Lady Mary Wortley Montagu, Emanuel Timoni and James Pylarini pioneered a smallpox inoculation, a course of action unparalleled in medical advance up to that point. Variolation, as it was known, used live smallpox virus in the liquid taken from a smallpox blister in a mild case of the disease and carried in a nutshell (1). In 1798 the first smallpox vaccination was more notably demonstrated by Edward Jenner. This was performed by inoculating a boy with the fluid from a cowpox pustule giving him immunity to the very similar but much more serious disease smallpox (2, 3).

The earliest reference to antibodies came from Emil von Behring and Shibasabura Kitasato in 1890. In a landmark publication they showed that the transfer of serum from animals immunized against diptheria to animals suffering from it could cure the infected animals (4). The potential for treatment in humans was immediately apparent and Behring was later awarded the Nobel Prize for this work in 1901.

In 1900 Paul Ehrlich, who is regarded as one of the fathers of modern immunology, proposed the side-chain theory, where he hypothesised that side chain receptors on cells bind to a given pathogen. He was the first to propose a model for an antibody molecule in which the antibody was branched and consisted of multiple sites for binding to foreign material, known as antigen, and for the activation of the complement pathway (5). This model agreed with the ‘lock and key’ hypothesis for enzymes proposed by Emil Fischer (6, 7) and still in general terms holds true today.

Astrid Fagraeus in 1948 described that plasma B cells are specifically involved in antibody generation and by 1957 Frank Burnet and David Talmage had developed the clonal selection theory (8). This stated that a lymphocyte makes a single specific antibody molecule that is determined before it encounters an antigen, which was in contrast to the instructive theory developed by Linus Pauling in 1940 where the antigen acted as a template for the antibody (9).

 By 1959 Gerald Edelman and Rodney Porter independently published the molecular structure of antibodies (10, 11), for which they were later jointly awarded the Nobel Prize in 1972. The first atomic resolution structure of an antibody fragment was published in 1973 (12) and this was quickly followed by the invention of monoclonal antibodies in 1975 by Georges Köhler and César Milstein (13) signalling the start of the modern era of antibody research and discovery.

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References

1. Case, C.L., and Chung, K.T. (1997). Montagu and Jenner: The Campaign Against Smallpox. SIM News 47, 58–60.
2. Jenner, E. An Inquiry Into the Causes and Effects of the Variolæ Vaccinæ, Or Cow-Pox.
3. Riedel, S. (2005). Edward Jenner and the history of smallpox and vaccination. Proc (Bayl Univ Med Cent) 18, 21–25.
4. Behring, E., and Kitasato, S. (1890). Uber das Zustandekommen Der Diphtherie- Immunitat Und der Tetanus-Immunitat Bei Thieren. Dtsch Med Wochenschr 49, 1113–1114.
5. Davies, D.R., and Chacko, S. (1993). Antibody structure. Acc. Chem. Res. 26, 421–427.
6. Fischer, E. (1894). Einfluss der Configuration auf die Wirkung der Enzyme. Berichte Der Deutschen Chemischen Gesellschaft 27, 2985–2993.
7. Lemieux, R.U., and Spohr, U. (1994). How Emil Fischer was led to the lock and key concept for enzyme specificity. Adv Carbohydr Chem Biochem 50, 1–20.
8. Edelman, G.M. (1959). Dissociation of γ-globulin. Am. Chem. Soc. 81, 3155–3156.
9. Burnet, F.M. (1957). A modification of Jerne’s theory of antibody production using the concept of clonal selection. The Australian Journal of Science 20, 67–69.
10. Pauling, L. (1940). A Theory of the Structure and Process of Formation of Antibodies. J. Am. Chem. Soc. 62, 2643–2657.
11. Porter, R.R. (1959). The hydrolysis of rabbit y-globulin and antibodies with crystalline papain. Biochem. J. 73, 119–126.
12. Inbar, D., Hochman, J., and Givol, D. (1972). Localization of antibody-combining sites within the variable portions of heavy and light chains. Proc. Natl. Acad. Sci. U.S.A. 69, 2659–2662.
13. Köhler, G., and Milstein, C. (1975). Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256, 495–497.