Milestone 2.1 Clonal Selection Theory
Antibody production according to Ehrlich
In 1894, well in advance of his time as usual, the remarkable Paul Ehrlich proposed the side‐chain theory of antibody production. Each cell would make a large variety of surface receptors that bound foreign antigens by complementary shape “lock and key” fit. Exposure to antigen would provoke overproduction of receptors (antibodies), which would then be shed into the circulation (Figure M2.1.1).
Ehrlich’s hypothesis implied that antibodies were preformed prior to antigen exposure. However, this view was difficult to accept when later work showed that antibodies could be formed to almost any organic structure synthesized in the chemist’s laboratory (e.g., m‐aminobenzene sulfonate; Figure 5.6) despite the fact that such molecules would never be encountered in the natural environment. Thus was born the idea that antibodies were synthesized by using the antigen as a template. Twenty years passed before this idea was “blown out of the water” by the observation that, after an antibody molecule is unfolded by guanidinium salts in the absence of antigen, it spontaneously refolds to regenerate its original specificity. It became clear that each antibody has a different amino acid sequence that governs its final folded shape and hence its ability to recognize antigen.
The wheel turns full circle and we once more live with the idea that, as different antibodies must be encoded by separate genes, the information for making these antibodies must pre‐exist in the host DNA. In 1955, Nils Jerne perceived that this could form the basis for a selective theory of antibody production. He suggested that the complete antibody repertoire is expressed at a low level and that, when antigen enters the body, it selects its complementary antibody to form a complex that in some way provokes further synthesis of that particular antibody. But how?
Frank Macfarlane Burnet now brilliantly conceived of a cellular basis for this selection process. Let each lymphocyte be programmed to make its own singular antibody that is inserted like an Ehrlich “side‐chain” into its surface membrane. Antigen will now form the complex envisaged by Jerne, on the surface of the lymphocyte, and by triggering its activation and clonal proliferation, large amounts of the specific antibody will be synthesized (Figure 2.11). Bow graciously to that soothsayer Ehrlich, he came so close in 1894!