Ehrlich’s Side-Chain Theory

Paul Ehrlich, born in Prussia in 1854, was a German medical scientist who conducted pioneering work in hematology, immunology, and chemotherapy, and discovered the first effective drug treatment for syphilis. Introduced to the staining of cells by his cousin Carl Weigert, a renowned neuropathologist, this interest—perhaps even obsession—persisted and influenced Ehrlich’s conceptual thinking for much of his scientific career. During his medical school days, while continuing to experiment with chemical dyes, Ehrlich observed that some cells and tissues selectively took up and bound chemical dyes and were stained, yet others did not. After completing medical school, he developed a dye that permitted the differentiation of the numerous blood cells, and this served as the basis for the study of hematology.

In 1893, while working on an antiserum for the treatment of diphtheria, Ehrlich began formulating his side-chain theory, which described how antibodies—proteins produced by the immune system— are formed, and how they interact with foreign substances (antigens). Based on an analogy of a lock and key, he postulated that the surface of each cell contains distinct receptors or “side chains” that specifically bind to disease-causing toxins produced by the infectious agent. The binding of the toxin to the side chain (key-to-lock) is an irreversible interaction, and prevents any additional binding of toxin molecules.

The “lock and key” analogy Ehrlich used to formulate his side-chain theory was also the basis for his attempt to develop a “magic bullet”: a drug that selectively kills a disease-causing microbe without harming the patient. This led to his 1910 discovery of Salvarsan, the first effective treatment for syphilis.

The body responds by producing an excess number of side chains (antibodies), but the cell lacks the capacity to accommodate all the side chains on its cell surface. The excess side chains are released, where they remain in circulation, prepared to protect the individual against subsequent attacks by the disease-causing toxins. Ehrlich’s first paper describing his side-chain theory appeared in 1897. The theory was publically presented at a Royal Society meeting in London in 1900, where it was enthusiastically received, and for which he was a co-recipient of the 1908 Nobel Prize. By 1915, the year of Ehrlich’s death, exceptions to his theory were identified, and many details were found to be incorrect. The theory fell into disfavor, but his concepts on antigens and antibodies serve as the basis for immunology.