The Many Sides of Paul Ehrlich

Home , Emil von Behring, Karl Landsteiner, Magic bullet (medicine), Paul Ehrlich

MILESTONES

MILESTONE 2 The many sides of Paul Ehrlich

In the final decade of the 19th required receptors. Furthermore, century, Emil von Behring and Karl Landsteiner’s studies showing Shibasaburo Kitasato developed the side-chain that antibodies can be generated serum therapy for the treatment of model ... paved against chemically synthesized diphtheria and tetanus (MILESTONE 1). the way for the haptens also suggested cracks in The contribution of the Berlin-based Ehrlich’s model—why would cells bacteriologist Paul Ehrlich was vital subsequent express pre-formed receptors for for the production of high-quality correct non-organic substances? anti-diphtheria serum that could be description It is now appreciated that used to passively vaccinate humans plasma cells are the dedicated anti- against this deadly disease. Ehrlich of antibody body-producing cells of the immune proceeded to show that feeding formation... system, developing from B cells that laboratory animals low doses of a express a single antigen-receptor toxin protected them against an type and undergo clonal expansion otherwise lethal dose of the same (MILESTONES 3, 5). Furthermore, B cell toxin, and he formulated the concept receptors for antigen are randomly of active and passive immuniza- generated (giving rise to a highly Ehrlich’s side-chain model looks spookily like our tion. However, the basis of the diverse receptor repertoire), and modern understanding of antibody production. Adapted from: Ehrlich, P. Croonian lecture: on immunological protection involved B cells that express self-reactive immunity with special reference to cell life. Proc. was unknown. receptors are purged to prevent Royal Soc. Lond. 66, 424–448 (1900). Courtesy of Stefan H. E. Kaufmann. In 1897, Ehrlich proposed the harmful autoimmune responses. In side-chain model of immunity to fact, Ehrlich himself observed that account for his experimental obser- animals could not be immunized Prize in physiology or medicine, with vations. He imagined that harmful against their own blood, and he Élie Metchnikoff, in recognition of compounds (toxins) could mimic introduced the term ‘horror autotox- their work on immunity. Not bad nutrients for which cells express side icus’ to describe the host’s aversion for a Jewish scientist considered a chains that he called ‘nutriceptors’. to autoantibody production. Despite ‘non-person’ during the Nazi regime, Each cell would express multiple its shortcomings, the side-chain a period that saw his manuscripts types of side chains to allow the model was ground-breaking; it paved scattered throughout Europe and specific uptake of essential nutrients. the way for the subsequent correct lost for almost a century. Mercifully, During an infection, the side chains description of antibody formation Ehrlich’s papers were eventually would bind to microbial toxins (MILESTONES 3, 5) and introduced the tracked down by his grandson and instead of nutrients and would ‘lock-and-key’ concept that became are now safely deposited in the thereby block the physiological the basis of our understanding of Rockefeller Archive Center—a lasting functions of the side chains. To adaptive immunity. tribute to perhaps the greatest medi- compensate, the cell would produce Ehrlich had many other notable cal scientist of the late 19th and early more side chains; these would be ‘side projects’. He developed chem- 20th centuries. shed into the bloodstream, where ical dyes for selective cell staining, Yvonne Bordon, they would accumulate and act as described mast cells, basophils, Senior Editor, Nature Reviews Immunology antitoxins or ‘antibodies’, protecting eosinophils and neutrophils, and ORGINAL RESEARCH PAPERS Ehrlich, P. against subsequent exposures to showed how the passive transfer of Experimentelle Untersuchungen über Immunität. the same infection. Ehrlich would antibodies via breast milk protects Dtsch. Med. Wschr. 17, 976 (1891) | Ehrlich, P. Die Seitenkettentheorie und ihre Gegner. Münch. Med. later introduce the term ‘receptor’ to infants. Moreover, he devised Wschr. 18, 2123 (1901) | Ehrlich, P. Die Schutzstoffe replace ‘side chain’. the concept of the ‘magic bullet’, des Blutes. Dtsch. Med. Wschr. 27, 865 (1901) Ultimately, the side-chain hypoth- proposing that invading microbes FURTHER READING Silverstein, A. M. The most elegant immunological experiment of the esis of immunity proved to be incor- could be specifically targeted without XIX century. Nat. Immunol. 1, 93–94 (2000) | Winau, rect. Ehrlich envisaged that all cells damage to the host. His discovery of F., Westphal, O. & Winau, R. Paul Ehrlich—in search express the receptors that can give Salvarsan as a ‘magic bullet’ for the of the magic bullet. J. Mic. Inf. 6, 786–789 (2004) | Silverstein, A. M. Paul Ehrlich, archives and the rise to antibodies and that any single treatment of syphilis (through the use history of immunology. Nat. Immunol. 6, 639 (2005) | cell expresses multiple receptor types. of a high-throughput screening sys- Kaufmann, S. H. E. Immunology’s foundation: the 100-year anniversary of the Nobel Prize to Paul When the sheer scale of the potential tem now routinely employed by the Ehrlich and Elie Metchnikoff. Nat. Immunol. 9, antibody repertoire was later realized, pharmaceutical industry) founded 705–712 (2008) | Kaufmann, S. H. E. Paul Ehrlich: it became improbable that any the field of chemotherapy. In 1908, founder of chemotherapy. Nat. Rev. Drug Disc. 7, 373 (2008) single cell could express all of the he was jointly awarded the Nobel