Paul Ehrlich

Paul Ehrlich: The Chemist Who Aimed at Disease

Compound 606 was called 606 because it was the six hundred and sixth arsenic derivative Paul Ehrlich's laboratory had synthesised and tested. Most researchers would have stopped somewhere in the low hundreds. Ehrlich did not, and in 1909, with his Japanese assistant Sahachiro Hata, he found the one that killed the spirochaete of syphilis without killing the patient. He had been arguing for years that such a thing must exist — a *Zauberkugel*, a magic bullet, a substance that would seek out the parasite and ignore the host. Salvarsan proved him right and founded chemotherapy.

Dyes

Ehrlich was born on 14 March 1854 in Strehlen, Silesia, the son of Ismar Ehrlich, an innkeeper, distiller and leader of the local Jewish community. He studied medicine at Breslau from 1872, then at Strasbourg, Freiburg and Leipzig, and took his doctorate in 1878 under Julius Cohnheim with a dissertation on "Contributions to the Theory and Practice of Histological Staining."

That title contains his entire career in embryo. Germany in the 1870s had the world's most advanced synthetic dye industry, and Ehrlich was fascinated by a fact the industry treated as a technical nuisance: dyes are selective. A given dye stains one kind of cell and leaves its neighbour untouched. To Ehrlich this was not a nuisance but a message. Selectivity implied *affinity*; affinity implied specific chemical structures on the cell that the dye was binding to; and if a molecule could find a particular cell in a tissue, then in principle a molecule could be built to find a particular parasite in a body.

The immediate yield was practical. His staining methods allowed the different white blood cells to be told apart for the first time, which effectively created haematology as a diagnostic discipline; he discovered mast cells; and in 1881 he produced Ehrlich's reagent, a test that separated typhoid from ordinary diarrhoea. He habilitated at the Charité in Berlin in 1886 and joined Robert Koch's Institute for Infectious Diseases in 1891.

Side Chains

From the same intuition came his theory of immunity. Ehrlich proposed that the cell carries surface structures — side chains — that bind toxins by chemical fit, and that a cell stimulated by a toxin overproduces these side chains, which are shed into the blood and circulate as free-floating binders. Those circulating side chains are antibodies.

The specific picture has been superseded. The core idea has not: that immunity is a matter of complementary molecular shapes locking together, and that the cell surface bears receptors which are the point of contact between a body and everything that acts on it. That is the conceptual foundation of receptor pharmacology, which is to say of most drugs now in use.

The theory also had an immediate commercial application. From 1894 Ehrlich worked with Emil von Behring on the diphtheria antiserum, and it was Ehrlich who solved the problem that stood between the discovery and the medicine: how to measure the potency of a serum so that a doctor could give a known dose. Standardisation made mass manufacture possible. Behring, by most accounts, then manoeuvred Ehrlich out of the profits, and the friendship never fully recovered.

Frankfurt and the 606th Try

In 1896 Ehrlich was given his own Institute for Serum Research and Testing at Berlin-Steglitz; in 1899 it moved to Frankfurt and became the Institute of Experimental Therapy, and from 1906 he also directed the Georg Speyer House. There he built something that had not existed before: an industrial-scale screening laboratory, a machine for synthesising chemical variants and testing them one after another against infected animals.

Methylene blue, an ordinary textile dye, showed activity against malaria parasites. Trypan red attacked the trypanosomes of sleeping sickness. Then arsenicals, and the long grind through the hundreds. Compound 606, arsphenamine, went into infected rabbits and then into patients; Hoechst marketed it as Salvarsan from late 1910, with the better-tolerated Neosalvarsan following in 1912. Together they remained the standard treatment for syphilis — a disease that had disfigured, maddened and killed across Europe for four centuries — until penicillin arrived in the 1940s.

Success was not comfortable. Salvarsan was toxic, difficult to administer, and produced casualties; Ehrlich faced public attacks and accusations, some of them driven by moralists who objected to curing a venereal disease at all. He shared the 1908 Nobel Prize in Physiology or Medicine with Élie Metchnikoff "in recognition of their work on immunity," having already received Prussia's Great Golden Medal of Science in 1903. In 1911 he was made a Privy Councillor, the highest Prussian civilian honour; in 1914 he took the Cameron Prize at Edinburgh and a full professorship at Frankfurt.

Why Paul Is Called a Genius

Ehrlich's distinctive quality was analogical reach — the ability to carry a principle intact from one domain into a wholly different one and find it still load-bearing. He observed that a dye picks out one cell and passes over another, and from that ordinary laboratory fact he derived, over three decades, both a theory of how the immune system recognises an invader and a programme for building drugs that recognise a pathogen. The same idea of specific chemical affinity underwrites the side-chain theory, the standardisation of antiserum, the receptor concept and Salvarsan. Few scientists have got so much out of a single insight, and fewer still have had the stamina to convert an insight into 606 numbered experiments.

The counter-case is real. The side-chain theory as he framed it is wrong in detail. Salvarsan was a dangerous compound whose toxicity he understated in public and whose reputation was justly contested. The screening method, brilliant as an engine of discovery, was closer to systematic brute force than to elegant deduction — a criticism made in his own time, and he was largely content to accept it, since the point was to find the drug. And in 1914 he put his name to the Manifesto of the Ninety-Three, the notorious declaration by German intellectuals defending their country's conduct in the war. He was a great scientist, not a saint, and the greatness lies precisely in the refusal to stop at 605.

Legacy

He married Hedwig Pinkus in 1883; they had two daughters, Stephanie and Marianne. He suffered a heart attack on 17 August 1915 and died three days later at Bad Homburg, aged 61; Kaiser Wilhelm II wrote of his "undying fame and the gratitude of both his contemporaries and posterity." Germany's federal institute for vaccines carries his name, as do a bacterial genus, a lunar crater and one of German medicine's leading prizes. The phrase he coined — the magic bullet — is still the standard shorthand for what pharmacology is trying to build.

Achievements

• Nobel Prize in Physiology or Medicine — 1908
• Foreign Member of the Royal Society — 1910
• Held posts at Charité, Frederick William University Berlin and Goethe University Frankfurt
• Educated at Leipzig University, Magdalenaeum Wrocław and University of Freiburg
• Fields of research: bacteriology, chemistry, chemotherapy and immunology