Ernst Chain

Ernst Chain: The Chemist Who Made Penicillin Real

On 25 May 1940, eight mice at Oxford were injected with streptococci and four of them were given a brownish powder that a German refugee had spent two years learning how to extract. The next morning the four treated mice were alive and the four untreated ones were dead. Alexander Fleming had noticed the mould twelve years earlier and left it. Ernst Chain turned it into a drug.

Berlin, and a Chemist's Son

Chain was born in Berlin on 19 June 1906. His father, Dr Michael Chain, was a chemist and industrialist who had emigrated from Mogilev in the Russian Empire to study chemistry abroad; his mother, Margarete Eisner, was Berlin-born. The family was Jewish. He went through the Luisengymnasium and took his chemistry degree at the Friedrich-Wilhelm University in 1930, then spent three years on enzyme research at the Charité hospital.

He read the Nazi rise correctly and early. On 2 April 1933 he arrived in England with £10. The geneticist J.B.S. Haldane found him a place at University College Hospital in London, and from there he went to Cambridge, to Fitzwilliam College, working on phospholipids under Sir Frederick Gowland Hopkins. He was naturalised as a British subject in April 1939, months before the war.

Oxford and the Systematic Search

In 1935 Oxford's Sir William Dunn School of Pathology invited him in; by 1936 he was a demonstrator and lecturer in chemical pathology. His early Oxford work ranged widely — snake venoms, tumour metabolism, the mechanism of lysozyme — and it was the lysozyme work that pointed at what came next.

In 1938 Chain and the school's Australian director, Howard Florey, decided to investigate the biochemical and biological properties of selected antibacterial substances produced by microorganisms. Penicillin was one item on a list. Their working assumption was wrong in an interesting way: they thought these agents would turn out to be enzymes like lysozyme. What mattered was the decision to treat the problem as chemistry rather than as microbiological curiosity.

Extraction was miserable. Chain, with Edward Penley Abraham, built a purification route out of careful pH control, low temperatures and repeated evaporation — freeze-drying, essentially — and the yields were humiliating. Many gallons of mould broth produced an amount just large enough to cover a fingernail. Norman Heatley later improved the process into something that could be scaled at all. The mouse experiment of 25 May 1940 caused great excitement in the department, and it was the first hard proof that the substance worked in a living animal against a lethal infection.

In February 1941 the team treated its first infected human patient, an Oxford policeman. He improved markedly and then relapsed when the penicillin ran out, and died. Florey took from that failure a vow that he would always have enough penicillin to complete a treatment. In July 1941 Florey and Heatley went to the United States and made contact with the Department of Agriculture's Northern Regional Research Laboratories at Peoria, Illinois, beginning a production effort that eventually pulled in thousands of people and some thirty-five institutions.

The Patent He Did Not Get

Chain wanted to patent penicillin. In the German institutes where he had trained, patenting was ordinary practice and the obvious way to fund further work. Florey refused, on the view that the discovery should benefit all mankind. The decision long rankled Chain, and it was not merely wounded pride: British medicine subsequently bought penicillin back from American manufacturers who had patented the production processes.

He kept doing the chemistry. In 1942, with Abraham, Chain proposed the beta-lactam ring at the heart of the penicillin molecule — a structure that was disputed at the time and confirmed in 1945 by Dorothy Hodgkin's X-ray crystallography. That ring is the reason there is a whole family of antibiotics rather than a single drug.

Toward the end of the war he learned that the Nazis had murdered his mother and his sister.

Rome, Imperial, and a Public Jewishness

The 1945 Nobel Prize in Physiology or Medicine went to Fleming, Florey and Chain "for the discovery of penicillin and its curative effect in various infectious diseases." Honours followed: the Silver Berzelius Medal in 1946, election as a Fellow of the Royal Society, the Paul Ehrlich Prize in 1954, the Gold Medal for Therapeutics in 1957, and a knighthood in the 1969 Birthday Honours.

Recognition did not make him welcome everywhere. The United States barred him under the McCarran Internal Security Act of 1950 and refused him a visa twice in 1951. In 1948 he left Oxford for Rome, as scientific director of the International Research Centre for Chemical Microbiology at the Istituto Superiore di Sanità, where he built up work on fermentation — the industrial biology that antibiotic manufacture actually runs on. In 1961 he came back to London as professor of biochemistry at Imperial College, and founded its biochemistry department.

He married the biochemist Anne Beloff in 1948; they had three children, Benjamin, Daniel and Judith, raised in the Jewish faith. His Jewish identity grew more central and more public with age. He joined the board of governors of the Weizmann Institute of Science in 1954, was an outspoken Zionist, and in 1965 gave an address titled "Why I am a Jew" to the World Jewish Congress Conference of Intellectuals.

Why Ernst Is Called a Genius

Chain's claim rests on a particular kind of intelligence: the ability to see that a biological observation is really a chemical problem, and then to solve the chemistry when nobody knows whether the target molecule even survives handling. Fleming had penicillin in 1928 and could not stabilise or concentrate it; the substance was famous and useless. Chain's insight in 1938 was that the antibacterial agents of moulds deserved a systematic biochemical assault rather than another round of admiring observation, and his skill was in devising an extraction — pH, cold, repeated evaporation — delicate enough not to destroy what it was isolating. The beta-lactam proposal of 1942, made from chemical reasoning years before crystallography could confirm it, is the sharpest single display of his mind.

The counter-case is real. He did not discover penicillin, and he said so; the popular version that credits Fleming irritated him for the rest of his life, but the corrected version that credits Chain alone would be equally wrong. Oxford's penicillin was a team result: Florey supplied the direction, the nerve and the American connection, Heatley the production engineering without which nothing scaled, Abraham much of the chemistry beside him, Hodgkin the structural proof. Chain was also, by common account, difficult and combative, quick to feel slighted over credit — and on the patent question, at least, he turned out to be right. What he possessed was not lonely brilliance but exceptional chemical judgment applied at the exact point where a curiosity became a medicine.

Legacy

Chain died on 12 August 1979 at Mayo General Hospital in Castlebar, County Mayo, aged seventy-three. The biochemistry building at Imperial College carries his name, as does a road in Castlebar. The larger memorial is structural: the beta-lactam ring he argued for in 1942 remains the scaffold of the most widely used class of antibiotics in the world, and every semisynthetic penicillin is a variation on a molecule he helped pin down when it was still a stain on a laboratory dish.

Achievements

• Nobel Prize in Physiology or Medicine — 1945
• Knight Bachelor — 1969
• Grand Officer of the Order of Merit of the Italian Republic — 1956
• Affiliated with Imperial College London, University of Oxford and Istituto Superiore di Sanità
• Educated at Humboldt-Universität zu Berlin and Imperial College School of Medicine
• Worked as biochemist, university teacher and chemist