Hans Krebs

Hans Krebs: The Chemistry of Staying Alive

In March 1937, in a laboratory in Sheffield, Hans Krebs and a colleague minced the breast muscle of a freshly killed pigeon, suspended it in solution and watched its metabolic rate fall away over the following half hour. Then they added salts of citric acid, and the tissue went on respiring roughly three times longer. The paper explaining why was rejected by *Nature*. Sixteen years later it won the Nobel Prize.

The Surgeon's Son

Krebs was born on 25 August 1900 in Hildesheim, Germany, to Georg Krebs, an ear, nose and throat surgeon, and Alma Davidson. He went to the Gymnasium Andreanum in his home town and then read medicine from 1918 to 1923 across three universities — Göttingen, Freiburg im Breisgau and Berlin — taking his M.D. at the University of Hamburg in 1925. He then spent a further year in Berlin studying chemistry, a decision that turned a physician into a biochemist.

Apprentice to Otto Warburg

From 1926 to 1930 Krebs worked as assistant to Otto Warburg at the Kaiser Wilhelm Institute for Biology in Berlin. Warburg was the most formidable experimentalist in German biochemistry, and the apprenticeship gave Krebs the technique that would define his career: the quantitative study of respiring tissue slices, in which the chemistry of a living preparation could be measured while it was still running. Krebs afterwards held hospital posts in Altona and Freiburg under Professors Lichtwitz and Thannhauser.

The First Cycle

At Freiburg, working with a research student named Kurt Henseleit, Krebs solved the problem of how mammals dispose of ammonia. The answer, published in 1932, was that ammonia is converted in the liver into urea — a far less toxic compound, excreted in urine and a major source of the amino acid arginine. The mechanism mattered less than its shape. It was a loop: a sequence of reactions that consumed its inputs, released its product and regenerated its own starting material, ready to run again. It was the first cyclic metabolic pathway ever discovered, and Frederick Gowland Hopkins presented the work to the Royal Society in the winter of 1932.

Dismissal, 1933

In April 1933 the Nazi government dismissed him from his post at the University of Freiburg's medical clinic; his appointment was formally terminated that June. Hopkins, who had followed the urea work in the German literature, invited him to Cambridge. Krebs arrived in July 1933 as a Rockefeller fellow and then as Demonstrator in the Department of Biochemistry, a post he held until 1935. Germany's loss was total and permanent: the man who would explain how every cell in the body extracts energy from food spent the rest of his working life in England.

The Pigeon Breast Experiment

In 1935 Krebs moved to Sheffield University as Lecturer in Pharmacology. There, with William Johnson, he ran the pigeon-muscle experiments that produced his second and greater cycle. The observation that citrate prolonged respiration threefold pointed to something counter-intuitive: citric acid was not being consumed as a fuel, but acting catalytically within a closed loop that consumed the breakdown products of sugar, released carbon dioxide, and regenerated itself.

What the citric acid cycle explains is the central transaction of animal life. Sugars, fats and the components of protein are fed into it and converted to carbon dioxide, water and energy, with the electrons released being used to build high-energy phosphate bonds in the form of adenosine triphosphate — the chemical-energy reservoir of the cell. Britannica's assessment is that the cycle is "central to nearly all metabolic reactions and the source of two-thirds of the food-derived energy in higher organisms." *Nature*, in 1937, declined to publish it.

Sheffield and Oxford

Krebs became Professor at Sheffield in 1945 and in 1954 moved to Oxford as Whitley Professor of Biochemistry, where he remained on the faculty until 1967. He continued to find loops: working with H. L. Kornberg he described the glyoxylate cycle in plants and microorganisms, and in 1957 the two published an account of energy transformations in living matter. He had been elected a Fellow of the Royal Society in 1947, received the Royal Medal in 1954, was knighted in 1958 and was awarded the Royal Society's Copley Medal in 1961. In 1953 he shared the Nobel Prize in Physiology or Medicine with Fritz Lipmann, the citation reading simply "for his discovery of the citric acid cycle."

He had married Margaret Cicely Fieldhouse in 1938; they had two sons, Paul and John, and a daughter, Helen. He died in Oxford on 22 November 1981, aged eighty-one.

Why Hans Is Called a Genius

The distinctive faculty here is not mathematical power or theoretical daring but a particular kind of pattern recognition: the ability to look at a list of chemical intermediates and see a circle where everyone else saw a line. Metabolism had been imagined as a chain running from food to waste. Krebs found, twice, that it runs in loops — that a molecule can be a catalyst for its own regeneration inside a living cell. The urea cycle was the first such pathway ever identified, and the citric acid cycle turned out to be the engine room of aerobic life. That is a conceptual move of the first order, and it was won not by speculation but by relentless quantitative measurement of tissue that was still alive.

The honest counter-case is worth stating. The technique that made it possible — manometric study of respiring tissue preparations — he inherited from Otto Warburg rather than invented. Both cycles were found in collaboration, with Henseleit and with Johnson, and the Nobel was shared. And the *Nature* rejection is instructive: to expert contemporaries in 1937, the work did not read as revolutionary, because it was assembled from increments rather than announced as a revelation. No law or equation carries Krebs's name; a metabolic pathway does. His achievement is empirical and cumulative rather than singular, which is precisely why it has never needed revising.

Legacy

The Krebs cycle is now taught to every biology student on earth, usually as a diagram on a single page, which disguises how hard it was to see. Its discovery converted biochemistry from a descriptive science into a mechanistic one and supplied the framework on which the modern understanding of cellular energy, and much of medicine's grasp of metabolic disease, still rests. A refugee dismissed by his own country in 1933 explained, from a provincial English laboratory, how living things stay alive.

Achievements

• Albert Lasker Award for Basic Medical Research — 1953
• Nobel Prize in Physiology or Medicine — 1953
• Copley Medal — 1961
• Notable work: urea cycle
• Notable work: tricarboxylic acid cycle
• Notable work: glyoxylate cycle
• Affiliated with University of Sheffield, University of Oxford and University of Freiburg
• Educated at University of Göttingen, University of Freiburg and University of Hamburg
• Worked as biochemist, physician and university teacher