Lives of the fellows

Hans Adolf (Sir) Krebs

b.25 August 1900 d.22 November 1981
Kt(1958) MD Hamburg(1925) MA Cantab(1934) FRS(1947) FRCP*(1958)†

Hans Krebs was born in Hildesheim, an old and beautiful town situated near Hannover. In his autobiography, which appeared about the time of his death, Krebs describes the town of his birth in some detail, and also mentions that it was almost completely destroyed during World War II. His father, Georg Krebs, was a surgeon who specialized in diseases of the ear, nose and throat, and his mother was Alma Davidson, the daughter of a banker.

Krebs received a humanistic education which put emphasis on Latin and Greek, with some mathematics and relatively little science. He appears to have enjoyed both his Latin and Greek, and in conversation he occasionally quoted Horace and the Iliad. Both his parents were Jewish but they had no religious association, and particularly his father was completely immersed in German culture. According to the autobiography already quoted, his father’s heroes were Goethe, Bismarck, and Frederick the Great.

The home background appears to have been fairly austere, indeed Spartan. High standards of behaviour were expected of the children, and according to Hans, demonstrations of emotion were frowned upon. There were ‘no spontaneous hugs or goodnight kisses.’ This upbringing left a permanent mark on him. He was reluctant to show emotion, and he remained essentially shy throughout his life.

The school career of Hans Krebs ended in 1918 with his conscription into the Army. He served for only a few months, but he wrote many years afterwards that some aspects of his Army service made a lasting impression, largely as a clear definition of responsibilities within a team, and the importance of ‘self- and corporate-discipline.’ After leaving the Army he went to Göttingen University, where he was much impressed by the lectures in chemistry of Adolf Windaus, the famous steroid chemist, and the professor in physics, Robert Pohl.

Krebs then transferred to Freiburg, where he came under the influence of Möllendorf and particularly Knoop, whose work was of considerable importance to Krebs later in his career. After passing the Physikum (equivalent to the Second MB) he went to Munich, where the professor of medicine, Friedrich von Müller, who was also a good biochemist, greatly impressed him. This was the time when the German inflation reached horrendous proportions, and life for a university student must have been particularly difficult.

After his finals, Krebs spent his pre-registration year in the Third Medical Clinic where he met David Nachmansohn and Bruno Mendel, who became life-long friends. In 1925 Krebs worked for a while in the department of Peter Rona, which was probably his first introduction into biochemistry, and his experience there may have decided him to concentrate on a clinical career with biochemistry as his major research interest. An opportunity offered itself soon, when he heard from Mendel that Otto Warburg was looking for a collaborator to work on cancer. Mendel suggested Krebs as a candidate, and he was duly appointed.

The four years which Krebs spent in the department of Otto Warburg were in many ways decisive for the future development of Krebs as a scientist. Krebs himself wrote a full appreciation of Otto Warburg in the Memoirs of The Royal Society (Vol. 18, 1972), of which Warburg was a foreign member, and also a full biography which appeared in German in 1979 and was translated into English in 1981.

Warburg, who was one of the greatest biochemists of the last hundred years, was an unusual person. He was autocratic, and the extent of his autocracy was unusual even in pre-war Germany. He was touchy, full of prejudices, and by no means an easy colleague. However, his penetrating mind, his intellectual honesty, his imagination, and his singularity of purpose were equally outstanding. Krebs was conscious of the weaknesses of his teacher, but his admiration for the man prevailed, and Warburg’s influence remained a dominant factor throughout the life and career of Krebs.

During the time that Krebs worked in Warburg’s laboratory he was engaged mainly on problems set by his chief, such as the biological function and estimation of copper, the metabolism of tumours, and model experiments on catalysis by haem derivatives. But he learned a variety of methods which Krebs later used in his own work, and above all he acquired high and demanding standards of scientific work. Krebs left Warburg’s laboratory in 1930 and joined the department of Lichtwitz, who was responsible for external medicine at the municipal hospital at Altona, now part of the city of Hamburg.

During his time with Lichtwitz, who was a general physician with special interest in metabolism, Krebs acquired a very good training in clinical medicine. His clinical duties were quite heavy, but he managed to spend some time in the laboratory. Before long he was invited to join Tannhauser who, in addition to being a good clinician, was a widely-recognized expert on lipid metabolism and its disturbances.

The university of Freiburg provided an excellent environment for Krebs. He was again responsible for a ward, he greatly enjoyed his clinical work, and his contact with patients. However, he had time for laboratory work, and it was here that he started to work completely on his own ideas, but using the techniques which he had learned in Warburg’s laboratory.

In this work Krebs used the tissue slice technique which Warburg had extensively used in his studies of cell metabolism. A major advance in this technique was the introduction by Krebs of a new medium, which simulated blood plasma as closely as possible with respect to many of its constituents. This medium, which is an improvement on that of Ringer and that of Locke, has been widely used all over the world.

Krebs found that liver slices could form urea from ammonia and carbon dioxide, but that the addition of the amino acid ornithine greatly stimulated this process. He showed that ornithine acted catalytically, as demonstrated by the fact that one mole of ornithine could promote the formation of something like 20 moles of urea. He further showed that the amino acid citrulline was the first product of the interaction of ornithine, carbon dioxide and ammonia, and that arginine was the next product which on interaction with the enzyme arginase gave rise to ornithine and urea. This was the first demonstration of a metabolic cycle, and since the discovery of the mechanism of urea synthesis, a large number of cycles have been demonstrated.

The detailed enzymatic mechanisms involved in these various reactions were largely discovered by other workers, but Kreb’s work on urea synthesis must be considered one of the important milestones in modern biochemistry. This work earned Krebs almost immediately a great international reputation and led to his appointment as Privat Dozent in the University of Freiburg.

Within three months of Hitler’s assumption of power all academic teachers who were of the Jewish race were either dismissed or placed on leave, and this meant that Krebs had to leave his laboratory in Freiburg in the middle of April 1933. Krebs had been working at that time on the biosynthesis, metabolism and function of glutamine, a topic which engaged his attention for many years.

Krebs realized that he had to leave Germany if he wanted to continue with his scientific work and he decided to seek a position in England, a country which he had visited in 1928, and where he had some professional contacts. Sir Frederick Gowland Hopkins, who was head of the biochemistry laboratory at Cambridge, and at that time president of The Royal Society, invited Krebs to work in his laboratory.

Throughout his life Krebs showed the utmost gratitude to Hopkins, and his feelings are well expressed in the third Hopkins Memorial lecture which he gave in 1961, and which is published in The Biochemical Journal (Vol. 80, p.225). In this lecture Krebs also relates in some detail how greatly impressed he was with the British way of life, and how he appreciated the friendly welcome he received from members of the Hopkins laboratory, and from the academic community generally in Cambridge.

During his Cambridge period he worked on topics which had already engaged his attention earlier, such as the synthesis and metabolism of uric acid, the biological function of glycarboxylic acids, and glutamine.

In 1935 Krebs was appointed lecturer in the department of pharmacology in the University of Sheffield. This department was headed by EJ Wayne, who was essentially a clinician trained by Sir Thomas Lewis, but who had taken a degree in chemistry. Krebs was able to transfer to Sheffield the equipment which he had originally brought from Freiburg. In time, a department of biochemistry was established in Sheffield, and ultimately Krebs was appointed professor of biochemistry.

During the first few years in Sheffield Krebs did probably his most important piece of research, i.e., the discovery of the tricarboxylic acid cycle, or Krebs cycle. By 1932 it was known that glucose is not directly burnt or oxidised, but is first converted to lactic acid or pyruvic acid. It had also been shown by Albert Szent-Györgyi that the rate of oxidation in muscle preparations was greatly increased by adding succinic acid or related dicarboxylic acids: thus suggesting a catalytic effect of these compounds.

The German chemists Knoop and Martius had shown that citric acid was converted by liver tissues to a-oxoglutaric acid. Krebs used these seminal findings and also some important new experiments of his own to suggest a cycle which starts with the condensation of oxaloacetate with acetic acid or acetyl-CoA to citrate, and then through a-oxoglutarate, succinate and fumarate back to oxaloacetate. One turn of the cycle brings about the production of two molecules of carbon dioxide associated with the consumption of two molecules of oxygen.

This cycle is responsible for the oxidation of most of our food to carbon dioxide and water, and is the main oxidative pathway in most forms of life from bacteria to mammals. It is of some interest that a description of the essential facts about this cycle is contained in a letter to the editor of Nature, sent by Krebs in June, 1937. The editor of Nature informed Krebs that, owing to congestion of papers, they could not publish his letter at the time, and advised him to submit his paper elsewhere.

This paper, or a greatly expanded version of it, was in fact sent to the journal Enzymologia, which published it a few months after submission. It is no exaggeration to say that the formulation of the tricarboxylic acid cycle was one of the most important milestones in the development of biochemistry.

Krebs became a British citizen a few days after the outbreak of war in 1939, and a large part of his activities during the following years was connected with the war effort. Some of his work, which was carried out in association with Kenneth Mellanby, was concerned with the use of high extraction flour for human diets, particularly its digestibility, and the effect of the national wheatmeal on the absorption of calcium. Other work involved studying vitamin A deficiency, but his most important work during this period was concerned with vitamin C.

By making use of conscientious objectors, he established quantitatively the minimum amounts of vitamin C required for the prevention of scurvy. The results of these experiments are still being quoted at the present time, especially the fact that 30 milligrams of vitamin C a day allow an ample margin of safety, and should be accepted as a reliable guide for formulating national policies.

In 1944 the Medical Research Council decided to set up a unit for research in cell metabolism at the University of Sheffield, with Krebs as its director. This unit, which was later transferred to Oxford, carried out research over a wide range of metabolism, such as gluconeogenesis, ketosis, energy changes in biological reactions, metabolism of purines, and related topics. The unit gave hospitality to many workers from overseas, particularly American scientists, and has been one of the focal points of biochemical research in the UK.

Krebs was very happy in Sheffield, and his outstanding contribution to science was becoming recognized to an increasing extent. In 1953 he received the Nobel Prize for physiology and medicine jointly with F Lipmann. In 1954 Krebs was invited to accept the chair of biochemistry in the University of Oxford, a chair which had been occupied by Sir Rudolph Peters for some years. Krebs was somewhat uncertain as to whether he should leave Sheffield and, before finally accepting the invitation, he consulted Peters.

As Krebs reports in his autobiography, Peters thought that Krebs was not the ideal person for the post, and that only a scientist firmly based on a college could succeed in bringing experimental science into close contact with non-scientific academics. Krebs decided, however, to accept the post, and he was particularly attracted by the increasing possibilities which an Oxford chair would offer him both regarding teaching and research.

Krebs probably found it not too easy to fit into Oxford, at least at first. He had relatively little small talk, and the weak position which professors in both Oxford and Cambridge occupy in relation to the colleges obviously disturbed him. He was fortunate in being able to transfer his unit from Sheffield to Oxford, and he was readily accepted by his academic colleagues. In time he became to an increasing extent part of Oxford life, and he greatly enjoyed being a member of Trinity College, of which he became an honorary fellow after his retirement.

A major scientific advance made during the Oxford period was the discovery of a new cycle, the glyoxylate cycle, which is a modification of the citric acid cycle, and which operates mainly in micro-organisms and in plants. This cycle represents the mechanism by which fat is converted into carbohydrate, a reaction which cannot be performed by higher animals. This work was done jointly with Sir Hans Kornberg.

Having reached the statutory age for retirement, Krebs relinquished his chair, but continued his research activities with the support of the MRC in a laboratory generously provided in the Radcliffe Infirmary by Paul Beeson, and this move was also supported by Sir George Pickering, the regius professor. A large number of the topics on which Hans Krebs and his co-workers were engaged were a continuation of their earlier activities. However, there was emphasis on problems which were related to medicine, and Krebs’ intrinsic interest in clinical problems never left him.

Krebs never did much work with isolated enzymes: his emphasis was either on the whole cell or on the whole organ, and thus work done with the perfused liver occupied much of his time. He also tried to integrate results obtained with systems such as tissue slices or perfused organs with what was happening in the whole organism. He made some progress with this work, but this was not completed by the time he died. Krebs remained in full possession of his physical and mental capacities until nearly the end of his life. He was much in demand at international meetings, and was a stimulus for others during the whole period of his retirement.

Although Krebs had some other interests, his devotion to science, and particularly the biochemistry of metabolism, dominated his life. He was delighted to have been able to train a large number of biochemists, and his influence on the development of biochemistry both nationally and internationally was profound. As already mentioned, he was a shy person, who had a very high standard of personal and professional integrity, and this was greatly appreciated by everybody who came into contact with him. His personal life was happy; he married Margaret Fieldhouse, and had two sons and a daughter.

A Neuberger

* Elected under the special bye-law which provides for the election to the fellowship of "Persons holding a medical qualification, but not Members of the College, who have distinguished themselves in the practice of medicine, or in the pursuit of Medical or General Science or Literature.."

† The list of honorary degrees is too lengthy to include in entirety.

[Brit.med.J., 1982, 284, 59 & 517; Lancet, 1981, 2, 1299; Times, 23 Nov 1981; Clinical Science, 1982, 63, 225-30]

(Volume VII, page 325)

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