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Krebs, Hans Adolf

KREBS, HANS ADOLF

(b. Hildesheim, Germany, 25 August 1900; d. Oxford, England, 22 November 1981)

biochemistry.

Hans Adolf Krebs was the elder son, and second of three children, of Georg Krebs, an otolaryngologist with a flourishing private practice, and Alma Davidson Krebs, the daughter of a banker and member of a close-knit family that had been settled in the Hildesheim area for several centuries. As a boy he was deeply impressed by the intact late-medieval and Renaissance architecture of the old city of Hildesheim, at the edge of which his family lived in a comfortable house with a spacious garden.

Through the diverse interests of his widely cultivated father, Krebs came into contact with music, poetry, art, and clever conversation. On the customary family Sunday hikes into the nearby wooded hills, his father instilled in Hans a strong interest in nature in general and in wildflowers in particular. His father remained for him, however, a somewhat aloof figure who was skeptical of his son’s intellectual abilities and made him feel that nothing he did was quite good enough. Shy and somewhat solitary, Hans made no close friends as a boy; but he was industrious and well organized, and he read widely, cycled the surrounding countryside, and pursued hobbies such as botanical collecting and bookbinding. For much of his boyhood, the activity that consumed most of his time was practicing the piano. Although his father and mother both came from Jewish families, Hans and his younger brother Wolf were raised outside the formal faith, because Georg Krebs believed that the best solution to the Jewish question in Germany was assimilation.

In Mittelschule Krebs ranked first in his class, but during his years in the classical Gymnasium Andreanum his record was not outstanding. He did well in all of his subjects without showing exceptional talent in any of them. His education was concentrated in Latin and Greek, modern languages, history, literature, and mathematics, with relatively little science. His favorite subject was history, in which he read, beyond his assigned textbooks, major works by eminent German historians such as Theodor Mommsen and Leopold von Ranke.

At the age of fifteen, Krebs decided that he wanted to follow his father into medicine. He envisioned that after completing his training he would probably join his father’s practice until he could establish himself on his own.

Along with most other Germans, during the years after the outbreak of the world war, the Krebs family experienced increasing austerity owing to shortages of food, fuel, and other commodities. By the late summer of 1918, Hans was old enough to be drafted into the army. Assigned to a signal corps regiment in Hanover, he had completed only a few weeks of basic training when mutinies by sailors at Kiel and elsewhere precipitated the end of the war. Returning home, Krebs was able to obtain an immediate discharge on the grounds that he intended to enroll as a medical student at the nearby University of Göttingen. Allowed to enter as a veteran midway through the school term, he had to work very hard to learn what he had missed, but his disciplined habits and capacity to absorb large amounts of information enabled him quickly to catch up. After completing the summer term, he transferred to the University of Freiburg in order to listen to lectures of its outstanding faculty, to broaden his cultural experience, and to enjoy hiking in the Black Forest.

Stimulated by accounts of their own scientific discoveries that some of his teachers gave in their lectures, Krebs became interested in trying his hand at research. In the anatomical institute at Freiburg, Wilhelm von Möllendorff, a leader in the field of vital staining, gave him a project to study comparatively the staining effects of different dyes on muscle tissue. Adopting Möllendorff’s general “physicalist” approach to staining, Krebs concluded that the intensity and distribution of the staining in muscle tissue are governed not by the respective chemical properties of the dyes but by the degree of their dispersibility and the varying densities of the tissue structures. Krebs wrote up his results in a wellcrafted research paper, and Möllendorff arranged for its publication with the young medical student as sole author.

After passing with high marks the examination that completed his preclinical training in March 1921, Krebs stayed on for one more semester in Freiburg in order to take in the lectures of the famed pathologist Ludwig Aschoff. Then he moved on to the University of Munich because of the general renown of its clinical faculty. After remaining for two semesters in Munich, Krebs spent the winter semester in Berlin in order to hear lectures by some of the leaders in that internationally famous center of medicine. He returned to Munich for the summer semester of 1923, and in the fall of that year passed, again with very good marks, the final medical examination known as the Ärtzliche Prüfung.

During the clinical years in medical school, Krebs was too busy studying and attending lectures and demonstrations to undertake any further research projects. The conviction nevertheless grew stronger that he wanted eventually to participate in scientific investigation. Warned by his father and others that it was not possible to make his living by science alone, he planned to enter internal medicine, in which he hoped to be able to combine clinical practice with experimental work.

Krebs went back to Berlin in January 1924 to fulfill his required year of hospital service at the Third Medical Clinic of the University of Berlin. There he carried out preliminary examinations in the outpatient clinic. Encouraged to use his spare time in the laboratory, he undertook on his own a study of the gold sol reaction that was currently in use in some clinical laboratories as a sensitive diagnostic test for syphilis. In collaboration with Annalise Wittgenstein, a member of the clinical staff. he began concurrently experiments on dogs on the passage of foreign substance from the blood into the cerebrospinal fluid, a problem also connected with syphilis, because of difficulties encountered in getting therapeutic drugs such as Salvarsan into the latter fluid to attack the spirochetes lodged in the central nervous system. Drawing on his experience in Möllendorff’s laboratory, Krebs decided to employ dyes whose presence in the cerebrospinal fluid could easily be detected colorimetrically. Wittgenstein proved to be untrained as an investigator, so it fell entirely to Krebs to design the experimental attack and to write the papers reporting their results.

In these efforts, carried out with little guidance. Krebs proved himself to be a resourceful independent investigator. The experience reinforced, however. a belief that he had already acquired through the lectures in biochemistry and other subjects that he had heard in medical school: that chemistry was becoming ever more important to medical research. and that he did not have enough systematic training in the subject to conduct investigations more fundamental than those he had so far done. He decided. therefore, after completing his hospital year, to enroll in a special chemistry course offered at the nearby Charité Hospital for doctors like himself who needed to strengthen their chemical backgrounds. There he spent most of 1925 learning to carry out basic methods of qualitative and quantitative analysis.

Through a series of contacts made by Bruno Mendel, a close friend he had met at the Third Medical Clinic, Krebs had a rare opportunity to become, at the beginning of 1926, a paid research assistant to the great biochemist Otto Warburg at the Kaiser-Wilhelm Institut für Biologie in BerlinDalheim. There he learned the tissue slice and manometric methods that Warburg had devised in order to measure the rates of respiration and glycolysis of cancer cells and to compare these with the rates in normal tissues. In one of his first assigned projects. Krebs extended the measurements that Warburg had made on rat tumor tissue to tissues obtained from human patients. In 1927 Warburg discovered that carbon monoxide inhibits the respiration of yeast cells, but that illuminating the cells diminishes the extent of the inhibition. He asked Krebs to find an oxidative iron-heme catalyst that would have similar characteristics. By early 1928 Krebs had identified a heme-pyridine compound whose responses to carbon monoxide in darkness and light, as well as its responses to HCN, were so similar to the responses of yeast cells that Warburg could regard the compound as a “model” of the respiratory enzyme (Atmungsferment) that he had postulated several years earlier, and could utilize Krebs’s results to strengthen his argument that the respiratory enzyme itself is an iron-heme compound.

Otto Warburg was a formidable chief: demanding and authoritarian, skeptical of much of what passed for scientific work in other laboratories, easily angered by opposition or criticism. He was also, however, a man of strong integrity and singleness of purpose, devoted wholly to his research and able to apply great experimental skill as well as theoretical acumen to the problems he pursued. In his small laboratory he required everyone present to work on the problems that interested him, and he required everyone to be present, without fail, from 8:00 A.M. to 6:00 P.M., six days per week. Krebs was both inspired and intimidated by Warburg. What he had previously done on his own now appeared to him narrow and dilettante. He was content to become a loyal apprentice, adopting with little question Warburg’s opinions and his approach to scientific investigation. From Warburg. Krebs learned that he should seek out the central questions in his field, rely on precise methods, carry out many experiments without hesitating about whether they were worthwhile, and write up his results in clear, concise papers.

After he had become skilled at the manometrictissue slice techniques that Warburg used, it occurred to Krebs that the method could be applied to great advantage to study intermediary metabolism. from some of his teachers in medical school, and particularly in the lectures of Franz Knoop in Freiburg, he had heard both that very little was known of the series of reactions between the foodstuffs that enter the body and their final decomposition products, and that it should be a central goal of biochemistry to establish the unbroken sequences of chemical equations that must connect them. When he was bold enough to suggest to Warburg that he might like to apply the manometric methods to these problems, Warburg told him that such experiments would be of no interest to him, and that there was not enough space in his laboratory for anyone to work on problems other than his own. Krebs had no choice but to conform; the idea nevertheless appeared so compelling to him that he kept it firmly in mind as a goal he would pursue when he eventually become free to define his own investigative pathway.

In 1929 Warburg told krebs that he could not remain as a research assistant beyond 31 March 1930. Since Warburg did not help him to find another research position, Krebs thought that Warburg did not consider him capable of independent scientific work. Doubting his own investigative talents, but still keen to continue if he could, Krebs looked for a position in clinical medicine that would also offer some chance to do laboratory work. After a number of fruitless inquiries, he obtained such a post at the municipal hospital of Altona, near Hamburg, in the Department of Medicine, directed by Leo Lichtwitz, an outstanding physician with an interest in metabolic diseases.

At Altona, Krebs had heavy clinical responsibilities. The medical staff was outstanding, however, and he learned to be a caring physician, sensitive to the individual needs of the patients in the wards of which he had charge. In order to obtain Warburg’s support for a grant to purchase manometers so that he could do research, he was obliged to undertake an investigation of proteolysis in tumor cells for Warburg. The project did not much interest him. While dutifully carrying it out, he searched for openings that would enable him to begin a research program of his own. His first successful idea came from the startling recent discovery by Einar Lundsgaard that muscles poisoned with iodoacetate could continue to contract for a short time even though they could not produce lactic acid. This finding upset the dominant current view, formulated by Otto Meyerhof, that the formation of lactic acid was directly connected with muscle contraction. Extending Lundsgaard’s results to other animal tissues, Krebs was able to show that lactic acid added to slices poisoned with iodoacetate restored their respiration. In March 1931 he published his results in a short paper that, although minor in itself, marked his emergence as an independent investigator and his entry into the field of intermediary carbohydrate metabolism.

Not long after arriving at Altona, Krebs had already made arrangements to move to Freiburg in April 1931, to become an assistant to Siegfried Thannhauser, an expert on metabolic diseases in the Department of Medicine. There too he spent much of his time on clinical duties; but he had more extensive laboratory facilities, increased support from research grants, independence from Warburg’s interests, and a university ethos that encouraged research on fundamental problems. During his first three months there, he continued the line of investigation of carbohydrate metabolism that he had begun in Altona, but in July he embarked on a major new problem: to determine how urea is synthesized in the animal organism.

During the previous sixty years, a succession of investigators had established, through feeding experiments on animals and the perfusion of isolated organs, that amino acids and ammonia give rise to urea in the liver. It was generally assumed that the amino acids were deaminated, yielding ammonia that served in turn as the source of the urea nitrogen. The methods employed in 1930, however, did not appear capable of answering such unresolved questions as whether ammonia was an obligatory intermediate or amino nitrogen could be incorporated directly into urea; whether all amino acids gave rise to urea through a common mechanism; and whether other proposed intermediates such as cyanate took part. Krebs began his investigation with similar questions in mind; more broadly, he hoped to test the suitability of the manometric-tissue slice method to study complex synthetic metabolic processes. To begin, he adapted the manometric urease methods of urea analysis of D. D. Van Slyke to use in the Warburg manometer, providing him with an exceptionally accurate and rapid means to measure the very small quantities of urea that would be produced by tissue slices. Shortly after he had begun, a medical student, Kurt Henseleit, came to him for an M. D. thesis problem, and Krebs soon turned most of the daily experimental operations for the urea investigation over to Henseleit. Between August and October 1931, Krebs and Henseleit carried out numberous experiments that only confirmed that amino acids and ammonia can produce urea in isolated liver slices and in no other animal tissues.

During November, Krebs and Henseleit tested the effects of several amino acids and some intermediates of carbohydrate metabolism, seeking to identify substances that might influence the rate of formation of urea in liver slices. In one of these experiments they included, almost as an afterthought the uncommon amino acid ornithine. Unlike anything else they had tried, ornithine, in combination with ammonia, dramatically increased the rate. During the following weeks they carried out experiments designed to test whether compounds chemically related in various ways to ornithine might exert an analogous effect, and whether ornithine acted as a nitrogen donor or only influenced the formation of urea from ammonia. By February 1932 Krebs had ascertained that the effect was specific to ornithine and that ornithine could act in catalytic quantities. He was also convinced that the effect must be related to the reaction arginine → ornithine + urea, well known to occur enzymatically in the liver; but for some time he could not visualize a specific connection between them.

In late March or early April, Krebs perceived that if ornithine gave rise to arginine by a route different from the reaction by which arginine yielded

ornithine and urea, then the catalytic action of ornithine would be explained, for the ornithine consumed in forming the intermediate would subsequently be regenerated. At first he constructed on paper the simplest possible alternative pathway to give a balanced equation: ornithine + 2NH3 + CO2 → arginine + H2O. His solution made all of the elements of the problem fit together so coherently that he believed it could not be wrong, and he quickly submitted a preliminary paper to Klinische Wochenschrift. He recognized immediately, however, that there must be further intermediates, because the above equation postulated a chemically implausible simultaneous reaction of four molecules. Even before the first paper appeared, he had established that one of the require intermediates is citrulline, and he published a second paper reporting that a further step had been identified in what he called the “Kreislauf des Ornithins,” a term shortly afterward translated into English as’ ornithine cycle.’ A year later he began to depict these reactions in a form that highlighted their cyclic nature (Figure 1).

The ornithine cycle was rapidly recognized as a major discovery earning Krebs the praise of leading biochemists in Germany and elsewhere. His achievement led to his appointment in December 1932 as a Privatdozent at the University of Freiburg. It caused Warburg to recognize the ability of his former assistant, and it gave Krebs a self–assurance that he never lost. Historically the discovery and the methods used to attain it now appear as the opening of a new era in metabolic biochemistry.

As his reputation spread, Krebs began to attract students to work with him in his well–equipped laboratory, and he appeared to be developing a small research school in intermediary metabolism. His students pursued questions related to his prior work on urea synthesis. Theodor Benzinger in particular applied the same strategies to study the corresponding process in birds, the synthesis of uric acid. Krebs himself attempted to demonstrate conclusively that amino acids are deaminated oxidatively, especially in the kidney. To his surprise, however, it turned out that the “unnatural” optical isomers of the amino acids were deaminated far more rapidly than their’ natural’ antipodes.

Early in 1933 Krebs took up a broad new research endeavor: to identify intermediates in the metabolic breakdown of foodstuffs, particularly of carbohydrates and fatty acids. He began in part empirically, intending to try out systematically a large number of possible intermediates to see whether they increased oxidized in tissue slices and whether they increased the respiration of the tissues. He was, however, strongly influenced by current hypotheses concerning metabolic reactions, especially a widely discussed closed circuit of oxidative reactions known as the Thunberg–Wieland–Knoop scheme that appeared capable, if confirmed, of connecting the metabolism of amino acids, carbohydrates, and fatty acids into a common pathway: 2 acetic acid → succinic acid → fumaric acid → malic acid → oxaloacetic acid → pyruvic acid + CO2 → acetaldehyde + CO2 → acetic acid. He also sought to elucidate the final steps of Franz Knoop’s long–known β–oxidation theory for fatty acids, and a recently proposed variation that postulated a double–ended oxidation. None of Krebs’s early experiments in this area yielded definite conclusions.

Meanwhile, in January 1933 Adolf Hitler became chancellor of Germany, and during the following weeks the Nazis swiftly consolidated their power and subverted democratic protections. On April 12 Krebs was among the numerous Jews who were dismissed from their academic posts in accordance with the newly decreed law for the reform of the civil service. Having learned of the admiration in which the leader of the Cambridge school of biochemistry, Frederick Gowland Hopkins, held his work on urea synthesis, Krebs wrote to him inquiring if he might work in the Cambridge laboratory. Although eager to make a place for him, Hopkins had no financial means available for him. Fortunately the Rockefeller Foundation, which had already supported Krebs’s work in Freiburg through a grant to Thannhauser, offered him a one–year fellowship. Krebs left for England in June, and within a month he had resumed his experimental research in Cambridge. Warmly received there, he quickly felt at home in England, even though he had no assurance that he would be permitted to remain there permanently.

In Cambridge, Krebs pursued for six more months the questions concerning the metabolism of carbohydrates, fatty acids, and related substances that he had begun in Freiburg. He included several efforts to connect the respiratory oxidation of citric acid with other metabolic pathways. None of these experiments led him beyond confirming what was already known about substances readily oxidized in animal tissues. Feeling that he was bogged down, he abruptly abandoned this line of investigation in December and turned to other metabolic questions.

In May 1934 Krebs’s position in Cambridge was consolidated when he was appointed demonstrator in biochemistry. Of the several dozen German refugee scientists by then in England, he was the first to receive a regular academic post.

After several further starts on problems that did not lead him to significant new findings, Krebs returned in the fall of 1934 to his earlier study of the deamination of amino acids. Pursuing an anomaly that he had first noticed in Freiburg, that the dicarboxylic amino acids glutamic and aspartic acid released much less ammonia than did other amino acids, he found that they absorbed ammonia added to the tissue medium. By the spring of 1935, he had amassed compelling evidence that the ammonia combines with glutamic acid to form glutamine. He thus established a previously unknown metabolic synthesis, a reaction whose significance was at first unclear but that became the starting point for an extensive field of investigation.

During the same period he extracted from kidney and liver tissue an enzyme able to catalyze the deamination of the “unnatural” optical isomers of amino acids. Neither he nor others were able to explain why organisms possessed a special enzyme to act upon a class of compounds that they do not normally encounter. During the summer of 1935, Krebs was invited to apply for a position as lecturer in the Department of Pharmacology at the University of Sheffield, with the understanding that his research and teaching would be in biochemistry. He did so, and took up his post on I October. Krebs chose to move from one of the international centers of biochemistry and a milieu that he valued highly, where he benefited from the intellectual stimulation of colleagues working on problems closely related to his own, to a small provincial university in a sooty industrial town, where he would be isolated in his field. He did so mainly because he had the prospect at Sheffield of sufficient laboratory facilities to begin to build a research team. At Cambridge, where research space was crowded, he had already begun to draw more students than he could accommodate. He was attracted also by the beauty of the countryside surrounding Sheffield and by the warmth and generosity of his new chief, Edward Wayne. In the months before leaving for Sheffield Krebs had undertaken, with two students, a further study of the synthesis of uric acid in birds. In Sheffield 50 1 he continued to work on this problem, keeping in close touch with the students, who remained in Cambridge. By October they had identified hypoxanthine and xanthine as two intermediates that give rise, by successive oxidations, to uric acid. Krebs hoped that he would then be able to find the precursors that joined to form the molecular skeleton common to these three purines. By the end of the year. however, he had made little progress in this direction, and he turned again to other problems. During his investigations of deamination, Krebs had several times turned briefly to the long-standing question of the converse process: how are amino acids formed in the organism’.’ Early in 1936 he tested a hypothesis first proposed twenty-five years before by Knoop: that pyruvic acid reacts with ammonia and a second ketonic acid to form an acetylamino acid, which then decomposes to yield the amino acid corresponding to the second ketonic acid. In experiments carried out on rat liver tissue. Krebs initially obtained results that appeared to support this hypothesis, but he soon recognized that the data could equally well fit an oxidoreduction reaction between the two ketonic acids for which the ammonia was unnecessary. This outcome induced him to study the anaerobic reactions of pyruvic and other ketonic acids as potential connections between the recently established Embden-Meyerhof pathway of glycolysis and the further oxidative breakdown of carbohydrates. By the summer of 1936, he was persuaded that he had sufficiently established the existence of a family of such reactions to submit to Nature a preliminary paper titled’ Intermediate Metabolism of Carbohydrates, ’ in which he claimed to have’ found some new chemical reactions in living cells which represent steps in the breakdown of carbohydrates.’ He presented a sequence of three dismutation reactions that he believed to be the’ primary steps of the oxidation of pyruvic acid.” Since the latter had long been viewed as one of the key substances linking the various paths of intermediary metabolism, Krebs was putting forth a scheme that could potentially join the fragmentary known reaction chains into a comprehensive network leading from the carbohydrate foodstuffs to their final oxidation products and connecting them as well with fatty acid metabolism.

Meanwhile, in Szeged, Hungary, Albert Szent-Györgyi was investigating respiration in isolated tissue with methods similar to those Krebs used. Instead of tissue slices, however, Szent-Gyorgyi employed suspensions of tissue coarsely minced so as to leave most of the cells intact. Between 1934 and 1936 Szent-Gyorgyi and his co-workers showed that fumaric acid added in catalytic quantities to pigeon breast muscle can sustain its respiration at a normal rate. From this and other supporting evidence, he developed a theory that the C4dicarboxylic acids long thought to be key intermediates in oxidative metabolism—succinic, fumaric, and oxaloacetic acids—formed instead a catalytic system that transports the hydrogen ions removed from foodstuffs to the respiratory chain of cytochromes and the Atmungsferment identified earlier by David Keilin and Otto Warburg, respectively. Szent-Györgyi proposed a cyclic scheme in which succinate was oxidized through fumarate to oxaloacetate, the latter being in turn converted directly to succinate by what he called’ overreduction.’

Krebs, who knew Szent-Györgyi personally, followed his publications on this subject closely. He was favorably impressed with the experimental work and adopted for some of his own experiments the minced pigeon breast muscle preparation. He was also influenced by Szent-Györgyi’s general concept of the catalytic cycle but was dissatisfied with the idea of the overreduction of oxaloacetate. During the summer and fall of 1936, Krebs extended his investigations of coupled oxidation-reduction reactions to include dehydrogenation reactions of fumaric, oxaloacetic, and malic acids. In this work he sought to combine the conception of intermediate reactions of carbohydrate metabolism he had recently presented in his Nature article with modifications of the views of Szent-Györgyi.

Citric acid had long been known to be one of the relatively few substances able to accelerate strongly the respiration of isolated tissues, but it had been left out of the various hypotheses that had been proposed to link the steps of oxidative metabolism. probably because it was difficult to envision the chemical steps that might connect it with other intermediates such as the C4dicarboxylic acids. From time to time Krebs tested possible reaction schemes experimentally, but he attained no promising results until the fall of 1936. Then he and his first graduate student at Sheffield, William Arthur Johnson, obtained experimental evidence that pyruvic and oxaloacetic acid added together to minced pigeon breast muscle gave rise to significant quantities of citric acid. Believing that he had found the pathway by which citric acid is formed, Krebs was still unable during this time to ascertain how that substance might be further oxidized, In October and November 1936, he discussed in several public lectures the various dismutation reactions he had found that appeared to be involoved in the oxidative breakdown of carbohydrates, but he qualified the scheme he presented as provisional and incomplete. He considered that he had shown citric acid to be’ an intermediate in the breakdown of pyruvic and malic acid, ’ but emphasized’ that it appears to be a side reaction only.’

Through the winter and spring of 1937, Krebs continued to gather data on the anaerobic dismutation reactions occurring in animal tissues, as well as in several types of bacteria. He now presented his results cautiously, without claiming that the particular reactions found in one organism or tissue necessarily occurred generally, and without attempting to organize them into sequential reaction schemes. In late April, by which time it probably appeared that this line of investigation was not leading toward broader conclusions, he saw in the latest issue of Biochemische Zeitschrift a preliminary paper by Carl Martius and Franz Knoop proposing a new pathway for the physiological decomposition of citric acid:

Citric acid→cis-aconitic acid→isocitric acid→oxaloacetic acid→α-ketoglutaric acid.

Martius had devised the mechanism from theoretical chemical considerations and verified that liver extract can cause citric acid to give rise enzymatically to α-ketoglutaric acid. It was already well established, as Martius and Knoop pointed out, that α-ketoglutaric acid is decarboxylated to form succinic acid, thus connecting this sequence with the C, dicarboxylic acid series.

When Krebs read this paper, he probably realized at once that these reactions might provide the crucial link between the decomposition of citric acid and the main pathways of oxidative metabolism. With the assistance of Johnson, he quickly confirmed that in the presence of suitable blocking agents, citric acid added to pigeon breast muscle gives rise to substantial quantities of α-ketoglutaric and succinic acid. By then he had probably arrived at the general conception that there is a cyclic pathway through which the succinic acid formed from citric acid gives rise to malic and oxaloacetic acid, which regenerate citric acid by means of the dismutation reaction he had found in pigeon muscle tissue during the previous autumn. Soon afterward, however, Johnson’s experiments showed that oxaloacetic acid alone produced citric acid anaerobically more rapidly than did oxaloacetic acid + pyruvic acid, so Krebs gave up the idea that a specifically identified dismutation was involved in the synthetic reaction that produced citric acid. He assumed then that oxaloacetic acid reacts with an unknown product of carbohydrate metabolism that he labeled provisionally as “triose.” On 7 June, Johnson performed an experiment showing that citric acid added in very small quantity to pigeon breast muscle caused the tissue to absorb “extra” O2 in quantities greater than those necessary to oxidize the citric acid completely. Krebs interpreted this result to mean that the citric acid was acting catalytically, being regenerated in a cyclic process whose net effect was to oxidize the “triose” that entered the cycle. BY now-only about six weeks after encountering Martius and Knoop’s article-Krebs had amassed what he considered convincing evidence for the existence of a “citric acid cycle” that constituted the “preferential” pathway “through which carbohydrate may be oxidized in animal tissues.” BY 10 June he had sent to Nature the short paper “The Role of Citric Acid in Intermediate Metabolism in Animal Tissues,” while he continued to gather supporting data. When the editor of Nature informed him that, because of a backlog, the paper would not be published without a substantial delay, Krebs wrote a longer version of the paper and sent it to Enzymologia, a recently founded stantial delay, Krebs wrote a longer version of the paper and sent it to Enzymologia, a recently founded Journal that was less prestigious than those in which he normally pubslihed, but in which he knew his paper would be accepted immediately and appear rapidly. He was impatient because he knew that he had arrived at a conclusion of fundamental importance in intermediary metabolism. The citric acid cycle that he presented, when coupled with the Embden-Meyerhof glycolytic pathway, enabled for the first time a coherent view of the principal steps in the process that was regarded as the chief source of energy for the vital activities of living organisms.

Late in 1936 Krebs met Margaret Fieldhouse, daughter of a Yorkshire family and a teacher of domestic science at a convent school in Sheffield. Although she was thirteen years younger than he, they quickly established an easy rapport, finding that they shared interests in hiking, botany, and other activities, and laughed at the same things. Shy but blunt and spirited, Margaret adapted to Hans’s disciplined style and his relentless absorption in his work, while leavening his life with her spontaneous warmth They were married in the spring of 1938 and spent their honeymoon in North America, where Margaret had to share his time with his professional colleagues as he attended meetings and engaged in an extensive speaking tour. They then settled in a small but comfortable house in Sheffield, in which they remained for nineteen years and raised three children, paul, Helen, and John.

In 1938 Krebs was given the title lecturer in biochemistry, and made head of a newly established Department of Biochemistry at Sheffield. The Rockefeller Foundation, which had until then supported his reported his research with annual research grants, began to fund the activity of his department in five-year grants, which were renewed regularly. The laboratory at Sheffield began to attract students and visiting investigators from both England and overseas. Krebs and his associates continued investigating the topics that he had previously pursued. By 1940 he had substantially strengthened the evidence for the citric acid cycle and refuted some criticisms that had been made of it. Early isotopic studies in other laboratories had by 1941 confirmed the main outlines of the theory, but seemed for a time to indicate that citric acid itself lay outside the main pathway. consequently the cycle was renamed the “tricarboxylic acid cycle,” although it was already referred to sometimes as the “Krebs cycle,”

During the war Krebs was able to carry on his normal research program. In addition he participated in a wartime project to test the adequacy of special diets intended to stretch food supplies made scarce by the German submarine attacks on British shipping. The experimental subjects were conscientious objectors who volunteered for the project as an alternative to military service. Near the end of the war, the Medical Research Council, planning for a postwar expansion of scientific investigation, offered to establish a research unit under Krebs’s leadership at Sheffield. With this support he was able to organize the Unit for Research in Cell Metabolism and assemble a team of workers, some of whom worked directly on projects of interest to him, others of whom developed more independent lines of investigation. In increasing numbers graduate students from Britain and abroad came to Sheffield to earn Ph.D. degrees within the unit.

Krebs had envisioned the citric acid cycle originally as the oxidative phase of carbohydrate metabolism, but it gradually became clear that it forms the final common pathway for the oxidative decomposition of all the major classes of foodstuffs. and that it is also involved in synthetic pathways. As the significance of this particular metabolic cycle expanded, Krebs began to ponder more deeply the general significance of metabolic cycles, of which the ornithine and citric acid cycles offered the paradigm examples. In 1947 he published a meditative paper titled “Cyclic Processes in Living Matter,” in which he maintained that “metabolic cycles seem to be a feature peculiar to life, and the question why they have arisen therefore deserves a more detailed enquiry,” Although acknowledging that “the specific meaning of cycles is still a puzzle,” he suggested that while studying metabolic processes it would be worthwhile to “expect and look for further cycles.”

Much of the research of Krebs’s laboratory in the postwar period was directed toward further development of investigations based on his brilliant prewar discoveries, especially the question of how widely the citric acid cycle occurs among different tissues and organisms. Until 1953 Krebs believed that the cycle did not operate within microorgainsms. Later it turned out that the apparent inability of intermediates of the cycle to activate respiration in these organisms resulted from the impermeability of their cell membranes to these substances and that the cycle is nearly universal. While pursuing that problem, Krebs raised the question of how microorganisms that subsist on acetic acid as the sole organic nutrient can synthesize large molecules, acetic acid enters the citric acid cycle, but the cycle cannot provide a net synthesis of larger molecules from it. He suggested that problem as a research topic to a former student. Hans Kornberg. who discovered in 1957 the glyoxylate cycle, a modification of the citric acid cycle.

In 1953 the paramount importance that the citric acid cycle had attained in biochemistry was recognized in the award of the Nobel Prize jointly to Krebs and to Fritz Lipmann, whose discovery of coenzyme-A had specified the details of the crucial synthetic step in the cycle. Soon afterward Krebs was invited to become Rudolph Peters’successor as professor of biochemistry at Oxford, and to assume responsibility for the large Department of Biochemistry there. After receiving assurances that he could bring his metabolic research unit along with him, he accepted.

By the time Krebs came to Oxford, radioactive isotopes, spectrophotometry, chromatography, and other new methods had greatly facilitated the investigation of the intermediary steps in metabolic pathways. Many laboratories had made contributions and most of the major pathways had been identified and linked up. Numerous details remained to be elucidated, and Krebs’s team continued to play a significant role in that work. He increasingly turned his attention, however, toward the question of how the rates and direction of the reactions are controlled to meet the varying requirements of the organism. In 1957 he sketched out his general approach to the problem. Of the many intermediary steps contained in such processes as anaerobic glycolysis or respiration, only a few serve as “pacemakers,” upon which the controlling factors operate. Control points that select between alternative metabolic pathways include the initial reaction at which a particular substrate enters a pathway, and “branching points.” Other control points determine the direction in which a particular pathway proceeds. For the regulation of the latter type. Krebs drew attention to the importance of the ratios of reduced and oxidized forms of catalysts. such as the pyridine nucleotides, which are linked to the metabolic pathways as hydrogen acceptors or donors, and the ratio of ATP to ADP and inorganic phosphate. These control systems operated on the principles of feedback mechanisms.

For the next two decades. Krebs directed the work of his group toward more detailed specification of these general ideas. In 1963 he explained how the formation of carbohydrates from noncarbohydrate sources, a process known as gluconeogenesis, is regulated. To critical steps in the pathway of gluconeogenesis—the conversion of fructose diphosphate to fructose-6-phosphate, and the conversion of pyruvate to phosphopyruvate—were identified as the pacemaker reactions. In order to attain experimental conditions more closely resembling the normal physiological circumstances that affect metabolic rates. Krebs switched from the minced tissue and tissues slice methods upon which he had relied for over twenty years to perfusing organs of small animals, especially the rat liver. Scientific progress itself sometimes displays cyclic patterns. When Krebs began his investigations in 1930.perfused whole organs had been the customary means to study metabolic processes, but they were tedious and did not permit close control of experimental conditions. His introduction of tissue slices quickly replaced whole organs in such research. Thirty years later, more advanced analytical technique made the reintroduction of perfusion methods a progressive move.

During the late 1960’s Krebs developed methods to measure the “redox state” of the pyridine nucleotides within cells. He regarded the ratio of the oxidized to the reduced form of these coenzymes as a central factor in controlling the direction of metabolic reactions. Theratio itself was not directly measurable, but he and his colleagues were able to determine it by measuring the concentrations of substrates involved in particular dehydrogenation reactions catalyzed by the pyridine nucleotides, and in this way they could distinguish the redox state in the cytoplasm from that in the mitochondria. During the 1970’s he returned to the subject of his earliest major discovery, the synthesis of urea, in order to examine the regulatory mechanisms controlling that process.

In 1967 Krebs reached the mandatory retirement age at Oxford, and it appeared that he would be forced to end his research career despite the active leadership he still provided for his department. Arrangements were made, however, largely through the support of George Pickering and Paul Beeson, to provide a small laboratory for Krebs and his own unit at the Radcliffe Hospital. Several of the members of his team who had already served with him for a long time—in particular Leonard Eggleston, Reginald Hems, Patricia Lund, and Derek Williamson— came with him. There he continued his work with undiminished energy.

Ever since he formulated the citric acid cycle, Krebs had wondered what was the advantage to organisms of oxidizing their foodstuffs through such a complex, circuitous pathway instead of a simpler, more direct one. Forty–five years later he had still not found a satisfying explanation. Then, in April 1980, Jack Baldwin, an organic chemist at Oxford, suggested to him that acetic acid, the immediate substrate oxidized by the cycle, cannot, on chemical grounds, be directly dehydrogenated. It therefore must become attached to another more molecule in order to complete its oxidative decomposition. Stimulated by this idea, Krebs quickly worked out an explanation for the necessity of a cyclic process as the most efficient mechanism for the utilization of the energy available in the foodstuffs. Obviously excited by finding an answer to a question that had for so long puzzled him, he embarked on a general inquiry into the broader question of whether all metabolic pathways can be shown to be the most efficient possible for achieving their particular functions, and whether they can be explained in this way as the expected outcome of evolution. During the following months Krebs participated in celebrations of his eightieth birthday at symposia in Dallas and in Sheffield. At each of these occasions, he invoked his new ideas concerning the evolution of metabolic pathways to illustrate the creative satisfaction he felt in continuing an active scientific life as long as he felt scientifically competent. The suggestion that he could retire and enjoy the things for which he had never had time he repeatedly rejected as “irritating.”

Krebs carried on his scientific activity vigorously, until September 1981. Then, after returning from a trip to Germany, he experienced a loss of appetite that lasted for several weeks. Admitted to the hospital for observation, he rapidly weakened, and died on 22 November. His sudden passing was a severe and unexpected loss to his family, his many friends, and his colleagues. There was some consolation in the fact that he had maintained a rich scientific and personal life for over eighty years without finally having to endure that enforced inactivity of retirement that held so little appeal to him.

Hans Krebs combined in an extraordinarily fruitful manner the discipline to carry on a steady investigative pace day after day, year after year, with the imagination to connect the results of his experiments and other work into broadly unifying insights. He was not given to planning very far ahead, and he often shifted from one problem to another when he thought he was getting bogged down in a given investigation. Nevertheless, looking back, one can see that he pursued persistently a coherent set of related problems in intermediary metabolism throughout his long research pathway. His early work was most innovative, but his later investigations and publications added significantly to the breadth and depth of the insights he had acquired. He was more gifted in the design than in the practical execution of experiments, and from the late 1930’s onward he relied almost entirely on his collaborators, students, and technicians to carry out the experiments he planned. Krebs was not, for everyone, easy to work for, because he demanded high standards of performance and was sparing in his praise of work well done—he expected good work as a matter of course. But he inspired in many a lifelong loyalty. His integrity was obvious to all who knew him. He did not allow his time to be wasted in idle talk, but he was generous with his help and his concern when it mattered. Accustomed in his later years to the adulation accorded a Nobel laureate, and to the deeper admiration of the many younger biochemists who looked upon him as one of the founders of their field, he was not falsely humble but he retained a genuine modesty. He could mention his “fame” without embarrassment, but he did not dwell on himself or his past achievements. Rather, until the very end he fixed his attention on his science and on what he conceived as his responsibilities toward the world at large.

BIBLIOGRAPHY

1. Original Works. Reminiscences and Reflections (Oxford, 1981), an autobiography written in collaboration with Anne Martin, includes a complete bibiography of Krebs’s scientific publications and those of his collaborators. An extensive collection of Krebs’s correspondence and papers, cataloged by the Contemporary Scientific Archives Centre, is deposited in the Sheffield University Library. Inquiries concerning this collection can be addressed to The Librarian, Sheffield University Library, Sheffield 510 2TN U.K.

II. Secondary Literature. The most comprehensive of the numerous biographical memoirs that appeared after Krebs’s death is Sir Hans Kornberg and D. H. Williamson, “Hans Adolf Krebs,” in Biographical Memoirs of Fellows of the Royal Society, 30 (1984), 351–385, which contains an extensive list of Krebs’s publications. Two articles that treat particular aspects of Krebs’s scientific work are Steven Benner. “The Tricarboxylic Acid Cycle,” in Yale Scientific Magazine, 50 , no. 7 (1976), 4–10, 34–36 and Frederic L. Holmes, “Hans Krebs and the Discovery of the Ornithine Cycle,” in Proceedings of the Federation of Biological Sciences, 39 (1980), 216–225

Frederic L. Holmes

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Krebs, Hans Adolf (1900-1981)

Krebs, Hans Adolf (1900-1981)

German biochemist

Few students complete an introductory biology course without learning about the Krebs cycle , an indispensable step in the process the body performs to convert food into energy. Also known as the citric acid cycle or tricarboxylic acid cycle, the Krebs cycle derives its name from one of the most influential biochemists of our time. Born in the same year as the twentieth century, Hans Adolf Krebs spent the greater part of his eighty-one years engaged in research on intermediary metabolism . First rising to scientific prominence for his work on the ornithine cycle of urea synthesis, Krebs shared the Nobel Prize for physiology and medicine in 1953 for his discovery of the citric acid cycle. Over the course of his career, the German-born scientist published, oversaw, or supervised a total of more than 350 scientific publications. But the story of Krebs's life is more than a tally of scientific achievements; his biography can be seen as emblematic of biochemistry's path to recognition as its own discipline.

In 1900, Alma Davidson Krebs gave birth to her second child, a boy named Hans Adolf. The Krebs familyHans, his parents, sister Elisabeth and brother Wolfganglived in Hildesheim, in Hanover, Germany. There his father Georg practiced medicine, specializing in surgery and diseases of the ear, nose, and throat. Hans developed a reputation as a loner at an early age. He enjoyed swimming, boating, and bicycling, but never excelled at athletic competitions. He also studied piano diligently, remaining close to his teacher throughout his university years. At the age of fifteen, the young Krebs decided he wanted to follow in his father's footsteps and become a physician. World War I had broken out, however, and before he could begin his medical studies, he was drafted into the army upon turning eighteen in August of 1918. The following month he reported for service in a signal corps regiment in Hanover. He expected to serve for at least a year, but shortly after he started basic training, the war ended. Krebs received a discharge from the army to commence his studies as soon as possible.

Krebs chose the University of Göttingen, located near his parents' home. There, he enrolled in the basic science curriculum necessary for a student planning a medical career and studied anatomy, histology, embryology and botanical science. After a year at Göttingen, Krebs transferred to the University of Freiburg. At Freiburg, Krebs encountered two faculty members who enticed him further into the world of academic research: Franz Knoop, who lectured on physiological chemistry, and Wilhelm von Möllendorff, who worked on histological staining. Möllendorff gave Krebs his first research project, a comparative study of the staining effects of different dyes on muscle tissues. Impressed with Krebs's insight that the efficacy of the different dyes stemmed from how dispersed and dense they were rather than from their chemical properties, Möllendorff helped Krebs write and publish his first scientific paper. In 1921, Krebs switched universities again, transferring to the University of Munich, where he started clinical work under the tutelage of two renowned surgeons. In 1923, he completed his medical examinations with an overall mark of "very good," the best score possible. Inspired by his university studies, Krebs decided against joining his father's practice as he had once planned; instead, he planned to balance a clinical career in medicine with experimental work. But before he could turn his attention to research, he had one more hurdle to complete, a required clinical year, which he served at the Third Medical Clinic of the University of Berlin.

Krebs spent his free time at the Third Medical Clinic engaged in scientific investigations connected to his clinical duties. At the hospital, Krebs met Annelise Wittgenstein, a more experienced clinician. The two began investigating physical and chemical factors that played substantial roles in the distribution of substances between blood, tissue, and cerebrospinal fluid, research that they hoped might shed some light on how pharmaceuticals such as those used in the treatment of syphilis penetrate the nervous system. Although Krebs published three articles on this work, later in life he belittled these early, independent efforts. His year in Berlin convinced Krebs that better knowledge of research chemistry was essential to medical practice.

Accordingly, the twenty-five-year-old Krebs enrolled in a course offered by Berlin's Charité Hospital for doctors who wanted additional training in laboratory chemistry. One year later, through a mutual acquaintance, he was offered a paid research assistantship by Otto Warburg, one of the leading biochemists of the time. Although many others who worked with Warburg called him autocratic, under his tutelage Krebs developed many habits that would stand him in good stead as his own research progressed. Six days a week work began at Warburg's laboratory at eight in the morning and concluded at six in the evening, with only a brief break for lunch. Warburg worked as hard as the students. Describing his mentor in his autobiography, Hans Krebs: Reminiscences and Reflections, Krebs noted that Warburg worked in his laboratory until eight days before he died from a pulmonary embolism. At the end of his career, Krebs wrote a biography of his teacher, the sub-title of which described his perception of Warburg: "cell physiologist, biochemist, and eccentric."

Krebs's first job in Warburg's laboratory entailed familiarizing himself with the tissue slice and manometric (pressure measurement) techniques the older scientist had developed. Until that time, biochemists had attempted to track chemical processes in whole organs, invariably experiencing difficulties controlling experimental conditions. Warburg's new technique, affording greater control, employed single layers of tissue suspended in solution and manometers (pressure gauges) to measure chemical reactions. In Warburg's lab, the tissue slice/manometric method was primarily used to measure rates of respiration and glycolysis, processes by which an organism delivers oxygen to tissue and converts carbohydrates to energy. Just as he did with all his assistants, Warburg assigned Krebs a problem related to his own researchthe role of heavy metals in the oxidation of sugar. Once Krebs completed that project, he began researching the metabolism of human cancer tissue, again at Warburg's suggestion. While Warburg was jealous of his researchers' laboratory time, he was not stingy with bylines; during Krebs's four years in Warburg's lab, he amassed sixteen published papers. Warburg had no room in his lab for a scientist interested in pursuing his own research. When Krebs proposed undertaking studies of intermediary metabolism that had little relevance for Warburg's work, the supervisor suggested Krebs switch jobs.

Unfortunately for Krebs, the year was 1930. Times were hard in Germany, and research opportunities were few. He accepted a mainly clinical position at the Altona Municipal Hospital, which supported him while he searched for a more research-oriented post. Within the year, he moved back to Freiburg, where he worked as an assistant to an expert on metabolic diseases with both clinical and research duties. In the well-equipped Freiburg laboratory, Krebs began to test whether the tissue slice technique and manometry he had mastered in Warburg's lab could shed light on complex synthetic metabolic processes. Improving on the master's methods, he began using saline solutions in which the concentrations of various ions matched their concentrations within the body, a technique which eventually was adopted in almost all biochemical, physiological, and pharmacological studies.

Working with a medical student named Kurt Henseleit, Krebs systematically investigated which substances most influenced the rate at which ureathe main solid component of mammalian urineforms in liver slices. Krebs noticed that the rate of urea synthesis increased dramatically in the presence of ornithine, an amino acid present during urine production. Inverting the reaction, he speculated that the same ornithine produced in this synthesis underwent a cycle of conversion and synthesis, eventually to yield more ornithine and urea. Scientific recognition of his work followed almost immediately, and at the end of 1932less than a year and a half after he began his researchKrebs found himself appointed as a Privatdozent at the University of Freiburg. He immediately embarked on the more ambitious project of identifying the intermediate steps in the metabolic breakdown of carbohydrates and fatty acids.

Krebs was not to enjoy his new position in Germany for long. In the spring of 1933, along with many other German scientists, he found himself dismissed from his job because of Nazi purging. Although Krebs had renounced the Jewish faith twelve years earlier at the urging of his patriotic father, who believed wholeheartedly in the assimilation of all German Jews, this legal declaration proved insufficiently strong for the Nazis. In June of 1933, he sailed for England to work in the biochemistry lab of Sir Frederick Gowland Hopkins of the Cambridge School of Biochemistry. Supported by a fellowship from the Rockefeller Foundation, Krebs resumed his research in the British laboratory. The following year, he augmented his research duties with the position of demonstrator in biochemistry. Laboratory space in Cambridge was cramped, however, and in 1935 Krebs was lured to the post of lecturer in the University of Sheffield's Department of Pharmacology by the prospect of more lab space, a semi-permanent appointment, and a salary almost double the one Cambridge was paying him.

His Sheffield laboratory established, Krebs returned to a problem that had long preoccupied him: how the body produced the essential amino acids that play such an important role in the metabolic process. By 1936, Krebs had begun to suspect that citric acid played an essential role in the oxidative metabolism by which the carbohydrate pyruvic acid is broken down so as to release energy. Together with his first Sheffield graduate student, William Arthur Johnson, Krebs observed a process akin to that in urea formation. The two researchers showed that even a small amount of citric acid could increase the oxygen absorption rate of living tissue. Because the amount of oxygen absorbed was greater than that needed to completely oxidize the citric acid, Krebs concluded that citric acid has a catalytic effect on the process of pyruvic acid conversion. He was also able to establish that the process is cyclical, citric acid being regenerated and replenished in a subsequent step. Although Krebs spent many more years refining the understanding of intermediary metabolism, these early results provided the key to the chemistry that sustains life processes. In June of 1937, he sent a letter to Nature reporting these preliminary findings. Within a week, the editor notified him that his paper could not be published without a delay. Undaunted, Krebs revised and expanded the paper and sent it to the new Dutch journal Enzymologia, which he knew would rapidly publicize this significant finding.

In 1938, Krebs married Margaret Fieldhouse, a teacher of domestic science in Sheffield. The couple eventually had three children. In the winter of 1939, the university named him lecturer in biochemistry and asked him to head their new department in the field. Married to an Englishwoman, Krebs became a naturalized English citizen in September, 1939, three days after World War II began.

The war affected Krebs's work minimally. He conducted experiments on vitamin deficiencies in conscientious objectors, while maintaining his own research on metabolic cycles. In 1944, the Medical Research Council asked him to head a new department of biological chemistry. Krebs refined his earlier discoveries throughout the war, particularly trying to determine how universal the Krebs cycle is among living organisms. He was ultimately able to establish that all organisms, even microorganisms , are sustained by the same chemical processes. These findings later prompted Krebs to speculate on the role of the metabolic cycle in evolution .

In 1953, Krebs received the Nobel Prize in physiology and medicine, which he shared with Fritz Lipmann, the discoverer of co-enzyme A. The following year, Oxford University offered him the Whitley professorship in biochemistry and the chair of its substantial department in that field. Once Krebs had ascertained that he could transfer his metabolic research unit to Oxford, he consented to the appointment. Throughout the next two decades, Krebs continued research into intermediary metabolism. He established how fatty acids are drawn into the metabolic cycle and studied the regulatory mechanism of intermediary metabolism. Research at the end of his life was focused on establishing that the metabolic cycle is the most efficient mechanism by which an organism can convert food to energy. When Krebs reached Oxford's mandatory retirement age of sixty-seven, he refused to end his research and made arrangements to move his research team to a laboratory established for him at the Radcliffe Hospital. Krebs died at the age of eighty-one.

See also Cell cycle and cell division; Cell membrane transport

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Krebs, Hans Adolf

Krebs, Hans Adolf


BRITISH BIOCHEMIST
19001981

Hans Krebs was born into a prosperous and well-educated family in Hildesheim, Germany. His father was a physician who specialized in otolaryngology, and it was Hans's intention to follow in his father's footsteps and become a physician. Krebs was educated at the Gymnasium Andreanum, and after World War I, he went on to study medicine at the Universities of Göttingen, Freiburg, and Berlin. In 1925 he earned an M.D. degree at the University of Hamburg. He was at this point passionately attracted to medical research, and he did not enter medical practice. In 1926, Krebs became an assistant to Professor Otto Warburg at the prestigious Kaiser Wilhelm Institute for Biology in Berlin, a post he held until 1930. Warburg (who later won the 1931 Nobel Prize in medicine) encouraged Krebs to pursue a career in research.

In 1931 Krebs moved to Freiburg to teach medicine. It was there that he authored (with Kurt Henseleit) his first important paper, which examined liver function in mammals and described how ammonia was converted to urea in liver cells. Krebs also studied the syntheses of uric acid and purines in birds. However, Krebs's research was cut short when the Nazis came to power in 1933. Krebs was Jewish, and he was therefore summarily fired from his post. He left Germany for England, taking a position at the School of Biochemistry at Cambridge University at the invitation of Sir Frederick Gowland Hopkins (who had won the 1929 Nobel Prize in medicine). In 1935 Krebs moved to the University of Sheffield to become a lecturer in pharmacology.

At Sheffield Krebs embarked upon the work that would elucidate some of the complex reactions of cell metabolism (the processes that extract energy from food). This extraction of energy is achieved via a series of chemical transformations that remove energy-rich electrons from molecules obtained from food. These electrons pass along a chain of molecular carriers in a way that ultimately gives rise to water and adenosine triphosphate (ATP) , which is the primary source of chemical energy that powers cellular activity.

Krebs found that the pivotal mechanism of cell metabolism was a cycle. The cycle starts with glycolysis, which produces acetyl coenzyme A (acetyl CoA) from food moleculescarbohydrates, fats, and certain amino acids. The acetyl CoA reacts with oxaloacetate to form citric acid. The citric acid then goes through seven reactions that reconvert it back to oxaloacetate, and the cycle repeats. There is a net gain of twelve molecules of ATP per cycle. Not only does this cycle (known as the Krebs cycle, and also as the tri-carboxylic acid cycle and the citric acid cycle) generate the chemical energy to run the cell, it is also a central component of the syntheses of other biomolecules.

Krebs published his groundbreaking paper on this cyclic component of cell metabolism in the journal Enzymologia in 1937, and it quickly became a foundational concept in biochemistry and cell biology. It was for this research that Krebs won the Nobel Prize in medicine in 1953. (He remains one of the most often cited scientists in cell biology, with his work being noted more than 11,000 times since 1961, when the citation records of original articles in cell biology began being counted.)

Krebs worked in both research and applied science in the area of cell metabolism and nutrition. During World War II he developed a bread that helped to keep the British people nourished at a time of food shortages. He developed new analytical techniques for research in cell biology and investigated other metabolic reactions, such as the synthesis of glutamic acid. He was also an energetic instructor. His students went on to become directors of laboratories and to win many prizes.

In 1954 Krebs was appointed the Whitley Chair of Biochemistry at Oxford University. That same year he received the Royal Medal of the Royal Society of London. In 1958, for his scientific work and his contributions to the lives of British people, Krebs was knighted. Even after his retirement in 1967, he continued to do research on liver disease, the genetic bases of metabolic diseases, and the link between poor nutrition and juvenile delinquency. In addition to his Nobel Prize and Royal Medal, he received honorary degrees from nine universities.

see also Glycolysis; Krebs Cycle.

Andrew Ede

Bibliography

Holmes, Frederic Lawrence (19911993). Hans Krebs, Vols. I and II. New York: Oxford University Press.

Krebs, Hans, and Johnson, W. A. (1937). "The Role of Citric Acid in Intermediate Metabolism in Animal Tissues." Enzymologia 4:148156.

Krebs, Hans, and Martin, Anne (1981). Reminiscences and Reflections. Oxford, UK: Clarendon Press.

Internet Resources

More information available from <www.nobel.se/medicine/laureates/1953/>.

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