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Home , Hans Kornberg, Hans Krebs (biochemist), Physiology

To Remember Sir Harss Krebs: Nobelist, Frfend, and Advfser

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I was deeply saddened to hear of the among the greatest.”4 Komberg will on , 1981, of my soon begin writing an official memoir of friend and colleague, Sir . 1 Krebs for the Royal Society of London. Krebs received the 1953 for Those interested in Krebs’s and work his discovery of the will afso find Krebs’s recently published cyclez—widely known as the Krebs cy- autobiography rewarding. s cle. He had become a good friend, al- Krebs was born , 1900, in though we never met in person. A long- Hiidesheirn, a smalf town in the northern time member of the Citation Irr- part of . His mother was the dex@ (SCP ) editorial advisory board, former Alma Davidson and his father, Krebs was a wonderful source of moral Georg, an otolaryngologist. Hans was and scientific support to me during the educated at the Hildesheim Gymnasium many years that it took for SCZ to gain Andreanum. He intended to follow his acceptance. He was also a regular reader father in a medical career and pursued of these essays and often suggested his education in many universities, as topics for my consideration. He occa- was the custom of the day. Moving free- sionally contacted me with some kind ly from one setting to the next, Hans words about an essay he particularly ad- studied at the Universities of Gottingen, mired. And I will always cherish a letter Freiburg, Munich, and from 1918 he wrote in reaction to an essay memori- to 1923. In 1924, he interned at the Third alizing my mothers This helps to explain Medical University Cliiic in Berlin. He how I could feel so close to a colleague received his medical degree from the through correspondence. I know that University of in 1925.5 Current Contents@ (CC@ ) readers every- According to Hermann Blaschko, the where have these kinds of friendships pharmacologist who profiled because science is so dependent upon Krebs for hk eightieth birthday ~e~t- written communication, schrift issue of FEBS Letters, Hans was The impact of Krebs’s work upon bio- noticed by Bruno Mendel was recently attested to by his while int eming in Berlin. b It was Mendel longtime collaborator, biochemist Sir who recommended Hans to Otto War- , University of Cam- burg at the Kaiser Wilhelm Institute for bridge. In the pages of New , at Berlin-Dahlem. Warburg was Komberg wrote: “Of all the biochemists an acclaimed scientist in his own right, whose work has given us insight into the who would win the Nobel prize in 1931 molecular events that characterize living for his research into the respiratory en- matter, Sir Hans Krebs was indisputably zyme.T,s In his 1953 Nobel prize lecture,

627 the proposal ot the “ cycle.’ “0 Joseph S. Fruton, , stated that the paper “marked a new stage in the development of biochemical thought.”lz As Krebs told CC readers in a Cita~ion Claxric commentary, the paper also reported some new methodologies. These concerned the use of slices to study , and a new saline solution with which to preserve them.ls Ten years earlier, Krebs had written: “The use of tissue slices which I had learned in Otto W arburg’s laboratory, so it seemed to me, opened up an entirely Hans Krebs new kind of approach to many problems of metabolism. ”14 The saline solution Krebs acknowledged Warburg’s influ- “proved superior to all earfier plasma ence. He stated that he learned more saline substitutes. ”IS It is for this solu- from Warburg than from any other sin- tion, he believed, that the paper is so gle teacher,g and eventually published a highly cited—more than 2,400 explicit biography of his mentor. 10 citations between 1961 and 1981. This is Although he had proved himself in the remarkable considering its 1932 publica- laboratory, Hans continued to seek a tion date. We’ll only know its impact for medical career. He obtained a position the previous 30 years when we compile at the Municipal Hospital at Altona, a the SCI for that period. suburb of Hamburg, in 1930. In 1931, he About the time of the publication of became privatdocent of internal medi- the paper, the Nazis came to cine at the . (A power in Germany. Because he was a privatdocent is a teacher who receives Jew, Hans lost his university position. payment directly from students’ fees.s) However, he had several offers from in- At Freiburg, Hans also found time for stitutions in . He was able to laboratory work. He collaborated with a emigrate before the situation for in student, Kurt Henseleit, to produce the Germany worsened. ~ In the Citation classic paper that demonstrated how Classic mentioned earlier, he pointed is converted to urea in ani- out that his coauthor Henseleit also suf- mals. 11 Thk paper immediately estab- fered under the Hitler regime. “Having lished Krebs’s reputation. In Blaschko’s been associated with me and not being a analysis, “It gave the answer to an im- Nazi, he was told that in the ‘Third portant unsolved problem, that of the Reich’ he had no future in academic site and of the mechanism of urea . ” Henseleit eventually became biosynthesis in the mammalian . It a successful practicing internist in also demonstrated a physiological role Friedrichshafen in south Germany, for , an enzyme that had been where he died in 1972. known for some time. The most impor- His reputation secured through his tant features of the work were the dis- outstanding publications, Krebs ac- covery of the catalytic role of cepted an invitation from Sir Frederick [an amino acid found in bird urine] and Gowland Hopkins to come to the de-

628 partment of at the Univer- leads to the re-formation of oxaloacetic sity of Cambridge. Hopkins had won the acid, but allows packets of electrons to Nobel prize in 1929 for his pioneering be released in small steps that can be work on vitamins. Supported by the strictly controlled. Figure 1 presents an , Hans contin- illustration of the Krebs cycle. ued the work on amino acid metabolism As Krebs explained in his Nobel prize that he had begun at Freiburg. This led lecture, “Of major significance was an- to an appointment to the position of other new observation. Citrate was not university demonstrator in biochemistry only broken down at a rapid rate but was at Cambridge. 15 also readily formed in muscle and in In 1935, Krebs moved to the Universi- other tissues. ”g The Krebs cycle, ac- ty of Sheffield to become lecturer in cording to E. Hammarsten, Karohnska . At Sheffield, he did his Institute, Sweden, explains “two simul- most acclaimed work. He discovered, taneous processes: the degradation reac- with William A. Johnson, a graduate stu- tions which yield energy, and the build- dent, the mechanism for the synthesis of ing-up processes which use up energy. ”g citric acid from and Krebs’s work also showed how ATP is , one of the major steps in formed and used in metabolism. The ceU metabolism. 2 Krebs cycle is also sometimes called the While much was known about cell me- tricarboxylic acid cycle. tabolism before this work, Hans sup- The paper reporting the Krebs cycle plied much missing information and was was published in 1937 in Enzymologia,2 able to organize the body of knowledge but not before it was rejected by . into a workable whole.G To understand As Nature recently acknowledged, the significance of this discovery, one Krebs cherished the rejection slip for the has to understand a little about cell article that reported hk Nobel prizewin- metabolism. ning work. 16We have no way of know- Celf metabolism can be viewed as the ing how often this paper was cited before way energy is released from foodstuffs the appearance of SCI, but it was cited and converted to chemical energy that is explicitly only about 30 times in the past useful to the body. In , this is 20 years. It is undoubtedly a good exam- done by stepwise oxidation, or removal ple of the “obliteration phenomenon. ” of electrons, from food materials. The The Krebs cycle is now common wisdom electrons are then fed into a chain of car- in biochemistry, riers that ultimately leads to their combi- Besides being a period of great profes- nation with to form water, and sional accomplishment, the late- 1930s the concomitant synthesis of the com- was a period of personal satisfaction as pound that is the carrier of chemical well. In 1938, Hans married Margaret energy, (ATP). Cicely Fieldhouse of Wickersley, York- The cycle discovered by Krebs de- shire. They had two sons, Paul and John, scribes how the two-carbon product of and a daughter, Helens A patriot in hk metabolism, acetyl coenzyme A, is new homeland, Krebs made many con- broken down, and its electrons removed tributions to British life during World in smalf steps. The ceU condenses this War II. He supervised research for the two-carbon compound with the four- British Council on the carbon intermediate oxaloacetic acid to reman nutritional requirements for form the six-carbon acid, citric acid. It is titamin A and ascorbic acid. 17 As a the oxidation of citric acid that not only “esult of his research, the official recom-

629 .-, ...... Figure 1: The Krebs cycle. The cycle begins with Award.~U lt M slgndlcant that Krebs and acetyl coenzyme A, an end product of the metabofic breakdown of amino acids, car- Lipmann both were among the 1,000 bohydrates, and fatty acids. Coenzyme A is a most-cited contemporary authors for catalyst, and is regenerated in the formation of their publications from 1965 to 1978.21 the next intermediate compound, c]tric acid. A series of reactions occurs, during which two car- At Sheffield, Hans continued his re- bon atoms are lost, the end pruduct being ox- search on the oxidation of carbohy- aloacelic acid. Oxaloacetic acid combines with drates by as well as ani- acetyl coenzyme A, which is converted to citric acid, and the cycle begins anew. Each turn of the mal tissues. S He afso discovered a num- cycle liberates eight hydrogen atoms. These in ber of new analytical techniques. His ex- turn are incorporated into ATP, from which the periments on the accumulation of glu- body draws energy. tamic acid within isolated tissue slices CH,CO– SC.A A,sw.,., Acec.1CO.”.vm. A were important in adding to our under- standing of metabolic chemical reac- \ C..”>< COO* O.c . “,0 HOCCHZCOOH CHZCOOH tions. 17 Glutamic acid is an amino acid CM,COOH Cltrk acid O“.l ...... which mammals can synthesize them- -ml selves. / \ “OC”COOH HOCHCOOH Krebs was a magnet for students and CH,COOH HOOCCHZCHCOOH M.llc WIGI !,. <11,1. ..44 endeavored to teach them all he knew. 1~

/ :% An editorial in Nature pointed out, “At H,0 \ \ ~H,COOH one stage, more than a dozen British CHCOOH ,, CHgCO COOH CHCOOM m ha,o~l”l, rlc ,cld chairs of biochemistry were occupied by Funm,tc ..14 his students. He was a giant eager that ,’ \ .& ,“2=00”CH,COOH /co’.;.COZ G1ulam, te, his shoulders should be used by younger S,.. (.1C..,6 people.”lb In 1954, when Sir Rudolph Peters

Povhy,lns retired from the Whitley chair of bio- chemistry at Oxford University, Hans mended dietary requirement for ascor- was appointed to the post. The Medical bic acid was reduced from 70 mg per day Research Council Unit moved to Oxford to 30 mg. Hans is credited with helping with him. Is That same year, Krebs to develop the national wholemeal loaf received the of the Royal that “kept the English people well- Society of London.aa At Oxford, his nourished through the war years despite laboratory continued the study of meta- food shortages. ”la bolic regulation. In 1958, Krebs received After the war, Krebs returned to his one of the highest honors his adopted research. In 1945, he was appointed the country could bestow when he was first professor of biochemistry at the knighted. and the honorary After 13 years at Oxford, Sir Hans director of the Medical Research Coun- Krebs retired from the Whitley chair, cil Unit for Research in Cell Metabo- but he continued hk work with his close lism. He received more honors, and in collaborators L.V. Eggleston, R. Hems, 1947, he was elected a Fellow of the Patricia Lund, and D.H. Williamson. He Royal Society of London. In 1953, he set up the Metabolic Research Labora- won the Nobel prize for his discovery of tory in the Radcliffe Infirmary, Oxford, the . He shared the in 1967. $33,840 cash award with Fritz A. Lip- In recent years, Krebs studied, among mann, 19although the two were not col- other things, ways to preserve the liver laborators. Earlier that same year, for long periods after removal for trans- Krebs received the Lasker Health plantation to other . He was also

630 Table 1: The most-cited papers of Hans Krebs in which he appears as first author

Total citations 1%1-81 Bfbffogrnpbfe Data

2492 Kreha H A & Henseleit K. Studies on urea formation in the . Hoppe-Sey[ers Z. Physiol. Chem. 210:33-66, 1932, 581 Krebs H A. Body size and tissue . Ifiochim. Biophys, Acts 4:249-69, 1954. 418 Krebs H A, Bennett D A H, de Gmquet P, Gascoyne T & Yosbkfa T. Renal gluconeogenesis. Biochem, J. 86:22-’7, 1%3. 315 Kreba H A. The Crcmnian lecture, 1%3. Gluconeogenesis. Proc. Roy. Sot. London Ser. B 159:545-64, 1964. 265 Kreba H A & Hems R. Some reactions of adenosinc and inosine in animal tissues, l?iodtim. Biophy$. A cfa 12:172-80, 1953. 18’7 Kreba H A & Eggleston L V. The role of pyruvate kinase in the regulation of gluconeogenesis. Bmchem. J. 94 :3c-4c, 1%5. 140 Krebs H A & Woodford M. Fructose 1,b-dipbosphatase in striated muscle. Biochem. J. 94:436-45, 1%5. 139 Krebs H A, Speake R N & Hems R. Acceleration of renal gluconectgenesis by ketone bodies and fatty acids, Biochem. J. 94:712-20, 1%5. 137 Krebs H A. CCXXX, Metabolism of amino-acids. fv, The synthesk of glutamine from glutamic acid and ammonia, and the enzymic hydrolysis of glutamine in animal tissues. Biochem. J. 29:1951-69, 1935. 136 Krebs H A, Freedfand R A, Hems R & Stubba M. lnbibition of hepafic gluconeogenesis by ethanol. Bioc+wm. J. 112:117-24, 1%9. 134 Krebs H A & Beftnmy D. The interconversion of glutamic acid and aspartic acid in respiring tissues. Biochem. J. 75:523-9, 1960, 133 Kmbs H A, Hems R, Wefdemarm M J & SpeaJte R N. The fate of isotopic carbon in kidney cortex synthesizing from laclate. Biochem. J. 101:242-9, 1966. 130 Krebs H A. The regulation of the release of ketone bodies by the liter. AdVan. Enzyme Regul. 4:339-53, 1966. 129 Krebs H A. CXCVII, Metabolism of amino-acids. fII. Delamination of amino-acids. Biochem. L 29:1620-44, 1935, 121 Kreba H A. Considerations concerning the pathways of syntheses in Ibing matter. Bull. Johns Hopkins Hosp. 95:19-44, 1954. 115 Krebs H A, Komberg H L & Burton K. A survey of the energy transformations in Ihing matter. Ergebmsse Physio[. Biol. Chem. Exp. Pharmucol. 49:212-98, 1957. 108 Krebs H A, Dferks C & Gascoyne T. Carbohydrate synthesis from lactate in pigeon- Iiver homogenate. Biochem. J, 93:112-21, 1964. 105 Krebs H A, Gascoyne T & Notton B M. Generation of extramitochondrial reducing power in ghmoneogenesis. Biochem. J. 102:275-82, 1%7. 103 Kreha H A & E@ston L V. 55. The oxidation of pyruvate in pigeon muscle. Biochem. J. 34:442-59, 1940. interested in known as “inborn once commented to me about his own errors of metabolism. ” Thus his interests citedness and about the fact that many came full circle, back to research with most-cited articles are cited for their direct application to medicine.b methodology. “Oddly enough,” he said, Over the years, Krebs compiled an im- “the only paper of mine ever rejected pressive citation history. His work has outright by an editor was a purely meth- been cited more than 11,000 times since orological one. It was a paper on the 1961. A bibliography of the most-cited handling of biological material for meta- papers in which he appears as first bolic experiments. The editor believed, author is presented in Table 1. Hans I think wrongly, that results are more im-

631 portant than methods. The frequent The example he set was one of excel- quotation of methods papers unequivo- lent science, innovative methods, and cally demonstrates the usefulness of care for his fellow . Much has such papers. ”~j been said about the atmosphere in his When budgetary considerations laboratories. “For those eager to work prompted governments in the US and there was no better place to go to. He Britain to cut back on science-related always created an air of cheerful activity spending, Krebs became concerned around him,” Blaschko said.b E.A. Ev- with the issue of waste in science. In ans and K. Burton, both of whom had 1970, he told the American Philosophi- worked with Krebs, wrote that the atmo- cal Society that “casual and ineffectual sphere in his Sheffield laboratory was use of research facilities means irrespon- “one of unusual harmony as well as intel- sible wastefulness. In view of the lectual stimulation. This is due in no unavoidable financial stringencies it is small measure to Krebs’ personal and in- essential to deploy the limited resources tellectual qualities... .“17 They also effectively .’’l’l He also pointed out that praised his ability to plan the exact on visits to laboratories “one is liable to necessary experiment and efficient use see valuable space, equipment, and per- of time and facilities. sonnel involved in work which over Up until his last days, Krebs remained many years has produced nothing tangi- interested in both biochemistry and ble. This sterile research and pretension other aspects of the world around him. of doing research have been called ‘oc- He sent me a copy of a manuscript on cupational therapy for university juvenile delinquency. In this piece, staff.’ “Z4 published in Unesco’s New Horizons of He suggested that universities allocate Kno wledge, zb he argued that an resources more effectively. “There is too inadequate understanding of fundamen- great a tendency to regard all staff mem- tal biological principles is one of the bers of a science department as equal in causes of juvenile delinquency. respect to their abilities in teaching, It is always difficult to sum up the life research, and administration and to give of an extraordinary and prolific scien- them an equal share of the various tist. The task is even more difficult if his departmental responsibilities. They are interests outside of science were wide- of course very unequal, and duties and ranging. Although I can only envy the facilities should be dktributed according intimacy others shared in working in his to ability and inclinations. ”z~ laboratory, I feel that I was privileged to Krebs also continued to edit FEBS know him in a special way. I was fortu- Letters, along with Kornberg and nate to have his support during some try- others, In the issue dedicated to Krebs’s ing times. But undoubtedly, a real eightieth birthday, the edhors noted, measure of his life is that humanity prof- “There is nothing that his friends can of- ited vastly from the work of this giant. fer him that will be more to his liking ***** than the demonstration that they have profited from his teaching and by his ex- My thanks to Esther Surden for her ample.”ls help in the preparation of this essayo,w, ,$,

REFERENCES

1. Altman L K. Sir Hans Krebs, winner of Nobel for research on fomf cycles, dies NY 7tmes 9 December 1981, p. D23.

632 2, Kreba H A & Johnson W A. The role of citric acid in intermedmte metabolism in animal tissues, Enzymologia 4:148-56, 1937. (Reprinted in: lZElfS .Letf, 117(SUPPI.):K2-KIO, 1980. ) 3. Garfield E. To remember my mother. Essays of an information scientist. Philadelphia: 1S1Press, 1977. Vol. 2. p, 535-6. (Reprinted from: Current Corr@us (30):5-6, 26 July 1976.) 4. Kornberg H. Chance favours the prepared . Review of “Remini=ences and reflections’” by H. Krebs. New Sci. 93:385-6, 1982. 5. Kreba H. Reminiscences and reffectionf. Oxford, UK: Oxford University Press, 1981.298 p. 6. Blascbko H. Hans Krebs: nineteen nineteen and after. FElfS Lett. 117(Suppl.):KI 1-K15, 1980. 7. Warburg, Otto Heinrich. (Crouse W H, cd, ) &fcGrow-Hi/l modern men of science. New York: McGrsw-Hifl, 1968. Vol. II. p. 577-9. 8. Kornherg H. Biochemist extraordinary. Review of “Otto Warburg: cell physiologist, biochemist and eccentric” by H. Krebs, Nature 294:595, 1981. 9. or medicine 1953: Hans Adolf Krebs. Nobel lectures. Physiology or medtcine 1942-1962. New York: Efsevier, 1964, p. 392-412. 10. Krebs H. Otto Warburg: cell physiologist, biochemist and eccentn’c. Oxford, UK: Oxford University Press, 1981.141 p. 11, Krebs H A & Henselelt K. Studies on urea formation in the animal organism. Hoppe-Seylers Z. Physiol. Chem. 210:33-66, 1932. 12. Fruton J S. Molecu/e~ and /ife. New York: Wiley, 1972. p. 436-45. 13. KrefJs H A. Citation Classic. Commentary on Hoppe-Sey/ers Z. Phy.rio(. Chem. 210:33-66, 1932. Current Contenfs/L~e Science.r 23452): 12, 29 December 1980. 14. ------The history of the tricarboxylic acid cycle. Perspect. Ifio/. Med. 14:154-70, 1970. 15. WffJiamson D H. Regulation of cell metabolism: tribute to Sir Hans Krebs. Biochem. Sot, Tmns. 9:1-2, 1981. 16. Monument for a giant. Nature 294:2%, 1981. 17. Evans E A & BurIon K. The 1953 Nobel prize awards. Science 118:711-2, 1953. 18. Nobel prize shared. Sci. News Let[. 64:275, 1953. 19. Cmworkers & coenzymes. Time 62(18): 104-5, 1953. 20. Lsaker Health Award. Sci. News Letf. 64:274, 1953. 21. Garffeld E. The 1,CWl contemporary scientists most-cited 1965-1978. Part I. The basic list and introduction. Current Contem$ (41):5-14, 12 October 1981. 22. Royal Medal (E): Prof. H.A. Krebs, F.R.S. Nature 174:1031, 1954. 23. Krebs H A. Personal communication. 23 October 1980. 24. ------The goafs of science. Amer. Phil. Sot. Yearbook 115:1-3, 1971. 25. Kornberg H & Lured P. Editors’ note. FEES LerI. 117(Suppl,):Kl, 1980. 26. Krebs H. Biological and medical aspects of juvenile delinquency. New horizon., of human knowledge. New York: Unesco Press, 1981. p. 79-88.

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