To Remember Sir Harss Krebs: Nobelist, Frfend, and Advfser k,. .—- l--- -1-1 * -. -, .fi#, -) fiugusK A, IYUL I was deeply saddened to hear of the among the greatest.”4 Komberg will death on November 22, 1981, of my soon begin writing an official memoir of friend and colleague, Sir Hans Krebs. 1 Krebs for the Royal Society of London. Krebs received the 1953 Nobel prize for Those interested in Krebs’s life and work his discovery of the citric acid 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 August 25, 1900, in though we never met in person. A long- Hiidesheirn, a smalf town in the northern time member of the Science Citation Irr- part of Germany. 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 Berlin 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 Hamburg in 1925.5 Current Contents@ (CC@ ) readers every- According to Hermann Blaschko, the where have these kinds of friendships Oxford 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 physician Bruno Mendel chemistry 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- Hans Kornberg, University of Cam- burg at the Kaiser Wilhelm Institute for bridge. In the pages of New Scientist, Biology 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 “urea cycle.’ “0 Joseph S. Fruton, Yale University, 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 tissue slices to study metabolism, 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 urea cycle paper, the Nazis came to cine at the University of Freiburg. (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 England. He was able to laboratory work. He collaborated with a emigrate before the situation for Jews in student, Kurt Henseleit, to produce the Germany worsened. ~ In the Citation classic paper that demonstrated how Classic mentioned earlier, he pointed ammonia 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 medicine. ” Henseleit eventually became biosynthesis in the mammalian body. It a successful practicing internist in also demonstrated a physiological role Friedrichshafen in south Germany, for arginase, 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 ornithine cepted an invitation from Sir Frederick [an amino acid found in bird urine] and Gowland Hopkins to come to the de- 628 partment of biochemistry 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 Rockefeller Foundation, 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 pharmacology. 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 oxaloacetic acid and Krebs’s work also showed how ATP is pyruvic acid, one of the major steps in formed and used in cell 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 Nature. 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 animals, 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 oxygen 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, adenosine triphosphate (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 Medical Research 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 .-, .