Hitler's Gift and the Era of Biosynthesis

Before the Second World War biochemistry in the United States had a strong flavor of clinical chemistry. It was much occupied with problems of analysis of blood and tissues and the determination of the structures of body constituents. This was important and indeed essential work, but American students had to go abroad to Germany or to England for training in what came to be called dynamic aspects of biochemistry. After the war, the flow of students was largely reversed. This transformation was in considerable part the result of new insights and new approaches brought to America by immigrant scientists. It is a remarkable fact that as late as 1945 when I began graduate studies in biochemistry at the University of Chicago almost nothing was known about the linked reactions leading to the biosynthesis ofany of the major types of cell constituents, carbohydrates, lipids, proteins, or nucleic acids. However, this picture was about to change with dramatic rapidity. The latter half of the 20th century became the era of biosynthesis. Now, in 2001, we know in great detail the patterns of reactions leading to the formation of each of these classes of cellular materials, although to be sure much remains to be learned about the regulation and integration of biosynthetic processes in living organisms. The achievements of three biochemists, Fritz Lipmann, Rudolf Schoenheimer, and Konrad Bloch, greatly stimulated this flowering of biosynthetic studies in the United States at the mid-20th century. Each had been driven out of Germany by the brutal anti-Semitism of the Nazi regime. Each was an important part of what has been called Hitler's gift (1Medawar J. Pyke D. Hitler's Gift. Arcade Publishing, New York2001Google Scholar) to American and British science. In helping to bring about the transition to the era of biosynthesis, Fritz Lipmann made clear the crucial role of “energy-rich” phosphates in driving biosynthetic reactions and showed how this principle operated in the formation of the much sought and highly elusive “active acetate” involved in so many pathways. Rudolf Schoenheimer helped put into the hands of biochemists their most subtle and versatile approach, that of the isotope tracer technique, and with its aid revealed the dynamic state of body constituents. Konrad Bloch's work on the formation of cholesterol illustrated how the insights of Lipmann and Schoenheimer could be combined in a masterpiece of biochemistry to solve a problem of great medical as well as biological significance. Fritz Lipmann (Fig. 1), who helped to shape the development of modern biochemistry, was born in Koenigsberg, East Prussia in 1899 into a Jewish family of the professional class (2Lipmann F. Annu. Rev. Biochem. 1953; 54: 1-32Google Scholar). In 1917, he began the study of medicine. In 1918, while still a medical student, he was drafted into the German army and spent the rest of the war in the medical corps in France. Released from the army, Lipmann resumed his medical studies and received the M.D. degree in 1921. He soon abandoned plans for the practice of medicine in favor of biochemical research, but he always valued the broad view of biology his medical education had given him, concluding: “The biological education to which the observant student is exposed in medicine is a superior preparation for any career.” Indeed, the study of medicine offered the most comprehensive view of biology then available. Many of the greatest figures in biochemistry early in the 20th century, including Warburg, Meyerhof, and Krebs, were trained as physicians. The breadth of his background helped give Lipmann the confidence that nothing in biology was beyond his range. Again and again, he proved ready to tackle new problems, no matter how far removed from previous work in his laboratory. Turning to a career in research rather than the practice of medicine, Lipmann realized that the most fruitful approach to biological problems was through chemistry. He began a program leading to a Ph.D. in chemistry. His work for the dissertation, begun in 1927, was carried out in the laboratory of Otto Meyerhof. Meyerhof, whose work on glycolysis in muscle earned him a Nobel Prize, had a laboratory on the first floor of the Kaiser-Wilhelm Institute for Biology in Berlin, a city that was then the leading center of science in the world. Lipmann felt that his experience in Meyerhof's laboratory was in many ways the origin of all his later work. His most intense admiration, however, was reserved for Warburg. As Lipmann later recalled (3Lipmann F. Wanderings of a Biochemist. Wiley-Interscience, New York1971Google Scholar): “At the top of everything, on the uppermost floor, was Otto Warburg. Warburg already had a mystery about him. We admired him boundlessly but saw little of him … ” In Meyerhof's laboratory, Lipmann worked on the role of creatine phosphate in muscle contraction. It was of course known that muscle contraction, with its attendant production of lactic acid, is intimately linked to glycolysis. The energetics of this linkage, however, remained obscure. Lipmann (3Lipmann F. Wanderings of a Biochemist. Wiley-Interscience, New York1971Google Scholar) commented on “ … the vagueness of the understanding, then prevalent, of both the intermediary path of glycolysis and the mechanism of action of energy-rich phosphate.” This work did much to turn Lipmann's thinking to the role of phosphorylated intermediates in energy transduction. In 1930, Lipmann was already aware that a career for a Jewish scientist in Germany was fraught with difficulty and peril. began a of he a that offered both and However, he to in at for a to be his (3Lipmann F. Wanderings of a Biochemist. Wiley-Interscience, New York1971Google Scholar). He became an to on problems of In a in the work of laboratory by its from to Lipmann, to to the United States to work at the Institute in New in the laboratory of on the biochemistry of he in from of In Lipmann in its new in the in he was to He was to work in of his about this Otto Warburg was his great the of glycolysis. the of involved phosphorylated intermediates had been a great which Warburg In in had that glycolysis a which he This proved to be In than received a Nobel for his work on its and but is clear from his Nobel that he had at that no of its and It was Warburg and his Scholar) who and showed that a that and It is of course the known to in many of Warburg that the of by is linked to the of and the formation of This phosphate then with to the first the of glycolysis became of the energy the of is made to the cell as Lipmann these and his In he to an of the role of phosphate in the of in of the then called He F. Scholar) that the of was to the of and the of with the formation of with the role of in he the from these of highly phosphate in was with the then available. Lipmann this difficulty by phosphate from and He then showed that this the was for the formation of in these when I worked in Lipmann's laboratory and his early I was greatly by this I learned from that is to a in an than to a that to first and then its role as The work on phosphate the of Lipmann's and with both the role of phosphate in energy and the problem of “active In of with the Nazi Fritz and Lipmann for the United a in which he sought a that him and with his In he was to a in a at the University of in by many of the leading figures in American biochemistry. Lipmann, a or the for the he to and through his had to be by the of the (3Lipmann F. Wanderings of a Biochemist. Wiley-Interscience, New York1971Google Scholar). he felt that this was of the that made for him to a In Lipmann was by F. F. to a to the first of the in As Lipmann later (3Lipmann F. Wanderings of a Biochemist. Wiley-Interscience, New York1971Google Scholar) “ … I was when he that I about the role of phosphate as in energy and in biosynthesis. This had begun to as an of experience with of the made in that been than I Now, in 2001, is to the of this F. on American biochemists who had the work in Lipmann classes of phosphate in living The first phosphate of as with a energy of of was by Lipmann as in the which he as were to be from class and phosphates as The energy of of phosphates of this class is of the of In Lipmann's these energy-rich phosphate with a that was to as the great was in his and the of energy to living part of which is in as “energy-rich” leading to the formation of Lipmann that the phosphate be to out work … to as nucleic acid, and so Lipmann made clear that the energy to biosynthetic processes from as was soon to be Before this biosynthetic processes could be in or in as by in which cellular remained The to the study of was began to of to their when for biosynthetic The is in many ways of Lipmann's which had a flavor when with were problems about which he had and he his in and he of a in to an and a that energy as “energy-rich” phosphates out that his of the to the energy in a was the of the to the energy of but Lipmann (3Lipmann F. Wanderings of a Biochemist. Wiley-Interscience, New York1971Google Scholar) to “The remains He be to the but he from to the who Lipmann's for a a in a rather In offered him an in the of at the the made was at first he was given to his Lipmann's at the were highly and him to a Nobel in In the of “active as the was of the most problems in intermediary body of that “active acetate” was the for the of and acids. from the of or of could with to and the for the of by his in phosphate as an in the of Lipmann out to its role as the elusive “active acetate” in He to study the of known to in of the with which this could be and with a to an The of to the could be He in from that but to his considerable that phosphate did but was F. J. Scholar). however, he that as well as was for and that by at could be to by the of and had a for the of the of in his laboratory, Lipmann's was about and to be in the of F. J. Scholar). It to be a for and the or The was the F. J. Scholar) in that by then about the This was a great little in by I Lipmann's laboratory as a the of who had to a at the of had to Lipmann from laboratory. Lipmann's at this and Lipmann's research We were into a laboratory in the to the of the first so was of as an In the course of the we were to into rather in a research and a and a Lipmann a to that of an rather than a He and his into the Lipmann's who worked in his laboratory was rather He was but a little He and but in who worked his this Lipmann's was the of which was and the determination of the of “active the with so many crucial in to be an of in was so we that its be and this was to the of to in I came an in F. Scholar) from the laboratory of He and his student for an essential in had and proved to be a I brought the at to Lipmann who had learned of this He was in of the work although had of his He was by the fact that in from had begun by the We Lipmann that an that is to be so as we had Lipmann that be to the of “energy-rich” he in a at this is a of the of In Lipmann the Nobel with the for the his work on Lipmann on his to he (3Lipmann F. Wanderings of a Biochemist. Wiley-Interscience, New York1971Google was in the that as I had was as a biological energy energy to and In he to the He to be in a of biosynthetic problems, his of and the energetics of biosynthesis his in at the of The most important that biochemistry in the 20th century was the isotope tracer the of of biosynthesis be was the first to the biological of in studies of the of and its into tissues of Biochem. J. Scholar). It is to Rudolf Schoenheimer (Fig. however, that we the of the of that is the of into of whose could then be of career been by Scholar) and by and Scholar). He was born in in Scholar). Lipmann, he medicine and received the M.D. degree from the University of in Again Lipmann, he the for of and spent in the laboratory of in largely on problems as the of In Schoenheimer to the Institute of in as to a leading on Scholar). Schoenheimer began an on the of cholesterol into the of a of cholesterol in the He was to his in cholesterol for the rest of his It was in in that Schoenheimer who to study the of and Scholar). his background in to a for this work. 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Biochem. the many which to University from the by the the was the in laboratory of biochemists, Rudolf Schoenheimer and who the this The achievements made by these so well known that their is to that his and in these were by no to be in American In at University in the of the isotope of by the of new in the for a of of in the of a of in the isotope by of In received a Nobel for this work. of the of an is a of the of their of the to however, has the of and its preparation in or as is and was soon in the of and many The of a new of a of as great all the world. received his Nobel in in his of that of were already by an at the in at the of about a Nobel New Scholar). 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Scholar): Schoenheimer made a new which proved to a on the of his work … came from to the laboratory in which Schoenheimer had been for a their the of a isotope as a in for in intermediary which be from their … ” This new of Schoenheimer and his was a far from the of the of a from part of a or to as had been by In the new approach, the of the into which the isotope had been was the isotope the of this was the approach of who in by the of a to the that the had an of to in a was from the of to which had been on the the had an of was that the could be from the to which was linked and that in tissues at the This result later studies of but the work was to the that from and a was that this of was for than acids. Schoenheimer was well aware of work. In a in D. 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Scholar) from the of of into that cholesterol be with a of the of for the of into the cholesterol was that its that of the of many major of the came with the of the isotope by and his in It was to studies of the of and In D. J. Scholar) the first in which an in the was “The of this was to out in the in the is from the or is with of an of for … The that in the of at acid, was in the while almost half of was in the body was at the that were and the Schoenheimer this view a into a he and a the turn into Schoenheimer had the in of New and laboratory were made for him. His and and As Scholar) has he had the of the first biochemical laboratory. was for the preparation and of was for the of of course were were for the and analysis of cell constituents. for were background in as well as in biology and medicine made him in the of this of carried out with in the and on the that had the greatest on biochemical The of University body were to be in a state of “The to be as essential of the and that and and in the of The give no as to the is or The work that were to the of with the work on a new and remarkable picture of the of Schoenheimer his The of University Scholar): “The and and their and nucleic involved in and the with from and with from the to a of as to origin … This be with the of a living to a with the of and types of … The picture be by which of the dynamic state of body In Schoenheimer was to give the at the The and that he for the from which of the were later The of University Scholar) the “The of This of his work made a on the biochemists of the to Schoenheimer had been to of and was a of considerable when in of he his Scholar). of at the of his he was at the of his many of the that he had begun were carried by the cholesterol Konrad (Fig. was born in in a in the German of the of a Jewish family Annu. Rev. Biochem. Scholar). In his little in science than but his in a course of at the by a for him. later to a Nobel Prize, was of the remarkable of German who then the study of were in a the and he realized that he had his Annu. Rev. Biochem. Scholar). In the brutal of Germany from his studies came to his by his at the in the the in his The In worked for a on the of the In however, he was to to in he to J. at with he had his He received the first from the of the of University him that he had been in and the from him that was no to this He showed the first but the to the United States in and received a to to the United in New to for as a graduate The in was an with The most important later a could that he the an to who of his work for the Ph.D. degree In Schoenheimer that he the origin of the in or The that be showed the remarkable of Schoenheimer was at that the problems of the of in the state of of and was to give the In however, he to the problem and with his student J. Scholar) showed that is indeed the of the As Annu. Rev. Biochem. Scholar) in his the and the so We that we to for but to as to the of Schoenheimer had begun and … the of came about I been by any which to his work on biosynthesis. was to his in and and were to be began his studies of the biosynthesis of It was a In the era and the determination of the of with its in and with a had been a to the greatest of The Nobel in for and had been to and for their work on the of cholesterol and the but was that the was In his Nobel Nobel New is and has no to the of or the which in The of a to the and to I to as is the of been to the of a for is known that that of and in the of course that view of the of the was Schoenheimer and had the of from into cholesterol in the and that cholesterol be by the of a of The for the biosynthesis of cholesterol from than be in of biochemistry. is beyond the of this we the in its three major to to and to Bloch's studies began with of the of formation of cholesterol in the by a from the German and that is into the of began a of studies the of into cholesterol in the studies were and his in to the of at the University of his a of had I was a graduate student in the at this and so I came to know Konrad Bloch, first as a and later as a and He was a of with his great His with students was and He was in the research of his and of He was to and In the Annu. Rev. Biochem. Scholar) was of the of Lipmann's that biosynthetic reactions driven by or Before this the of had been by of the reactions by In a to the cholesterol he and his students began to the of the as a of were indeed to that the of the of and by but the mechanism proved to little on the of was much aware of the of for the analysis of and he as a student in the course in by at the in a of the was in laboratory that when was to the was to this He and his that was to in this of the the could be from In the of to which of the of cholesterol were from the and which from the carried out a of in the of and of as well as of Bloch, the of the origin of each of the of cholesterol as the or the of This work important on structures of intermediates in the It had been known for that in in the of when to the of cholesterol in their the that be a of to the in to the preparation of in but the proved to be an for study Annu. Rev. Biochem. Scholar). I was to was that of to and their to at the University of however, his student was to by with as an so was then to and to be to cholesterol J. Scholar). This was an important In the of biosynthetic is to an in the of the of the then the both and this in his work, in to the of at he was to for the rest of his could be to be from of a was already known to be a of as although the of the remained J. Scholar) had that be to the of cholesterol Bloch, however, with his that with a to cholesterol but with three was to be an in this to this Bloch's approach to the cholesterol problem had been largely to tracer studies with or with in which cellular was but he to the study of by the by were to the transformation of to and of to much work remained to be had the for the of the biosynthesis of cholesterol Scholar). The was to the first of the the of to the “active of had been to when was to the that the was by at and J. Scholar) as as the was then to be a of and of cholesterol in of J. Scholar). the for the of the reactions leading to the formation of the “active of which was the in this became and with important from the of and and his showed that the of to in of as well as and His then the of to a The of this to the important intermediates and was largely by work in laboratory. The of and was As by the early studies of Bloch, is in a of to which to It is of in this highly to to the of work, still in the that has to of the biosynthesis of It was Bloch, however, who was a in all three of the this work he was a Nobel Prize, with in out the for the of the of cholesterol was an of the era of biosynthesis, important of the of its but of its for medicine. of blood of in the of and of the of biosynthesis made to that the of from is a in the production of This made the development of the family of that of blood cholesterol with a of the most in modern medicine. Konrad made to than the biosynthesis of including the of and the mechanism of action Annu. Rev. Biochem. Scholar). He on at the of The development of any of science is the work of many Lipmann, Schoenheimer, and be as American biochemistry. work was a great gift to their and a of the of science.