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Schoenheimer, Rudolf

SCHOENHEIMER, RUDOLF

(b. Berlin, Germany, 10 May 1898; d. Yonkers, New York, 11 September 1941)

biochemistry.

The son of Hugo Schoenheimer, a physician, and of Oertrud Edel Schoenheimer, Rudolf attended school in Berlin and graduated from the Dorotheen-städtische Gymnasium in 1916. He was then drafted into the army and served in the artillery on the western front until the end of World War I. This traumatic experience affected his view of himself and of the world around him, and his forced emigration upon Hitler’s rise to power further deepened his despair.

Upon returning from the war, Schoenheimer studied medicine at the University of Berlin and received his degree in 1922; his M.D. dissertation (dated 1923) was entitled “Über die experimentelle Cholesterinkrankheit der Kaninchen.” He then spent a year as a pathologist at the Moabit Hospital in Berlin, where he continued research on sterol metabolism, with special reference to the production of atherosclerosis in experimental animals by the administration of cholesterol. He also worked briefly in the laboratory of Peter Rona at the Berlin Municipal Hospital am Urban. In 1924, Schoenheimer took advantage of the establishment by Karl Thomas,1 professor of physiological chemistry at Leipzig, of a postgraduate program for young physicians who wished to improve their knowledge of chemistry. This program was supported through fellowships funded by the Rockefeller Foundation. Schoenheimer was one of the recipients.

An important component of the program was synthetic organic chemistry, in which Schoenheimer showed exceptional aptitude through a contribution to the methodology of peptide synthesis. The work of Emil Fischer from 1903 to 1909 had led to the synthesis of many peptides, but his halogen acyl halide coupling method had serious limitations. There was a recognized need for a method in which an amino-terminal blocking group could be selectively removed from a peptide by a nonhydrolytic process so as not to cleave the newly formed peptide bonds. Schoenheimer proposed such a procedure. In 1915, Max Bergmann, working in Fischer’s laboratory, had found that p-toluenesulfonylamino acids (to-sylamino acids) can be detosylated selectively by reduction with a mixture of hydriodic acid and phosphonium iodide. In 1926 Schoenheimer made several free peptides in this manner by using the azide coupling method, introduced by Theodor Curtius, Schoenheimer’s procedure was superseded by the important carbobenzoxy method2 introduced in 1932 by Bergmann and Leonidas Zervas, but the subsequent use of sodium in liquid ammonia to reduce tosylamino groups greatly enhanced the practicability of Schoenheimer’s idea. In his later work, which involved the synthesis of organic compounds labeled with isotopes, Schoenheimer repeatedly demonstrated his excellent knowledge of synthetic organic chemistry.

Schoenheimer’s work on sterol metabolism and especially on atherosclerosis brought him to the attention of Ludwig Aschoff, professor of pathological anatomy at Freiburg im Breisgau. A distinguished contributor to the study of many aspects of human pathology. Aschoff was particularly interested in atherosclerosis and abnormalities of the gall bladder, in which he had observed the deposition of cholesterol and its esters. In 1926. Aschoff invited Schoenheimer to become the chemist at his institute. This appointment was a significant one in Schoenheimer’s scientific career. With Aschoff’s encouragement, he energetically investigated several aspects of sterol metabolism by the use of chemical methods and those of experimental surgery. Among his many important results was the demonstration that cholestanol (dihydrocholesterol) is formed from cholesterol in animal tissues, thus disproving the then-current view that the conversion of dietary cholesterol occurs only by bacterial action in the intestinal tract.

Schoenheimer also extended the scope of his M.D. dissertation by examining the extent of atherosclerosis in rabbits after the administration of various sterols. He found that the absorption of cholesterol from the intestinal tract proceeds by way of the lymphatic channels and that other sterols (sitosterol, ergosterol) are not absorbed at all. Some of these studies formed the subject of his Habilitationsschrift, “Chemische and experimentelle Untersuchurngen über die Athersklerose” (Freiburg, 1928), which gained him the title Privatdozent. Moreover, shortly before his forced departure from Germany, Schoen-heimer made a particularly significant contribution by showing that mice are able to synthesize and degrade cholesterol in their tissues.

In 1930 Schoenheimer was called upon by Siegfried Thannhauser, recently appointed professor of medicine at Freiburg, for advice about a patient with high blood cholesterol who had been referred to him by a Chicago clinic. As a consequence Schoenheimer was invitated to visit the University of Chicago as Douglas Smith Fellow in the department of surgery. During his year in the United States, he drew the interest of Ludwig Kast, president of the Josiah Macy, Jr., Foundation, which began to support Schoenheimer’s research at Freiburg. Upon his return there in 1931, he was made titular head of the chemical division of Aschoff’s institute. On 27 October 1932, Schoenheimer married Salome Glücksohn, an embryologist; they had no children.

Upon being obliged to leave Germany. Schoenheimer returned to the United States, where in 1933 he received a research appointment in the department of biological chemistry of the College of Physicians and Surgeons at Columbia University. His salary and research support came from the Macy Foundation. He was subsequently made assistant professor; at the time of his death he held the rank of associate professor. The head of the department was Hans Thatcher Clarke3 an organic chemist who had been associated with the Eastman Kodak Company for many years before his appointment at the College of Physicians and Surgeons in 1928. A man of generous tolerance and modest scientific ambition, Clarke encouraged his departmental colleagues to develop their own research programs and put his extensive knowledge of organic chemistry at the disposal of everyone who sought his help. He transformed the scientific atmosphere of his department by welcoming to its faculty, as regular or adjunct members, able young chemists and biochemists who had been trained in Germany or Austria.

Schoenheimer had been preceded by Oskar Wintersteiner and Erwin Brand; between 1933 and 1945, Erwin Chargaff, Zacharias Dische, Karl Meyer, and Heinrich Waelsch were added. As a consequence of the achievements of these men and their American students, by the 1940’s Clarke’s department had become one of the leading centers of biochemical research. Schoenheimer’s contribution to this development cannot be overestimated.

At Columbia, Schoenheimer continued his work on sterol metabolism and completed a study begun at Freiburg on the occurrence, in the animal body, of cetyl alcohol [CH3,(CH2)14CH2OH]. During 1934 and 1935 he published a series of short papers on sterol chemistry and metabolism, and (with Warren M. Sperry) developed a valuable micromethod for the determination of free and combined blood cholesterol. By the end of 1934, however, he was engaged in the isotope studies for which he became famous.

Shortly after his return to the United States, Schoenheimer learned of the discovery of deuterium, the stable hydrogen isotope of mass 2, by Harold Urey of the department of chemistry at Columbia. Urey expressed interest in the use of deuterium in biological studies, and a program was established with the aid of the Rockefeller Foundation to promote such efforts in several Columbia departments.4 Among them was that of Clarke, who was placed in charge; David Rittenberg, one of Urey’s former graduate students, joined Clarke’s staff in the latter part of 1934.

The circumstances that led to Schoenheimer’s entry into the isotope program are uncertain, and the question has been raised whether he fully appreciated the potential of the isotope-labeling method for metabolic studies before Rittenberg’s arrival at the College of Physicians and Surgeons.5 That Schoenheimer had been introduced to the use of isotopes for biological studies before coming to Columbia is evident from the account by György (George) Hevesy of his association with Schoenheimer at Freiburg, where Hevesy had been professor of physical chemistry from 1926 to 1934.6 Moreover, unlike Rittenberg, Schoenheimer was thoroughly steeped in the German biochemical tradition, and was familiar with the work of Franz Knoop in 1903 on the use of phenyl-labeled fatty acids for the study of their metabolic degradation.

To this should be added the fact that, as shown by his peptide work, Schoenheimer was a skilled organic chemist (which Rittenberg was not) and could readily see how organic substances needed for metabolic studies might be labeled with deuterium. All these factors must be considered in relation to the origin of Schoenheimer’s insight into the problem. In my view, his mind was prepared, and he seized the opportunity to use deuterium as a label in metabolic studies when it was made available to him. Indeed, it may be that no other scientist then at Columbia, including Urey, Clarke, or Rittenberg, was so uniquely ready to do so.

The first papers from Schoenheimer’s laboratory on the isotope technique appeared in 1935. They described the methodology for generating deuterium gas from the “heavy” water supplied by Urey, for the catalytic hydrogenation of unsaturated compounds with deuterium, and for the purification of the water obtained by the combustion of organic material for deuterium analysis; these methods were considerably improved a few years later.

The first papers also described exploratory experiments on the metabolism of fatty acids and sterols. The most important initial finding was that when mice were fed linseed oil that had been partially hydrogenated with deuterium, the isotope appeared in the depot fats, whose amount had remained constant. This result indicated that the depot fats are not inert storage materials, mobilized only at times of starvation, but that they are involved in continuous metabolic processes.

The further study of fatty acid metabolism by means of the isotope technique, reported in subsequent papers, showed that some fatty acids are reversibly saturated and desaturated, and also undergo stepwise degradation in accord with Knoop’s β-oxidation theory. Of particular importance (and elegance) were experiments by Schoenheimer’s Ph.D. student DeWitt Stetten, Jr., reported in 1940. Rats were fed deuterium-labeled palmitic acid [CH3(CH2)14COOH], and several fatty acids were isolated from the fat tissues. Not only was the palmitic acid found to be heavily labeled, but so were its higher homologue stearic acid [CH3(CH2)16COOH] and its monounsaturated C16 derivative palmitoleic acid. The finding that the doubly unsaturated derivative linoleic acid was not labeled was in accord with its known requirement in the animal diet. Moreover, the C16 compound cetyl alcohol (mentioned above), obtained from the feces, also contained considerable isotope.

Another important set of experiments on the metabolism of fatty acids, reported in 1937 by Rittenberg and Schoenheimer, involved the injection of heavy water into groups of mice, whose drinking water also was labeled so as to maintain the deuterium content of the body fluids at a constant level. At various times some of the mice were killed, and the deuterium content of their fatty acids was determined. It rose steadily until a plateau was reached. From the rate at which the isotope was taken up, it could be estimated that the half-life of the fatty acids was five to nine days.

During the course of the experiments just mentioned, the body cholesterol was also isolated; its isotope content increased steadily, and a half-life of about twenty days was estimated. At the time these experiments were performed, little was known about the chemical steps in the biosynthesis of cholesterol, but the isotope data suggested that this process involves the condensation of many small molecules; this surmise was later shown to be correct. Schoenheimer’s continued interest in the problems of sterol metabolism that he had investigated in Germany is evident from the isotope experiments of his Ph.D. student Marjorie Anchel on the possible role of cholestenone and coprastanone in the conversion of dietary cholesterol to fecal coprosterol, as well as from the work in his Columbia laboratory on other aspects of the chemistry and metabolism of sterols.

By 1937, Urey had succeeded in concentrating the stable nitrogen isotope of mass 15 (N15) by a chemical exchange reaction, and some of it (in the form of ammonium salts) was made available to Schoenheimer for studies on protein metabolism. In this research, Sarah Ratner, who had received her Ph.D. shortly before with Clarke, played a major role; Schoenheimer’s other collaborators, in addition to Rittenberg, included Goodwin LeBaron Foster and Albert Keston.

The first set of papers, published in 1939, dealt with methodology: the Kjeldahl procedure was used to convert organic nitrogen to ammonia, which was then oxidized to nitrogen gas (N2) with alkaline hypochlorite. A mass spectrometer was constructed that allowed the separation of molecules of mass 29 (N14N15) from nitrogen of mass 28. Since N15 is a naturally occurring isotope (0.37 atom percent), the data obtained by mass-spectrometric analysis were expressed in terms of “atom percent excess” of N15 Methods were described for the synthesis of amino acids labeled with N15; except for glycine, the procedure involved the catalytic hydrogenation of the corresponding α-keto acid in the presence of N15-ammonia (a reaction introduced by Knoop and Oesterlin in 1927). The products were racemic (DL) amino acids, and some of them were resolved into the L-form (present in proteins) and its enantiomeric D-isomer.

Exploratory experiments also were reported on the administration of N15-labeled ammonium citrate to rats. Amino acids were isolated from hydrolysates of body proteins and, except for lysine, all of the amino acids contained significant amounts of the isotope. As in the studies on fatty acid metabolism with deuterium, this result indicated at once that the body proteins undergo continuous metabolic change. The finding that lysine was not labeled was consistent with its known requirement in the animal diet.

In succeeding papers, the results of feeding individual N15-labeled amino acids were reported. Of special significance were experiments in which L-leucine labeled with N15 in its α-amino group and deuterium in its carbon chain was used., and amino acids were isolated from the proteins of various tissues (liver, intestinal wall, and others). It was found that the a-amino nitrogen of leucine had been transferred to other amino acids (not lysine); this discovery clearly indicated that the body proteins undergo continuous breakdown and regeneration. The finding also disproved the widely accepted theory of Otto Folin, who had proposed that, in the animal body, protein breakdown is of two kinds: a variable (exogenous) metabolism that yields chiefly urea and no creatinine, and a constant (endogenous) metabolism that leads to the excretion of creatinine and uric acid. According to this concept, most of the dietary N15 should have appeared in the urine, but the isotope data showed that more than two-thirds of the leucine-nitrogen had been retained in the tissues.

Further studies in Schoenheimer’s laboratory on the metabolic utilization of individual amino acids gave valuable information about the chemical reactions they undergo in the animal body. Evidence was provided for the importance of enzyme-catalyzed transamination reactions, discovered a few years earlier by Aleksandr Evseevich Braunstein, and for the role of arginine and ornithine in the biosynthesis of urea, elucidated in 1932 by Hans Adolf Krebs. Moreover, it was shown that phenylalanine is converted directly into tyrosine, and that ornithine is a metabolic precursor of proline and glutamic acid. Also, in the study of the metabolism of the muscle constituent creatine, the isotope data supported the suggestion offered in 1926 by Bergmann and Zervas. On the basis of purely chemical data, that the metabolic synthesis of creatine involves the transfer of an amidine group (present in arginine) to glycine.

Some of Schoenheimer’s papers appeared post-humously. Among them was an important study conducted in collaboration with the immunologist Michael Heidelberger, showing that the administration of N15-labeled amino acids to actively immunized animals leads to the uptake of the isotope into antibodies, followed by a decline in N15-content; from their data a half-life of about two weeks was estimated for the antibodies. That antibodies are made only in the presence of an antigen was evident from the finding that mere injection of an antibody (passive immunity) did not lead to its uptake of isotopic nitrogen. Other posthumous publications dealt with the utilization of N15-labeled purines and pyrimidines into nucleic acids.

In the background of Schoenheimer’s isotope studies were hypotheses in the biochemical literature about the chemical steps in the metabolic conversion of body constituents. That he first chose fatty acids for investigation is understandable, not only because in 1933 deuterium was the only isotope available for labeling studies, but also because he had extensive experience in the lipid field. In his studies on protein metabolism, in particular the intermediary metabolism of individual amino acids, he recognized the opportunity to test numerous hypotheses about their synthesis and degradation, as well as about the mode of the formation of the end products of their metabolism, such as urea and creatinine.

It should be noted that the most important general concept to emerge from Schoenheimer’s work with N15, that of the dynamic state of the cellular proteins, was questioned in 1955 by Jacques Monod, who suggested that protein degradation occurs only in dead cells. This conclusion was based on his studies with bacteria, but subsequent work by Joel Mandelstam showed that both the breakdown and the synthesis of proteins occur in living bacteria.

After World War II, radioactive isotopes (C14, P32, S35) became available for biochemical research. Because of their greater utility for metabolic studies, compared with the stable isotopes used by Schoenheimer, they became the tracers of choice in the exploration of the pathways of intermediary metabolism, and between 1950 and 1970 there was a flood of publications that illuminated the details of many metabolic conversions.7 Especially notable among these achievements were those of two men who had worked in the Columbia department of biological chemistry: Konrad Bloch, in the elucidation of the pathway for the biosynthesis of cholesterol, and David Shemin, in tracing the route of the biosynthesis of the porphyrins. Thus, Schoen-heimer not only pioneered in the isotope technique but also left behind a progeny imbued with his organic-chemical approach to the study of biological processes.

Schoenheimer took his own life by the ingestion of potassium cyanide.

NOTES

1. Karl Thomas, “Fifty Years of Biochemistry in Germany,” in Annual Review of Biochemistry, 23 (1954), 1-16.

2. Joseph S. Fruton, “The Carbobenzoxy Method of Peptide Synthesis,” in Trends in Biochemical Sciences, 7 (1982), 37-39.

3. Hans T. Clarke, “Impressions of an Organic Chemist in Biochemistry” in Annual Review of Biochemistry, 27 (1958), 1-14.

4. Robert E. Kohler, Jr..“Rudolf Schoenheimer. Isotopic Tracers, and Biochemistry in the 1930’s” in Historical Studies in the Physical Sciences, 8 (1977), 257-298.

5. According to Clarke (op. cit., p. 5), this came about as a consequence of a conversation between Rittenberg and Schoenheimer. As Kohler (op. cit., p. 274) describes it. “Rittenberg’s overture to Schoenheimer in the summer or fall of 1934 struck sparks because Schoenheimer had a pressing problem that the use of deuterated compounds could solve.” This account is at variance with my recollection of the convenations I had with Schoenheimer during 1933 (I was one of Clarke’s graduate students from June 1931 to May 1934), when he told me one evening that earlier in the day he had visited Urey to discuss the possible use of deuterium for his metabolic studies. Perhaps Clarke did not know of this visit, or had forgotten about it. Kohler (op, cit., pp. 275-276) offers as “direct evidence” for his interpretation of the origins of Schoenheimer’s insight a report submitted in 1938 by Clarke to Warren Weaver of the Rockefeller Foundation; Kohler considers the report to have been “obviously written by Schoenheimer,” but no “direct evidence” is provided for this conclusion.

6. George Hevesy, “Historical Sketch of the Biological Application of Tracer Elements,” in Cold Spring Harbor Symposia on Quantitative Biology, 13 (1948), 129-150.

7. Marcel Florkin and Elmer H. Stotz, eds.. Comprehensive Biochemistry, sec. 6, A History of Biochemistry, pi. V. The Unravelling of Biosynthetic Pathways. 2 vols. (Amsterdam, 1979).

BIBLIOGRAPHY

I. Original Works. Sehoenheimer’s only book, The Dynamic State of Body Constituents (Cambridge, Mass., 1941; 2nd ed., 1946), appeared posthumously; it was based on the Edward K. Dunham Lectures for the Promotion of the Medical Sciences at Harvard University. The lectures had been drafted by Schoenheimer and delivered by Hans Clarke, who prepared them for publication with the assistance of David Rittenberg and Sarah Ratner.

A nearly complete list of Schoenheimer’s journal articles is in Poggendorff, VI, 2355-2356, and VIIA, pt. 4, 225-226. Among them are “Ein Beitrag zur Bereitung der Peptiden,” in Hoppe-Seyler’s Zeitschriftfür physkridgisehe Chemie, 154 (1926), 203-224; New Contributions in Sterol Metabolism, in Science, 74 (1931), 579-584; “Synthesis and Destruction of Cholesterol in the Organism,” in Journal of Biological Chemistry, 103 (1933), 439-448, written with Fritz Breusch; “Deuterium as an Indicator in the Study of Intermediary Metabolism,” I-VI and XI, ibid.. III (1935), 163-192, 113 (1936), 505-510, 114 (1936), 381-36, and 121 (1937), 235-253, written with David Rittenberg, pt. IV also written with M. Graff; “Studies in Protein Metabolism, X, The Metabolic Activity of Body Proteins Investigated with l (-)-Leucine Containing Two Isotopes,” ibid., 130 (1939), 703-732, written with Sarah Ratner and David Rittenberg; “The Conversion of Palmitic Acid into Stearic Acid and Palmitoleic Acids in Rats,” ibid., 133 (1940), 329-345, written with Dewitt Stetten, Jr.; and “The Biological Precursors of Creatine,” ibid., 138 (1941), 167-194, written with Konrad Bloch.

II. Secondary Literature. Obituary notices are by Hans T. Clarke, in Science, 94 (1941), 553-554; and J. H. Quastel, in Nature, 149 (1942), 15-16. Other biographical writings include Aaron J. Ihde, in Dictionary of American Biography, supp. 3, 693-694; Robert E. Kohier. Jr. (see note 4); David Nachmanson, German-Jewish Pioneers in Science (New York, 1979), 357-360; Urs Peyer, Rudolf Schoenheimer (1898-1941) und der Beginn der Tracer-Technik bet Stoffwechselttntersuchungen (Zurich, 1972), with an English summary; and Dewitt Stetten, Jr., “Rudi, in Perspectives in Biology and Medicine, 25 (1982), 354-368.

Joseph S. Fruton

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