Neuberg, Carl Alexander
NEUBERG, CARL ALEXANDER
chemistry, biochemistry, dynamic biochemistry.
Neuberg, a German-Jewish pioneer in dynamic biochemistry, gained international recognition through his elucidation of the biochemical reactions of alcoholic fermentation in which he discovered a number of different enzymes such as carboxylase and of intermediates such as fructose-6-phosphate (Neuberg ester). In 1906 Neuberg founded Biochemische Zeitschrift, the second journal of the young discipline of biochemistry, and he also became the founding director of the Kaiser-Wilhelm-Institut für Biochemie (Kaiser Wilhelm Institute of Biochemistry) in Berlin in 1925. In 1934 he was forced out of his position by Nazi legislation. After emigrating from Germany in 1939, he tried unsuccessfully to find appropriate working conditions in various other countries. In 1941 he found refuge in the United States, where he was able to conduct research in unpaid academic positions, earning his money as a consultant to industry.
Early Life and Career Carl Neuberg was the first child of Julius Sandel Neuberg, a Jewish cloth and leather merchant in Hanover, and his wife Alma Niemann; he had two younger sisters. In 1892 the family moved to Berlin, where Carl Neuberg attended a humanistisches Gymnasium (high school with focus on the classical languages) in Berlin and graduated with distinction in March 1896.
Neuberg then studied chemistry in Berlin and Würzburg and at the Technische Hochschule (Technical University) in Charlottenburg. In addition to his chemical studies, he attended courses in mathematics, philosophy, and physics. Conducting experiments for his doctoral thesis at Emil Fischer’s Institute of Chemistry at the University of Berlin under the supervision of Alfred Wohl, Neuberg obtained his PhD in 1900. Emil Fischer, Nobel laureate in chemistry of 1902, was one of most prominent organic chemists of his time, with pathbreaking work in, among other things, the chemistry of proteins and carbohydrates. He was known for stressing exact experimentation. Alfred Wohl, a specialist in carbohydrate chemistry, directed Neuberg’s interest to the chemistry of organic compounds containing three carbon atoms. The first part of Neuberg’s thesis dealt mainly with two of these compounds, acrolein and glycerinaldehyde, the latter substance playing a major role in Neuberg’s wartime research 14 years later. The two other parts of his thesis, researched with the analytical correctness required of Emil Fischer’s students, consisted of the application of analytical methods to characterize esters of boric acid and the purification of osazone.
In 1899, before finishing his dissertation, Neuberg was appointed a chemical assistant at the Pathological Institute of the university hospital “Charité” in Berlin. The institute was founded in 1856 and from 1893 to 1902 headed by Rudolf Virchow. Neuberg worked in the institute’s chemical department under Ernst Salkowski, a clinical analytical chemist, and was responsible for teaching medical students various aspects of physiological chemistry. In 1903 Neuberg became a Privatdozent (private lecturer) at the University of Berlin. There, in 1906 at the age of twenty-eight, he was appointed an außerplanmäßiger, or extraordinary professor, which meant he had the right to teach at a university but had no paid permanent position. When he left the Charité in 1909, Neuberg had published around 120 papers, mostly concerning carbohydrate and fatty acid chemistry, but also on the characterization of alcohol, aldehyde, and ketone reactions. He had also completed some studies on the chemistry of malignant tumors.
As a Jewish scientist, however, his chances of appointment to one of the few full professorships in physiological chemistry in Germany were nearly nonexistent. Therefore, Neuberg, despite his ambition and growing reputation in the field, accepted in 1909 the offer of the physiologist Nathan Zuntz, the director of the Institut für Tierphysiologie (Institute of Animal Physiology) at the Landwirtschaftliche Hochschule Berlin (Agricultural College in Berlin). Zuntz wanted Neuberg to become head of the institute’s chemical department.
In 1911 Neuberg edited a comprehensive volume titled Der Harn sowie die übrigen Ausscheidungen und Körperflüssigkeiten von Mensch und Tier (Urine as well as other excretions and bodily fluids in man and animal), which soon became a standard work in analytical medical chemistry, published by Julius Springer’s publishing house. The majority of its contributors were, like Neuberg, Jewish university teachers in Berlin, among them Wilhelm Caspari, Ludwig Halberstaedter, Adolf Loewy, Julius Morgen-roth, Artur Pappenheim, and Carl Posner.
When August Wassermann was appointed director of the newly founded Kaiser-Wilhelm-Institut für experimentelle Therapie (Kaiser Wilhelm Institute for Experimental Therapy) in Berlin in 1913, Neuberg became head of the institute’s chemical department, a position in which he remained until Wassermann’s death in 1925. Early on, the Kaiser-Wilhelm-Gesellschaft (Kaiser Wilhelm Society) made efforts to establish an Institut für Biochemie (Institute for Biochemistry) for Neuberg. In 1917 a preliminary institute was founded with Neuberg officially as director; it remained, however, affiliated to Wassermann’s institute. The plans for a new building seemed to materialize only when through Neuberg’s connections the Goldenberg-Oetker-Stiftung, a foundation, donated two million Reichmark in 1919. The money was given to the Kaiser Wilhelm Society for the establishment of a Kaiser Wilhelm Institute for Biochemistry, which they did in 1920. But the donated money lost its value through the great inflation in the early 1920s, and so the building could not be constructed. Neuberg had to wait until Wassermann’s death before he became the director of his own Kaiser Wilhelm Institute for Biochemistry in the old building of the Institute of Experimental Therapy. He also became provisional head of the rest of that institute, a small department of immunochemistry that was closed down in 1936.
Family and Values . Carl Neuberg was deeply rooted in German culture. He was strongly attached to imperial Germany and especially loyal to Kaiser Wilhelm II, whom he met during the inauguration ceremony of the Kaiser Wilhelm Institute for Experimental Therapy. A photograph of this meeting hung above his desk even during his exile in New York much later. This loyalty, however, did not bring him into conflict with his Jewishness. Despite his strong assimilation to German culture and politics, he was proud of the high esteem in which intellectual and ethical values were held in Jewish tradition, and he was well versed in the Bible and Jewish history and was fluent in Latin, Greek, and Hebrew. He would not convert to Christianity for opportunistic reasons, such as having a better chance to receive a professorship. Neuberg became a member of the Central-Verein deutscher Staatsbürger jüdischen Glaubens (Central Association of German Citizens of Jewish Faith), founded in 1893 in response to anti-Semitism in Germany. The association fought for full citizenship rights of German Jews.
In 1907 Neuberg married Helene “Hela” Lewinski. They had two daughters, Irene and Marianne. Hela died from leukemia in 1929. Their elder daughter Irene studied biochemistry, conducted her graduate studies in her father’s laboratory and at the Institut Pasteur in Paris, and received her PhD from the University of Berlin in 1932. After 1933 Irene and Marianne emigrated and eventually settled in the United States, where Irene first lived in New York and later moved to California.
Research on Fermentation Neuberg’s most brilliant and lasting achievements were in the biochemistry of alcoholic fermentation. By the mid-nineteenth century, it was widely accepted that alcoholic fermentation and other fermentations were catalyzed by living organisms, such as yeast. However, there remained a bitter dispute about the mechanism underlying fermentation, which was finally resolved in 1897 by the chemist Eduard Buchner. Buchner demonstrated that, contrary to a widespread assumption shared by Louis Pasteur, alcoholic fermentation was not dependent on whole yeast cells but took place also in cell-free extracts from yeast. Buchner concluded that these extracts contain a fermentation enzyme, zymase, and that fermentation is a purely chemical process. This discovery, for which Buchner was awarded the Nobel Prize in Chemistry in 1907, marks the beginning of biochemical research on enzymes and a new approach to studies on alcoholic fermentation. Subsequently Neuberg was among the first to examine and clarify the metabolic complexity hidden behind Buchner’s zymase.
Around 1910, the elucidation of intermediate biochemical pathways in cells began with biochemical studies on the degradation of sugar, glycolysis, and fermentation. In the process of glycolysis, glucose—containing six carbon atoms—is degraded to pyruvate, containing three carbon atoms. In alcoholic fermentation, which occurs in the absence of oxygen, sugar is degraded via pyruvate to carbon dioxide (containing one carbon atom) and alcohol (ethanol, containing two carbon atoms). Given his expertise in the field of three-carbon-compounds, Neuberg was able to pioneer studies on the elucidation of both glycolysis and alcoholic fermentation, by creating chemical methods to examine steps and compounds of metabolic pathways and by shedding light on the sequence of reactions leading to alcoholic fermentation.
In 1911 he reported, at a meeting of the Deutsche Physiologische Gesellschaft (German Physiological Society), that contrary to a widespread assumption, yeast was able to ferment pyruvate in the presence of hydrogen peroxide and iron salts. He thus confirmed a suggestion by Otto Neubauer and Konrad Fromherz that pyruvate might be an intermediate in ethanolic fermentation. Neuberg showed that pyruvate is decarboxylated into carbon dioxide and acetaldehyde, which is then further reduced to ethanol. These results for the first time showed a splitting up of the reactions of sugar degradation into different steps and proved wrong the mode of action Eduard Buchner had suggested for his zymase; Buchner thought that a single enzyme would catalyze the whole sugar degradation process. Neuberg and his colleague Lázló Karczag recommended in 1911 that the enzyme they had discovered, catalyzing the process of pyruvate oxidation, be named carboxylase.
Following a suggestion of Alfred Wohl that a pathway be found which would arrange these intermediates, Neuberg in 1913 developed his first fermentation diagram (Neuberg schema). He wrote it as a working hypothesis for the first edition of the textbook Handbuch der Biochemie des Menschen und der Tiere (Manual of Biochemistry of Men and Animals) published by the Gustav Fischer Verlag and edited by Carl Oppenheimer. In his diagram, which Neuberg spread in advance of publication among his colleagues as a preprint of his chapter in the book, he suggested the production of pyruvate and glycerol through degradation of a hexose (a sugar containing six carbon atoms, as in glucose) through intermediate steps. The fermentation diagram was generally accepted by the scientific community. The fact that later research revealed some flaws, such as the assumption of methylglyoxal as an intermediate, did not depreciate the general value of the scheme as the first biochemical sequence showing the degradation of a sugar to alcohol in a certain specific stepwise order.
Neuberg’s discovery of the production of glycerol by fermentation and his introduction of a new method into fermentation analysis, the trapping method, turned out to be of great importance for industry and the military. When he tested the addition of sodium bisulfite on pyruvate degradation, Neuberg found a considerable amount of glycerol emerging besides acetaldehyde and carbon dioxide. The removal of acetaldehyde by bisulfite affects the chemical equilibrium of the reaction chain and thus promotes the formation of glycerol derivatives. This method became known as the acetaldeyde trapping method. It enabled Neuberg to elucidate steps of alcoholic fermentation, interpreting the results—as it turned out, correctly—as a question of available hydrogen acceptors. The method also allowed the production of the glycerol substitutes perglycerine and perkaglycerine.
Wilhelm Connstein and Karl Lüdecke modified the trapping method for industrial use in glycerol production. It is an example of the impact of basic chemical research on industrial chemistry. The process provided a nearly unlimited source of glycerol derivatives during World War I in Germany, when shortages of fatty acids stopped common glycerol production at the same time that large amounts of it were needed to produce nitroglycerine for explosives, brake fluids, and other lubricants for military use. Using Neuberg, Connstein, and Lüdecke’s method of production, several hundred tons of glycerol were produced by three different chemical companies in Germany during the war; because of the war, however, the researchers did not publish their method until 1918.
The relationship of Neuberg’s work with the chemical industry affected Neuberg’s life in two different ways. First, during World War I, he was asked to carry out frontline inspections in order to examine the properties of the brake fluids produced by his method. For his some seven missions he received the status of combatant, which later, when the Nazis came to power, enabled him to avoid being dismissed as a Jew in 1933. Second, one of the three chemical companies producing glycerol, Goldenberg, Geromont, and Company, was headed by a second cousin of Neuberg. After World War I, the Goldenberg-OetkerStiftung, a joint foundation of that company and the industrialist Dr. August Oetker, donated the profits of glycerol production, two million Reichmark, to the Kaiser Wilhelm Society. As was mentioned above, this donation obliged the society to found a new Kaiser Wilhelm Institute for Biochemistry, headed by Neuberg.
Neuberg’s war service did not prevent him from continuing his work on fermentation during the war. He tested chemically synthesized three- and four-carbon-compounds as a starting point for fermentations and found many of them underwent fermentation with different end-products. He set up two more diagrams of fermentation, first for the degradation of sugar into certain amounts of alcohol, acetic acid, glycerol, and carbon dioxide, and second, for the degradation of sugar under different conditions into equal amounts of pyruvate and glycerol. In 1918 he succeeded in preparing a hexose-monophosphate that was later found to be fructose-6-phosphate as an intermediate of fermentation. Fructose-6-phosphate was subsequently named Neuberg ester. Like the discoveries of fructose-biphosphate by Arthur Harden and William John Young and glucose-6-phosphate by Robert Robison, Neuberg’s discovery was of great biochemical importance because it unraveled a further component of the glycolysis, the glucose degradation pathway. In addition to carboxylase, Neuberg discovered a number of other enzymes. Later he studied reduction processes of various sugars in plants.
Neuberg’s discovery of carboxylase and his fermentation diagram became the basis for understanding the biochemical processes of alcoholic fermentation. They marked a turning point in the history of biochemistry and had a profound impact on its development. They motivated many biochemists, who would otherwise have continued work on the isolation and investigation of cell constituents, to shift their focus to the elucidation of metabolic pathways and to isolating and characterizing the enzymes responsible for the reactions.
Biochemische Zeitschrift (Biochemical Journal) . By October 1906, Carl Neuberg had completed his editing of the papers that appeared in the first volume of his newly founded journal, Biochemische Zeitschrift, published with the Julius Springer publishing house. By choosing this title, he became one of the first researchers in Germany to use the term Biochemie instead of Physiologische Chemie. The plans for a new journal of biochemistry—around thirty years after Zeitschrift für Physiologische Chemie was founded by Felix Hoppe-Seyler—had already been made two years earlier. Neuberg and Ferdinand Springer, head of the Springer publishing house, had convinced five well-known biochemists (at the time usually called physiological chemists)—among them Eduard Buchner (Nobel Prize in Chemistry, 1907), Paul Ehrlich (Nobel Prize in Physiology or Medicine, 1908) and Nathan Zuntz—to serve as editors of the first edition. Their names on the cover of the journal were followed by Neuberg’s as the acting editor and those of forty-one scientists from twelve countries as contributors. During the following years, the Biochemische Zeitschrift gained a high international reputation among biochemists and was one of the publisher’s best-selling journals. As was true with some other journals at the time, Neuberg as the acting editor (despite being only at the beginning of his career) decided by himself which articles would be published. Helped by his wife, Helene, he edited over 8,500 articles in 230 volumes of his journal until 1930.
In 1933, after the Nazis came to power, Wolfgang Grassmann, a student of Richard Willstätter's, became co-editor of the journal. When Neuberg was dismissed by the Kaiser Wilhelm Society in 1934, Grassmann became its sole editor and Neuberg’s name no longer appeared on the title page. After the war, Neuberg’s name was reinstated. Interestingly, the dates of his period as sole editor, were wrongly stated to end in 1932 instead of 1933, implying that he left before the dismissal of Jewish scientists by Nazi laws.
Dismissal and Emigration . In accordance with a Nazi civil service law, almost all Jewish scientists were dismissed from universities in April 1933 and, shortly after, from the Kaiser Wilhelm Institutes, Neuberg was still exempted from dismissal because of his combatant status in World War I. However, when in 1934 a Nazi mechanic at the institute whom Neuberg had tried to dismiss because of his disturbing political activities, denounced Neuberg for defaming Adolf Hitler as behaving like an “Elefant im Porzellanladen” (a bull in a china shop), the Kaiser Wilhelm Society forced Neuberg to retire. Neuberg remained provisional head until his successor, Adolf Butenandt, was appointed in May 1936. Neuberg was not allowed to continue his work at the Kaiser Wilhelm Institute, but he found work at the private laboratory of a bread factory in Berlin. The reasons why he remained in Germany although both his daughters were already living in the United States are unclear.
Neuberg fled to the Netherlands in August 1939 just a month before World War II began. After an odyssey of one and a half years, during which he spent three months at the University of Amsterdam and eight months at the Hebrew University in Jerusalem and traveled to the United States via Iraq, Iran, India, and New Guinea, Neuberg arrived in New York City in February 1941. He became affiliated for a short while with the Brooklyn Polytechnic Institute and the New York Medical College, and later on worked as a consultant to industry. Neuberg resumed contact with a number of his former colleagues in Germany. But in spite of spending some time as guest researcher at the Technical University of Munich in 1952, he refused to accept an invitation to return as researcher on a long-term basis to the Max Planck Institute for Biochemistry in Tübingen.
Neuberg was a prolific writer. He published around nine hundred papers and wrote six books. The many honors he received included his fellowships of the academies of science in Göttingen in Germany, Copenhagen in Denmark, Leningrad in the Soviet Union, and New York, along with his eight honorary doctorates, the Emil Fischer Medal of the Gesellschaft Deutscher Chemiker (German Chemical Society), and the Carl Neuberg Medal of the New York Academy of Sciences. He died of pneumonia on 30 May 1956 in New York at the age of seventy-eight.
Carl Neuberg was one of the greatest biochemists of his generation. By elucidating basic compounds of sugar degradation and alcoholic fermentation, he became a pioneer of research in intermediate metabolism. In addition, the methods that he developed remained important in biochemistry for decades. Neuberg, together with the Nobel laureates Otto Warburg and Otto Meyerhof, made Germany the international leader in biochemistry before the Nazis came to power.
Neuberg’s papers are in the American Philosophical Society in Philadelphia.
WORKS BY NEUBERG
“Die Kohlenhydrate.” In: Handbuch der Biochemie des Menschen und der Tiere, edited by Carl Oppenheimer. Vol. 1. Jena, Germany: Fischer, 1909: 159–225.
Der Harn sowie die übrigen Ausscheidungen und Körperflüssigkeiten von Mensch und Tier. Edited by Carl Neuberg. Berlin, Germany: Julius Springer, 1911.
With Lázló Karczag. “Über zuckerfreie Hefegärungen. IV. Carboxylase, ein neues Enzym der Hefe.” Biochemische Zeitschrift 36 (1911): 68–75.
“Die Gärungsvorgänge und der Zuckerumsatz der Zelle.” In Handbuch der Biochemie des Menschen und der Tiere, extension of Vol. 1, edited by Carl Oppenheimer. Jena, Germany: Fischer, 1913.
With E. Reinfurth. “Natürliche und erzwungene Glycerinbildung bei der alkoholischen Gärung.” Biochemische Zeitschrift 92 (1918): 234–266.
Auhagen, Ernst. “Carl Neuberg.” Biochemische Zeitschrift 328 (1956): 322–324.
Barnett, James A. “A History of Research on Yeasts 5: The Fermentation Pathway.” Yeast20 (2003): 509–543.
Björk, Ragnar. “Inside the Nobel Committee on Medicine: Prize Competition Procedures 1901–1950 and the Fate of Carl Neuberg.” Minerva 39 (2001): 393–408.
Conrads, Hinderk, and Brigitte Lohff. Carl Neuberg—Biochemie, Politik und Geschichte: Lebenswege und Werk eines fast verdrängten Forschers. Geschichte und Philosophie der Medizin. Stuttgart, Germany: Franz Steiner Verlag, 2006.
Engel, Michael. “Enzymologie und Gärungschemie: Alfred Wohls und Carl Neubergs Reaktionschemata der alkoholischen Gärung. Der ‘chemische Gesichtspunkt’ als Kennzeichen der Berliner Schule.” Mitteilungen der Fachgruppe für Geschichte der Chemie der Gesellschaft deutscher Chemiker 12 (1996): 3–29.
Gottschalk, Alfred. “Prof. Carl Neuberg.” Nature178, no. 4536 (6 October 1956): 722–723.
Nachmansohn, David. German-Jewish Pioneers in Science, 1900–1933: Highlights in Atomic Physics, Chemistry, and Biochemistry. Berlin, Germany: Springer-Verlag, 1979.
Nord, F. F. “Carl Neuberg, 1877–1956.” Advances in Carbohydrate Chemistry 13 (1958): 1–7.