LEDERER, EDGAR

(b. Vienna, Austria, 5 June 1908; d. Sceaux, near Paris, 19 October 1988),

chemistry of natural products, biochemistry, immunology.

Lederer was one of France’s leading mid- and late-twentieth-century chemists and biochemists. He left his mark on the chemistry of natural products (plant and animal pigments and odorants) and saw to a rebirth of chromatography as a tool for microanalysis. His elucidation of the structure and role of lipids and peptidolipids from mycobacteria led to the discovery of novel immunostimulants.

Early Life and Turmoil . The turmoil of the twentieth century did not spare Edgar Lederer and his family. Fleeing anti-Semitism in his native Vienna, he went in 1930 to Heidelberg, Germany. He had to leave Germany in a rush when the Nazis came to power in 1933. A refugee in Paris, he accepted a call to work in Leningrad. His stay there, too, was curtailed by the Stalinist purges. He was unaware to some extent of the magnitude of the danger, but his wife was politically more critical, and her good advice prevailed. Lederer returned to France—only to be drafted as a soldier in the so-called Phony War, and to be subsequently hounded as a Jew by the Vichy police and by the fascist thugs of the Milice. Only at age thirty-six could he resume his scientific work in relative peace.

Regardless of the turbulence of his life, Lederer was always dapper, with the appearance and demeanor of a British gentleman. Tall and bony, he seemed devoid of muscle and fat. His blue-eyed face, somewhat equine and crowned with blond hair, had a kind look. Furthering the impression of Britishness was the fact that English was his first language; he learned it from his English nurse. A polyglot, he also spoke and wrote German, French, Russian, and Italian.

Lederer came from a Jewish family in Vienna. His father was a business attorney. His mother, highly cultured, taught him French. The influence of his maternal uncles, Hans Przibram, a biologist, and Karl Przibram, a physicist, together with that of his natural history teacher in the gymnasium, caused him to opt for the sciences. At the University of Vienna he went on to receive his PhD in 1930 after two years in Ernst Späth’s laboratory, working on the synthesis of indole alkaloids. Meanwhile, he began lifelong friendships with fellow students Erwin Chargaff and Percy Lavon Julian, who went on to distinguished careers in the United States. After he had obtained his PhD degree, his advisor told him bluntly that he had to leave the university. His being Jewish precluded any university appointment, even as a research assistant. Anti-Semitism in Austria was indeed virulent.

The Rediscovery of Chromatography . Compared to Austria, Germany seemed more lenient. In September 1930 Lederer joined Richard Kuhn’s group at the Kaiser Wilhelm Institut für Medizinische Forschung (Kaiser Wilhelm Institute for Medical Research) in Heidelberg. As a postdoctoral fellow in Kuhn’s laboratory, Lederer applied himself to clarifying the structure of vitamin A. His first results contradicted the structure proposed by Paul Karrer. In early 1931 he isolated two isomers, alpha- and beta-carotene. Two years later, he discovered a third isomer, gamma-carotene.

In doing this work, Kuhn and Lederer rediscovered partition chromatography; Michael Tswett, a botanist, described it in a book published in 1906 in Warsaw. The method of chemical separation fell into disrepute among chemists, however, especially after Richard Willstätter was unable to purify chlorophyll with it. Ironically, when in 1930 Kuhn was struggling with impure polyene pigments, Willstätter sent him a German translation of Tswett’s book. Kuhn assigned Lederer the task of purifying carotene using Tswett’s methodology. Lederer made significant technical changes, especially in regard to adsorbent materials. Kuhn and Lederer then were also able to isolate and purify a large number of carotenoids, such as astaxan-thin, which gives lobsters and shrimps their orange-red color when cooked.

While in Heidelberg, Lederer met two people who would become important in his life and career. Hélène Fréchet was the daughter of a French mathematician and a professor at the Sorbonne. She married Lederer in June 1932. André Lwoff, who would win the Nobel Prize in Physiology or Medicine in 1965, was working in the laboratory of Otto Meyerhof, who had won that prize in 1922. Lwoff would remain a lifelong friend.

Two Dangerous Decades . In March 1933, two months after the Nazis came to power, the Lederers precipitously left for Paris. Lederer—already having two children—had to support his family. He was helped by Harry Plotz, a Boston banker, medical doctor, and philanthropist and was able to find a small laboratory on rue Pierre-Curie. In 1935, Caisse de la recherche scientifique (the then-existing Fund for Scientific Research) gave him a small grant to investigate the polio virus. He then moved into a nearby laboratory in the Institut de biologie physicochimique, otherwise known as Fondation Edmond de Rothschild.

Because of his need for a greater income and his strong Communist convictions, Lederer approached the Soviet scientific attaché in Paris in 1935. He was offered and accepted a fellowship in the Vitamins Institute in Leningrad. He left for the Soviet Union with his family in October 1935 with a three-year contract. After only two years, with the Moscow trials and the Stalinist purges in full gear, the Lederers hurried back to France in December 1937.

The seed for the Centre national de la recherche scientifique (National Center for Scientific Research), known as CNRS, had been sown in the 1920s with the Caisse nationale des sciences (National Fund for the Sciences), started by Jean Perrin with funding by Baron Edmond de Rothschild. The French Popular Front government of 1936–1937, comprising the Nobel Prize–winners Irène Joliot-Curie and Jean Perrin, with its socialist belief in science for the common good, greatly increased funding for Caisse nationale des sciences, which would become CNRS in 1939, with an initial budget of one million francs. Its aim, not unlike that of the Kaiser Wilhelm Society in Germany (later known as the Max Planck Society), was to launch institutes in promising disciplines neglected by French universities. As a side effect, a significant one in the wake of World War II, CNRS offered a shelter to foreign scientists, often persons displaced from their countries by the war who lacked the credentials for a university career in France. In later years, Lederer would welcome numerous such refugees in the two institutes he headed.

In January 1938, Lederer returned to the Institut de biologie physico-chimique. In April, having started to write his dissertation in Russian, then translating it into French and completing it, he was awarded his French doctorate in the sciences. The dissertation presented his work on a dozen carotenoid pigments of invertebrates and plants which he had isolated and characterized while in Leningrad. He became a French citizen in December 1938. Soon afterward, he was drafted as a private into an artillery regiment. At the start of World War II, French cannons were still drawn by horses. Lederer was in charge of taking care of the animals and cleaning their stables. After the French capitulation in 1940, he resumed his work at CNRS as a hired attaché de recherches (research assistant). Then, Claude Fromageot, a professor of biochemistry in Lyon, helped by getting him promoted from attaché to chargé de recherches (group leader) and transferred to his laboratory. Lederer was fired from CNRS in 1941 because of the Vichy laws against Jews. He would be reintegrated only in the spring of 1944, because the Vichy authorities realized that the war tide was turning and on the basis of his having a French wife, and hence an Aryan family.

Meanwhile, the war years were filled with threats for the Lederers and their four children. They lived near Lyon until 1947. Toward the end of the war, Lederer protected himself with a forged identification. He narrowly escaped an arrest by the Milice. On 25 May 1944, when Lyon was bombed, five persons were killed in Fromageot’s institute. Lederer was away in central France, where he had gone to find a shelter for his children.

Moves to Orsay, Gif . After France was liberated, Lederer continued work in Fromageot’s Lyon laboratory. Fromageot received a professorial appointment at the Sorbonne, and Lederer moved back to Paris and to the Rothschild Foundation in March 1947.

After Fromageot died in January 1958, Lederer succeeded him in his chair at the Sorbonne, as well as heading a large biochemical laboratory on Boulevard Raspail in Paris. Moreover, his high reputation granted him the building of a brand-new CNRS institute, to be devoted to the chemistry of natural products, in Gif-Sur-Yvette, a distant southern suburb of Paris. In December 1960, Lederer moved into this new building.

At that time he was contacted by a physicist, André Guinier, the dean of the new Faculté des sciences (Faculty of Sciences) that had opened in Orsay, also in the southern suburbs of Paris, rather close to Gif. Many of the professors in Orsay leaned toward the Left in politics, which was not the norm at the Sorbonne. Lederer thus all the more readily accepted the offer. In 1963 he was able to move his biochemistry staff from Paris to a new institute in Orsay.

Thus wearing several hats signals membership in the power elite. Lederer’s industrial contacts, on the one hand, gave him precious support during difficult times in the 1930s and early 1940s but, on the other hand, were frowned upon by the administrative officers at CNRS. Before the onset of World War II, he had been contacted by Max Roger, who directed the perfume factory Roure-Bertrand in Argenteuil, near Paris, and the Justin Dupont enterprise in Grasse, near the Riviera. Roger gave him funding for two coworkers together with a small amount

for Lederer himself. They were to work on animal ingredients for perfumes, such as whale ambergris and castoreum, derived from the scent gland of the Canadian beaver. Lederer showed that ambrein, a constituent of ambergris, is a triterpene with a squalene-based biosynthesis. Lederer also showed that most other ingredients of ambergris were oxidation products of ambrein.

Another source of funding that allowed Lederer to survive while cut off from CNRS during the war years was from Henri Pénau, the director of research of the Roussel Laboratories, near Paris. He contacted Lederer in 1942, offering a contract for the isolation of cholesterol from sheep wool, needed to replace imports from Argentina that the war had dried up.

Lederer’s work on ambergris came to the notice of Leopold Ruzicka at the Eidgenössiche Technische Hochschule (ETH) in Zürich. Ruzicka was a consultant to the Firmenich perfumery company in Geneva. In 1949 a collaboration began between Lederer and Firmenich, whose laboratories were headed by talented scientists, first Max Stoll and then Günther Ohloff. This collaboration included, besides natural products with an amber fragrance, the constituents of the essential oil of jasmine, the sesquiterpenes from that of bourbon geranium, and in subsequent years, the aroma of cocoa.

Research on Mycobacteria . Soon after his return to Paris in 1947, Lederer started work on mycobacteria. These are aerobic, rod-shaped germs (bacilli). The genus Mycobacterium includes the bacteria causing both tuberculosis and leprosy. Lederer perchance had met Dr. Nine Choucroun in Paris, who before the war had isolated from Mycobacterium tuberculosis, a complex lipidic fraction with interesting properties for the immunization of guinea pigs against tuberculosis, induction of delayed hypersensitivity, and so on. Lederer and his coworker, Jean Asselineau, began the study of the lipids from the cell wall of mycobacteria.

Tuberculosis was at that time still an endemic disease in western Europe. Half a century later, it still kills more than two million people per year worldwide. Antibiotics have to some extent muzzled Mycobacterium tuberculosis.

However, strains have become increasingly resistant to antibiotics.

Two French bacteriologists, Albert Calmette and Camille Guérin, after joining the Institut Pasteur in Paris in 1919, found a growth medium for the bacillus that made it less virulent. In so doing, they produced the BCG vaccine against tuberculosis, with which infants and children are inoculated in many countries.

Asselineau and Lederer established that mycolic acids are major and specific components of the cell envelope of mycobacteria, including M. tuberculosis. The cell wall skeleton of M. bovis bacillus Calmette-Guérin (BCGCWS), a purified noninfectious material, consists of peptidoglycan, arabinogalactan, and mycolic acids.

Having benefited in 1950 from a contract awarded by the Ciba pharmaceutical company in Basel for this line of research, which would be renewed over the next twenty years, Lederer subsequently studied the enzymes that are involved in the production of mycolic acids. Among these are the S-adenosylmethionine-dependent methyltransferases that catalyze the introduction of key chemical modifications in defined positions of mycolic acids. Some of these subtle structural variations are crucial for both the virulence of the tubercle bacillus and the permeability of the mycobacterial cell envelope.

Colonial morphology of pathogenic bacteria is often associated with virulence. For M. tuberculosis, the causative agent of tuberculosis, virulence is correlated with the formation of serpentine cords, a morphology that was first noted by Robert Koch.

Cord factor (trehalose 6,6’-dimycolate, TDM) is a unique glycolipid with a trehalose and two molecules of mycolic acids in the mycobacterial cell envelope. Since TDM consists of two molecules of very long branched-chain 3-hydroxy fatty acids, the molecular mass ranges widely and in a complex manner. Trehalose (alpha-D-glucopyranosyl-alpha’-D-glucopyranoside) is essential for the growth of the human pathogen M. tuberculosis but not for the viability of the phylogenetically related corynebacteria. To isolate and determine the structure of peptidolipids and glycopeptidolipids in mycobacteria and their relatives, nocardiae and corynebacteria would become Lederer’s major research target, not only until he retired but afterward, until death claimed him.

Opening up French Chemistry . At the time Lederer was elected at the Sorbonne, French chemistry was still reeling from the consequences of World War I, when promising young scientists died in the trenches. (The British and the Germans were smarter, bringing theirs back to laboratories.) With few exceptions, therefore, members of the ensuing generation received their university appointments without competition. Distant from the Anglo-Saxon mainstream—few knew any English—and ruled over by a few Parisian professors, a mandarinate which saw to it that its students were appointed to the few vacant positions, French chemistry closed in upon itself and thus became insular, provincial, and mediocre.

Lederer’s contribution was to bring fresh air and ideas, drawing upon his international network of friends and colleagues. During the 1960s, the weekly seminars at his Gif institute, together with Alain Horeau’s lectures at the Collège de France in Paris, were a source of renewal. The Institut de chimie des substances naturelles (Institute for Chemistry of Natural Products), under the joint directorship of Maurice-Marie Janot, a pharmacist, and Lederer, became one of the prize holdings of CNRS, at the leading edge of French chemistry.

In such positions of leadership he enjoyed in French chemistry and biochemistry, Lederer had several interrelated qualities: he was forward-looking and optimistic, he had an imaginative intuition, he had foresight. Just as he had pioneered chromatography in the early 1930s, he knew how to bank on both nuclear magnetic resonance and mass spectrometry in the early 1960s. He realized that these would become analytical tools important to chemists, and he invested in them early on.

Political and Social Activism . During his whole career, Lederer was a political activist of the Left. He lent his name and prestige to many petitions and international campaigns. Being a Communist sympathizer, albeit a critical one, did not endear him to the U.S. government. In 1951, when Lederer was denied a visa by the United States to receive a prize awarded by the American Chemical Society, it became a cause célèbre. In the late 1960s he became a member of the Russell Tribunal investigating war crimes by the United States in the Vietnam War. In 1967 he authored a report castigating the Pentagon for its use of chemical weapons in that war. Together with the

French Fields medalist Laurent Schwartz, who became a friend, Lederer also helped dissident scientists to emigrate from the Soviet Union.

Lederer’s political conscience went with an equally acute social conscience. He saw to it that quite a few of his coworkers, recruited as technicians from low-status families, progressed and received their degrees, whether as engineers or as doctorate-holding scientists, with the attendant salary and status. He prided himself on facilitating this type of social advancement within the rather rigid French class system.

In the late 1960s, while on a visit to America after the State Department granted him a visa (following many years of denial because of his Communist sympathies), he visited this author’s home in Princeton, New Jersey. After dinner, we sat in the garden to chat. It was summer. There were fireflies about, which he had never seen before. Out of the corner of his eyes, Lederer watched them. He then remarked that they flashed only in upward flight. This was typical of his keen sense of observation. In this respect, he belonged to the grand tradition of natural historians, while practicing biochemistry and molecular biology in the modern manner.

Later Work . His retirement in 1978 from the directorship of the institute in Gif did not end his scientific career, to which he continued to apply himself with his usual zest and dynamism. About forty-five post-1978 publications bear his name. After his “retirement,” this organic chemist and biochemist taught himself immunology.

The study of mycobacteria rewarded his attention with a bounty of results with much pharmacological promise. Lederer found that the already-mentioned cord factors, consisting of esters of mycolic acids and sugars such as trehalose, were immunostimulants. He also found that muramyl dipeptides modulate or stimulate the body’s immune defense against hostile bacterial or viral invaders and against parasitic protozoans as well. In tumor immunology they can serve as immunoadjuvants when administered simultaneously with tumor antigens.

Lederer made yet another contribution to science: Edgar and Hélène Lederer had seven children, all of whom attended universities, one in the humanities and six in the sciences. Five of them espoused academic careers.

Among his numerous awards, he was proudest of the gold medal from CNRS in 1974 and of his belated (because of anti-Semitism) election to the French Academy of Sciences in 1982.

The pivotal character in Jean Renoir’s film masterpiece, La règle du jeu (1939; The Rules of the Game) is a French Jew. His wealth opened high society for him. He outshone the aristocrats around him with his humanity. Lederer, with his moral elegance, with his international outlook, with his concern for political refugees of every ilk, reminds one of this character.

BIBLIOGRAPHY

WORKS BY LEDERER

“Biochemistry of the Natural Pigments.” Annual Review of Biochemistry 17 (1948): 495–520.

With J. Asselineau. “Structure of the Mycolic Acids of Mycobacteria.” Nature 166 (1950): 782–783.

With Michael Lederer. Chromatography: A Review of Principles and Applications. Amsterdam; Houston, TX: Elsevier Publishing, 1953.

“Chemistry and Biochemistry of Some Biologically Active Bacterial Lipids.” Pure and Applied Chemistry 2 (1961): 587–605.

“The Origin and Function of Some Methyl Groups in Branched-Chain Fatty Acids, Plant Sterols, and Quinones.” Biochemical Journal 93 (1964): 449–468.

Report on Chemical Warfare in Vietnam. (Second Session, 20 November–1 December 1967). In Reports from the Sessions of the International War Crimes Tribunal Founded by Bertrand Russell. London: Russell Tribunal, 1967–1971.

“The Mycobacterial Cell Wall.” Pure and Applied Chemistry 25 (1971): 135–165.

“Cord Factor and Related Trehalose Esters.” Chemistry and Physics of Lipids 16 (1976): 91–106.

With L. Chedid, F. Audibert, P. Lefrancier, et al. “Modulation of the Immune Response by a Synthetic Adjuvant and Analogs.” Proceedings of the National Academy of Sciences of the United States of America 73 (1976): 2472–2475.

With L. Chedid. “Past, Present, and Future of the Synthetic Immunoadjuvant MDP and Its Analogs.” Biochemical Pharmacology 27 (1978): 2183–2186.

“Synthetic Immunostimulants Derived from the Bacterial Cell Wall.”Journal of Medicinal Chemistry 23 (1980): 819–825.

“Adventures and Research.” In Selected Topics in the History of Biochemistry: Personal Recollections, edited by Giorgio Semenza. Amsterdam: Elsevier, 1985.

“New Developments in the Field of Synthetic Muramyl Peptides, Especially as Adjuvants for Synthetic Vaccines.” Drugs and Experimental Clinical Research 12 (1986): 429–440.

“Edgar Lederer, la chimie des substances naturelles.” In Cahiers pour l’histoire du CNRS 1939–1989, 1989–1992, edited by J. F. Picard and E. Pradoura. Paris: Editions du CNRS, 1989.

OTHER SOURCES

Schmidt, M., ed. Hommes de Science. 28 Portraits. Paris: Hermann, 1990.

Tswett, M. S. “Physikalische-chemische Studien über das Chlorophyll. Die Adsorptionen.” Berichte der Deutschen Botanischen Gesellschaft 24 (1906): 316–328.

Witkop, B. “Paul Ehrlich and His Magic Bullets—Revisited.” Proceedings of the American Philosophical Society 143 (1999): 540–557.

Pierre Laszlo