TRéFOUëL, JACQUES GUSTAVE MARIE

(b. Le Raincy, France, 9 November 1897; d. Paris, France, 11 July 1977)

therapeutic chemistry.

Jacques’s father, Eugène Tréfouël, a former teacher of mathematics at the Collège Chaptal in Paris, earned his living in the textile trade. Through his mother, Jeanne Potttez, he was a grandnephew of the famous actors Constant and Ernest Coquelin, who belonged to the Comédie-Française. Jacques received a Catholic education and remained a religious believer. His family wanted him to become an actor like his uncles, but he preferred to study chemistry at the Sorbonne. In 1917 he courageously took part in World War I and received the Croix de Guerre.

Tréfouël entered Ernest Foumeau’s laboratory of therapeutic chemistry at the Pasteur Institute in 1920 and married a colleague, Thérèse Boyer, a young chemist he had met at the Sorbonne. Almost all his scientific writings were done with his wife and signed by both. The couple worked on chemotherapy, physiology, and chemistry. Their most famous contribution was the discovery in 1935 of the therapeutic properties of sulphanilamide against bacterial infections.

TréTouël became chef de service at the Pasteur Institute in 1938 and became director general in December 1940, a duty he carried out through difficult times until his retirement in December 1964. He was a modest, extremely courteous, brilliant, and witty man. He was a member, and became president of, both the French Academy of Sciences and the National Academy of Medicine. He belonged to numerous foreign societies, including the American Chemical Society and the Association of American Physicians.

Tréfouël’s master, Ernest Fourneau, a leading figure in chemotherapy, was a former student of Emil Fischer and Richard Willstaetter, and a follower of Paul Ehrlich, and he made every effort to surpass German research in that new field. When Tréfouël entered his laboratory, Fourneau was engaged in a systematic study of the therapeutic properties of arsenical derivatives against protozoa infections. Ehrlich had studied the properties of trivalent arsenical derivatives, but Foumeau preferred to study the properties of simpler pentavalent derivatives. In a first series of experiments, published between 1923 and 1927, the Tréfouëls and Foumeau synthesized hundreds of different derivatives and their isomers and discovered that two of the ten isomers of acetylaminohydroxyphenylarsonic acid were active against protozoa. The first isomer, stovarsol, was active against syphilis. The second, orsanine, was active against trypanosomal infections. Two position isomers had very different and specific actions. It was the first time that such specificity was shown in chemotherapy.

Another successful line of thinking was provided by the therapeutic properties of azo dyes against trypanosomes. The study of these dyes led in 1920 to the discovery of a new drug, germanine, whose activity was considerably more effective than any previous drug in this field. The German chemists at Bayers kept its formula secret. Foumeau studied the German patents from 1912 and made several guesses about the molecular structure. Working for nine months in 1924, the Tréfouëls synthesized hundreds of different derivatives, one of which, moranyl, showed the same impressive therapeutic activity as the German product. A position isomer of this derivative showed no activity. This was another example of the specificity principle in chemotherapy.

Between 1930 and 1933 the Tréfouëls, together with Daniel Bovet, Ernest Foumeau’s pharmacologist and later a Nobel Prize recipient (1957), investigated the properties of different classes of compounds against paludism. In 1926 the German company I. G. Farben had released a new drug, plasmoquin, which belongs to the quinolines. The Tréfouëls performed a systematic study of quinoline derivatives and found several active drugs. One of them, rhodoqutne, was less toxic and slightly more active than plasmoquine.

But the most fundamental contribution of the Tréfouëls was in antibacterial chemotherapy. The problem of killing the bacteria inside the organism without affecting the host remained unsolved for years, until preliminary results were obtained in 1933 with an azo dye synthesized by the I. G. Farben chemists F. Mietzseh and J. Klarer. The active substance carried a sulphanilamide group on one of the benzene rings. In 1935 Gerhard Dotnagk reported that this substance was active against streptococcal infections in mice.

The Tréfouëls, together with Bovet and bacteriologist Frederico Nitti, took a new route and tried several modifications to the active molecule, prontosil. All the modifications affecting the benzene ring that did not carry the sulphanilamide group left the therapeutic activity constant. Following the specificity principle, it meant that this part of the molecule did not participate in the therapeutic activity. This led the Pasteur group to postulate that the sulphanilamide half was the really active part and that the azo function – N = N – of the prontosil was reduced within the organism, thus splitting the molecule into one active and colorless part and another inactive and colored. In November 1935 they tested the therapeutic properties of the sulphanilamide on infectious mice and rabbits, Sulphanilamide was at least as active as prontosil. The hypothesis of a metabolic reduction of the prontosil within the organism was later proved to be true.

The discovery of sulphanilamide was a major breakthrough in therapeutic medicine. In 1937 physicians at the Pasteur Hospital reported two cases of spectacular recoveries of children with streptococcal meningitis following administration of sulphanilamide. This very simple molecule, and hundreds of its derivatives, could be easily synthesized, and tons of these products soon became available from the pharmaceutical industry. The Pasteur group went on with the study of sulphanilamide and established its bacteriostatic activity. Other sulfur derivatives were tried, among them the sulfones, which were especially useful against leprosy.

In December 1940 Tréfouël was nominated director of the Pasteur Institute. Paris was occupied by the Nazis, but despite countless obstacles, he kept the institute working and began to reorganize it. He was at the same time an active member of the Resistance. Tréfouël arranged that no worker at the institute would be taken for compulsory work service in Germany. In the cellars of the institute he hid pharmaceutical reserves that had been parachuted in for the Resistance. Tréfouël also prevented the Nazis from obtaining the vaccines produced by the institute. He was on a deportation list when Paris was liberated in August 1944. He was awarded the Resistance Medal and in 1963 received from Général de Gaulle the cross of Grand Officer of the Legion of Honor. After the war Tréfouël began to turn the Pasteur Institute into a modern research institution. He modernized and extended it without affecting its financial autonomy. Tréfouël showed insight in his choice of new researchers, and his activity is undoubtedly one of the main reasons for the institute’s major achievements in such fields as molecular biology, immunology, and virology. In Ernst Chain’s opinion, “the Pasteur Institute never had a more dedicated and successful director than Jacques Tréfouël.”

BIBLIOGRAPHY

I. Original Works. The library of the Pasteur Institute owns a bound, five-volume collection of the publications, notes, and manuscripts of Jacques and Thérèse Tréfouël. See also “Activité du p-aminophénylsulfamide sur les infections expérimentales de la souris et du lapin”, in Comptes-rendus des séances de la Société de biologie, 120 (1935), 756–758, written with Thérèse Tréfouël Frederico Nitti, and Daniel Bovet; and “Les débuts de la sulfamidothérapie, in Médecine et hygiene, 17 (1959), 459–460.

II. Secondary Literature. Obituaries are by Louis Aublant in Bulletin de l’Académie nationale de médecine, 161 (1977), 517–524; by Paul Bordet in Bulletin et mémoires, Académie royale de médecine de Belgique, 133 (1978), 201–210; and by Ernst Chain in Nature, 270 (1977), 647–648.

On sulfonamides and their discovery, see Gerhard Domagk, “Le dévelopement de la sulfamido-thérapie moderne”, in Terre d’Europe, 7 (1958), 52–53; H. A. Feldman, “The Beginning of Antimicrobial Therapy; Introduction of Sulfonamides and Penicillins”, in Journal of Infectious Diseases, 125 (March 1972, suppl.), 22–46; J. Kimmig, “Gerhard Domagk, 1895–1964. Ein Beitrag zur Chemotherapie der bakteriellen lnfektionen”, in Internist, 10 (1969), 116–120; and W. Schreiber, “Voi 50 Jahren: Entdeckung der Chemotherapie mit Sulfonamiden”, in Deutsche medizinische Wochenschrift, 110 (1985), 1138–1142.

Claude Debru