Félix d'Hérelle

Félix d'Herelle (April 25, 1873 – February 22, 1949) was a French-Canadian scientist, who, with only a high-school education, became one of the most accomplished bacteriologists of his day. d'Herelle is credited with discovering bacteriophages and inventing phage therapy and modern biological pest control. Subsequently, bacteriophages became the model organisms for the studies that spawned much of our knowledge of molecular genetics.

Felix d'Herelle

Early Years

D'Herelle was born in Montreal, Quebec, the son of French emigrants. His father, 30 years older than his wife, died when Félix was 6 years old. Following his father's death, Félix, his mother and his younger brother Daniel, moved to Paris. From 7 to 17 years of age, d'Herelle attended school in Paris, including the lycee. In the fall of 1891, d'Herelle traveled to Bonn where he attended lectures at the University of Bonn "for several months." Thus, d'Herelle only obtained a high school education and was self-taught in the sciences.

Between 16 and 24, d'Herelle traveled extensively via money given by his mother. When 16 years old, he started to travel through western Europe on bike. When 17, after finishing school, he traveled through South America. Afterwards, he continued his travels through Europe, including Turkey, where he, at 20 years of age, met his wife, Marie Caire.

At age 24, now father of a daughter, d'Herelle and his family moved to Canada. He built a home laboratory and studied microbiology from books and his own experiments. Through the influence of a friend of his late father, he earned a commission from the Canadian government to study the fermentation and distillation of maple syrup to schnapps. His father's friend shrewdly pointed out that Pasteur "made a good beginning by studying fermentations, so it might be interesting to you, too." He also worked as a medic for a geological expedition to Labrador, even though he had no medical degree or real experience. Together with his brother, he invested almost all his money in a chocolate factory, which soon went bankrupt.

During this period, d'Herelle published his first scientific paper, "De la formation du Carbone par les vegetaux" in the May 1901 issue of Le Naturaliste Canadien. The paper is noteworthy for two reasons: it shows an exceptional level of scientific development for a self-taught scientist and reveals a broad level of interest, namely the global balance of carbon in nature. However, the claims of the paper were in error, as d'Herelle contended that the results of his experiments indicated that carbon was a compound, not an element.

Guatemala and Mexico

With his money almost gone and his second daughter born, d'Herelle took a contract with the government of Guatemala as a bacteriologist at the General Hospital in Guatemala City. Some of his work included organizing defenses against the dread diseases of the time: malaria and yellow fever. He also studied a local fungal infection of coffee plants, and discovered that acidifying the soil could serve as an effective treatment. As a side job, he was asked to find a way to make whiskey from bananas. Life in the rough and dangerous environment of the country was hard on his family, but d'Herelle, always adventurer at heart, rather enjoyed working close to "real life", compared to the sterile environments of a "civilized" clinic. He later stated that his scientific path began on this occasion.

In 1907, he accepted an offer from the Mexican government to continue his studies on fermentation. He and his family moved to a sisal plantation near Mérida, Yucatán. Disease struck at him and his family, but in 1909, he had successfully established a method to produce sisal schnapps.

A Return to France

Machines for mass production of sisal schnapps were ordered in Paris, where d'Herelle oversaw the machines' construction. Meanwhile, in his spare time, he worked for free in a laboratory at the Pasteur Institute. Soon, he was offered the job of running the new Mexican plant, but declined, considering it "too boring". He did, however, take the time to attempt stopping a locust plague at the plantation using the locusts' own diseases. He extracted bacteria pathogenic to locusts from their guts. This innovative approach to locust plagues anticipated modern biological pest control using Bacillus thuringiensis also known as Bt.

D'Herelle and his family finally moved to Paris in early 1911, where he worked again as an unpaid assistant in a lab at the Pasteur Institute. He earned the attention of the scientific community the same year, when the results of his successful attempt to counter the Mexican locust plague with Coccobacillus were published.

Argentina

At the end of the year, restless d'Herelle was again on the road, this time in Argentina, where he was offered a chance to test these results on a much larger scale. Thus, in 1912 and 1913, he fought the Argentinian locust plagues with coccobacillus experiments. Even though Argentina claimed his success was inconsistent, he himself declared it a full success, and was subsequently invited to other countries to demonstrate the method.

France and Phage

During World War I, d'Herelle and assistants (his wife and daughters among them) produced over 12 million doses of medication for the allied military. At this point in history, medical treatments were primitive compared to today's standards. The smallpox vaccine, developed by Edward Jenner, was one of the few vaccines available. The primary antibiotic was the arsenic-based salvarsan against syphilis, with severe side effects. Common treatments were based mercury, strychnine, and cocaine. As a result, in 1900, the average life span was 45 years, and WWI did not change that for the better.

In 1915, British bacteriologist Frederick W. Twort discovered a small agent that infects and kills bacteria, but did not pursue the issue further. Independently, the discovery of "an invisible, antagonistic microbe of the dysentery bacillus" by d'Herelle was announced on September 3, 1917.

D'Herelle's own words describe his discovery:

"On my return to Paris in August 1915, I was asked by Dr. Roux to investigate an epidemic of dysentery which was raging in a cavalry squadron, then resting at Maisons-Laffitte. I thought the hypothesis, put forward for the locusts' illness might be helpful in understanding human dysentery. I therefore filtered emulsions of the faeces of the sick men, let the filtrates act on cultures of dysentery bacilli and spread them after incubation on nutritive agar in petri dishes: on various occasions I again found my clear spots, but the feeding of these cultures to guinea pigs and rabbits produced no disease.

"At this time we often got cases of bacillary dysentery in the hospital of the Institut Pasteur in Paris. I resolved to follow one of these patients through from the time of admission to the end of convalescence, to see at what time the principle causing the appearance of the clear patches first appeared. This is what I did with the first case which was available.

"The first day I isolated from the bloody stools a Shiga dysentery bacillus, but the spreading on agar of a broth culture, to which had been added a filtrate from the faeces of the same sick man, gave a normal growth. The same experiment, repeated on the second and third days, was equally negative. The fourth day, as on the preceding days, I made an emulsion with a few drops of the still bloody stools, and filtered it through a Chamberland candle; to a broth culture of the dysentery bacillus isolated the first day, I added a drop of the filtrate; then I spread a drop of this mixture on agar. I placed the tube of broth culture and the agar plate in an incubator at 37°. It was the end of the afternoon, in what was then the mortuary, where I had my laboratory.

"The next morning, on opening the incubator, I experienced one of those rare moments of intense emotion which reward the research worker for all his pains: at the first glance I saw that the broth culture, which the night beforehad been very turbid, was perfectly clear: all the bacteria had vanished, they had dissolved away like sugar in water. As for the agar spread, it was devoid of all growth and what caused my emotion was that in a flash I had understood: what caused my clear spots was, in fact, an invisible microbe, a filterable virus, but a virus parasitic on bacteria." (From F. d'Herelle, The bacteriophage, Sci. News 14:44-59, 1949.)

Negative stain electron micrograph of the gamma phage from which the PlyG lytic enzyme was cloned for use to control B. anthracis.
Photo courtesy of Vincent Fischetti and Raymond Schuch, The Rockefeller University.

In early 1919, d'Herelle isolated phages from chicken feces, successfully treating a plague of chicken typhus with them. After this successful experiment on chickens, he felt ready for the first trial on humans. The first patient was healed of dysentery using phage therapy in August 1919. Many more followed.

At the time, none, not even d'Herelle, knew exactly what a phage was. D'Herelle claimed that it was a biological organism that reproduces, somehow feeding off bacteria. Others, the Nobelist Jules Bordet chief among them, theorized that phages were inanimate chemicals, enzymes specifically, that were already present in bacteria, and only trigger the release of similar proteins, killing the bacteria in the process. Due to this uncertainty, and d'Herelle using phages without much hesitation on humans, his work was under constant attack from many other scientists. It was not until the first phage was observed under an electron microscope by Helmut Ruska in 1939 that its true nature was established.

In 1920, d'Herelle travelled to Indochina, pursuing studies of cholera and the plague, from where he returned at the end of the year. D'Herelle, officially still an unpaid assistant, found himself without a lab; d'Herelle later claimed this was a result of a quarrel with the assistant director of the Pasteur Institute, Albert Calmette. The biologist Edouard Pozerski had mercy on d'Herelle and lent him a stool (literally) in his laboratory. In 1921, he managed to publish a monograph, The Bacteriophage: Its Role in Immunity, about his works as an official Institute publication, by tricking Calmette. During the following year, doctors and scientists across western Europe took an interest in phage therapy, successfully testing it against a variety of diseases. Since, on rare occasions, bacteria become resistant against a single phage, d'Herelle suggested using "phage cocktails" containing different phage strains.

Phage therapy soon became a boom, and a great hope in medicine. In 1925, d'Herelle received the honorary doctorate of the University of Leiden, as well as the Leeuwenhoek medal, which is only awarded once every ten years. The latter was especially important to him, as his idol Louis Pasteur received the same medal in 1895.

Egypt and India

After holding a temporary position at the University of Leiden, d'Herelle was offered a position with the Conseil Sanitaire, Maritime et Quarantenaire d'Egypte in Alexandria. The Conseil was put in place to prevent plague and cholera spreading to Europe, with special emphasis on the sanitary concerns about muslim pilgrims returning from Mecca and Medina. D'Herelle used phages he collected from plague-infected rats during his 1920 visit to Indochina on human plague patients, with success. The British Empire initiated a vast campaign against plague based on his results. 1927, d'Herelle himself changed his focus to new targets: India and cholera.

D'Herelle isolated phages from cholera victims in India. As usual, he did not choose a hospital run by European standards, but rather sought out a medical tent in a slum. According to his theory, one had to leave the sterile hospitals and study and defeat illness in its "natural" environment. His team then dropped phage solution in the wells of villages with cholera patients, reducing the death toll from 60 to 8%. The whole India enterprise took less than seven month.

Felix d'Herelle in later years

United States

D'Herelle refused next year's request by the British government to work in India, as he had been offered a professorship at Yale University. He accepted. Meanwhile, European and US pharma companies had taken up the production of own phage medicine, and were promising impossible effects. To counteract this, d'Herelle co-founded a French phage-producing company, pumping the money back into phage research. But all companies suffered from production problems; results from commercial phage medicine were erratic, most likely due to the attempt to mass-produce something that was barely understood, leading to damaged phages in the product, or to insufficient amounts thereof. Also, wrong diagnoses often led to the use of the wrong type of phages, which are specific in the choice of their "victims". Furthermore, many studies on the healing effects of phages were badly conducted. All this led to important parts of the scientific community turning against d'Herelle, who, known for his temper, had made not a few enemies.

The USSR

But he was already on the move again. In or around 1934, he went to Tbilisi (Georgia, where Joseph Stalin was born). D'Herelle was welcomed to the Soviet Union as a hero, bringing the knowledge of salvation from diseases ravaging the eastern states all the way to Russia. He accepted Stalin's invitation for two reasons: it was said he was enamored of communism, and he was happy to be working with his friend, Prof. George Eliava, founder of the Tbilisi Institute, in 1923. Eliava had become friendly with d'Herelle during a visit to the Pasteur Institute in Paris, where he had learned about phages in 1926.

Elena Makashvili, Felix D'Herelle, and George Eliava (left to right), at the Eliava Institute in the Soviet Union.
Photo courtesy of Alexander Sulakvelidze, Intralytix, Inc.

D'Herelle worked at the Tbilisi Institute off and on for about a year—and even dedicated one of his books, "The Bacteriophage and the Phenomenon of Recovery," written and published in Tbilisi in 1935, to Comrade Stalin. He had planned to take up permanent residence in Tbililsi and had already started to build a cottage on the grounds of the Institute (it would later house the KGB's Georgian headquarters). But just then, his friend Eliava fell in love with the woman with whom the head of the secret police, Lavrenty Beria, also happened to be in love, and Eliava's fate was sealed. He was denounced as an enemy of the people and executed during one of Stalin's purges. D'Herelle ran for his life and never returned to Tbilisi. His book was banned from distribution. Then, World War II began.

France Again

Phage therapy boomed, despite all problems, driven by the military on both sides in an effort to keep the troops safe, at least from infections. D'Herelle could not really enjoy this development; he was kept under house arrest by the German "Wehrmacht" in Vichy, France. He used the time to write his book "The Value of Experiment", as well as his memoirs, the latter containing 800 pages.

After D-Day, the new antibiotic drug penicillin became public knowledge and found its way into the hospitals in the West. As it was more reliable and easier to use than phage therapy, it soon became the method of choice, despite side effects and problems with resistant bacteria. Phage therapy remained a common treatment in the states of the USSR, though, until its deconstruction.

Félix d'Herelle was striken with pancreatic cancer and died a forgotten man in Paris in 1949. He was buried in Saint-Mards-en-Othe in the department Aube in France.

In the 1960s Félix d’Hérelle's name appeared on a list published by the Nobel Foundation of scientists who had been worthy of receiving the Nobel Prize but did not, for one reason or another. It is believed that d'Herelle was nominated for the prize eight times.

However, France has not completely forgotten Félix d'Herelle. There is an avenue that bears his name in the 16th arrondissement in Paris.

Legacy

D'Herelle became widely known for his imaginative approaches to important problems in theoretical, as well as applied, microbiology. At the same time, he was widely reviled for his self-advertisement, his exaggerated claims of success and his sharp financial practices. He also had a talent for making enemies among powerful senior scientists.

D'Herelle's main legacy lies in the use of phage in the molecular revolution in biology. Max Delbruck and the "phage group" used bacteriophages to make the discoveries that led to the origins of molecular biology. Much of the initial work on the nature of genetic expression and its regulation was performed with bacteriophages by Francois Jacob, Andre Lwoff and Jacques Monod. In fact, immediately before his studies of the structure of DNA, James Watson had earned his Ph.D. by working on a bacteriophage-related project in Salvador Luria's laboratory. A more detailed account of the use of phage in major biological discoveries can be found on the page, bacteriophage.

Yet d'Herelle himself had scant interest in the field of molecular biology, for he was a life-long Lamarckian, and he clung to his own theory of elementary living "micellae," which would seem hopelessly old-fashioned after proteins were shown to be giant molecules.

Literary Note

The novel Arrowsmith written by Sinclair Lewis with scientific help from Paul de Kruif was based on the life of d'Herelle.

Books and Monographs Written by d'Herelle

• d'Hérelle, F. 1938. Le Phénomène de la Guérison dans les Maladies Infectieuses. Masson et cie, Paris. [French; The phenomenon of the Cure in the Infectious Diseases] OCLC 5784382
• d'Hérelle, F. 1933. Le Bactériophage et ses Applications Thérapeutiques. Doin, Paris. [French; The Bacteriophage and its Therapeutic Applications] OCLC 14749145
• d'Hérelle, F., and G. H. Smith. 1930. The Bacteriophage and its Clinical Application. p.165-243. Charles C. Thomas, Publisher, Springfield, Illinois. OCLC 347451
• d'Hérelle, F. 1929. Études sur le Choléra. Impr. A. Serafini, Alexandrie. [French; Studies on Asiatic Cholera] OCLC 15864352
• d'Hérelle, F. 1926. Le Bactériophage et son Comportement. Masson et Cie, Paris. [French; The Bacteriophage and its Behavior] OCLC 11981307
• d'Hérelle, F., and G. H. Smith. 1926. The Bacteriophage and Its Behavior. The Williams &Wilkins Co., Baltimore. OCLC 2394374
• d'Hérelle, F. 1924. Drie Voordrachten over het Verschijnsel der Bacteriophagie. J.B. Wolters, Groningen. [Dutch; Three presentations concerning the phenomenon of the bacteriophage] OCLC 17864544
• d'Hérelle, F., and G. H. Smith. 1924. Immunity in Natural Infectious Disease. Williams & Wilkins Co., Baltimore. OCLC 586303
• d'Hérelle, F. 1922. Der Bakteriophage und seine Bedeutung für die Immunität; nach einem erweiterten und verbesserten. F. Vieweg & Sohn, Braunschweig. [German; The Bacteriophage and its Meaning for Immunity: toward an extended and improved text of the author's translation] OCLC 36920828
• d'Hérelle, F. 1922. The Bacteriophage: Its Role in Immunity. Williams and Wilkins Co./Waverly Press, Baltimore. OCLC 14789160, ASIN B000H6G02O, B000H6EK2G
• d'Hérelle, F. 1921. Le Bactériophage: Son Rôle dans l'Immunité. Masson et cie, Paris. [French; The Bacteriophage: Its Role in Immunity] OCLC 14794182

References

• Summers, William C. (1999) Félix d'Herelle and the Origins of Molecular Biology, Yale University Press ISBN 0-300-07127-2
• For more information about Félix d'Herelle, including excerpts from his unpublished autobiography, see: Häusler, T. (2006) Viruses vs. Superbugs, Macmillan. [1]