ComradeHuxley
Donor
Hippocrates of the 20th Century
The Work of Felix d'Hergelle
Early history of Bacteriophage Therapy
Felix D'Herelle was born in Montreal, Quebec, the son of French emigrants. His father, 30 years older than Felix's mother, died when Félix was 6 years old. Following his father's death, Félix, his mother and his younger brother Daniel, moved back to Paris. From 7 to 17 years of age, d'Herelle attended school in Paris, including the Lycée Condorcet and Lycée Louis-le-Grand high schools. 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 by 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 back 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, even though he had no medical degree or real experience.
While working in Mexico d'Herelle was offered to attempt stopping a locust plague at a local plantation using their own diseases. He extracted bacteria pathogenic to locusts from their guts and cultivated them so they could be sprayed. An innovative approach to pest control.
D'Herelle and his family finally moved to Paris in early 1911, where he worked as an unpaid assistant in a lab at the Pasteur Institute. He got attention in the scientific community the same year, when the results of his successful attempt to counter the Mexican locust plague with Coccobacillus were published.
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.
During World War I, Félix d'Herelle and assistants (his wife and daughters among them) produced 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 to 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. The isolation of phages by d'Herelle worked like this:
1.Nutritional medium is infected with bacteria; the medium turns opaque.
2. The bacteria are infected with phages and die, producing new phages; the medium clears up.
3. The medium is filtered through porcelain filter, holding back bacteria and larger objects; only the smaller phages pass through.
In early 1919, d'Herelle isolated phages from chicken feces, successfully treating a plague of chicken typhus with them. After this successful experiment on chicken, 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 1937 that its true nature was established.
In 1920, d'Herelle traveled 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 a heightened 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. The next year, he was nominated eight times for the Nobel prize, though he was never awarded one.
After holding a temporary position at the University of Leiden, d'Herelle got 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 pilgrim groups 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 claimed 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; the death toll went down from 60% to 8%. The whole India enterprise took less than seven months.
D'Herelle refused next year's request by the British government to work in India, as he had been offered a position in Tbilisi.
Around 1929, he went to Georgi where he was welcomed to the Soviet Union as a hero. He accepted Bogdanov's invitation for two reasons: it was said he was enamored of socialism, and he was happy to be working with his friend, Prof. George Eliava, founder of the Tbilisi Institute. D'Hergelle was known for his temper and had made not a few enemies in the scientific community, however he and Eliava always enjoyed a warm personal and wokring relationship.
The Tbilisi Institute was active since the 1920s in the field of phage therapy, which was used to combat the devastating outbreaks of microbial infections during the class war.
The institute itself was opened in Tbilisi, Georgia in 1920, and was a bacteriology laboratory but with the research focus on the newly discovered Phage Therapy. Its founder, Prof. George Eliava, became aware of bacteriophages after he met Felix d'Herelle during a visit to the Pasteur Institute in Paris to prepare the creation of his own institute in Georgia. There, Eliava was enthusiastic about the potential of phage in the curing of bacterial disease, and invited d'Herelle to visit his soon to be established laboratory.
Eliava (left) D'Herelle (right)
D'Herelle visited Tbilisi twice before he agreed to work with Prof. Eliava. He stayed in Tbilisi and dedicated his life to improve the prospects and understanding of his therapy. He published "The Bacteriophage and the Phenomenon of Cure" in 1935 and dedicated it to Comrade Bogdanov.
D'Herelle took up permanent residence in Tbilisi and build a cottage on the grounds of the Institute. The cooperation between the two scientists was fruitful and established the Union as the world leader in Phage-Therapy.
The institute in Tbilisi became a general Soviet institute for the development and production of bacteriophage drugs. Patients with serious infectious diseases came from all over the Soviet Union to receive treatments there. Bacteriophages became a routine part of treatment in clinics and hospitals. Ointments for the skin, and pills, drops, and rinses consisting of phages were sold and are still sold at pharmacies throughout the Union at low prices. Over the years the Institute identified over many thousands of bacteriophage samples and catalogued them in huge, refrigerated libraries.
Discovery of Resistance Mechanism and Contribution to Evolutionary Theory
The Bacteriogpahge research at the Tbilisi Institute was responsible for many milestones in Genetics. But one of their most important discoveries were made by the founder d'Hergelle and Eliava in their d'Hergelle-Eliava Test in 1931. The Test was designed with theoretical but also practical questions in mind. Bacteria resistance to certain strains of Bacteriopages was a big problem that had to be understood and solved. They demonstrates that in bacteria, genetic mutations arise in the absence of selection, rather than being a response to selection. Therefore, Darwin's theory of natural selection acting on random mutations applies to bacteria as well as to more complex organisms. D'Hergelle and Eliava were inspired and in contact with the the works of the the soviet genetic researchers Sergei Chetverikov and Yuri Filipchenko, who combined Medelian Genetics with Darwin's Evolution Theory.
D'Hergelle and Eliava, inoculated a small number of bacteria into separate culture tubes. After a period of growth, they plated equal volumes of these separate cultures onto agar containing phage virus. If virus resistance in bacteria were caused by a spontaneous activation in bacteria—i.e., if resistance were not due to heritable genetic components, then each plate should contain roughly the same number of resistant colonies. This, however was not what they found. Instead, the number of resistant colonies on each plate varied drastically. They proposed that these results could be explained by the occurrence of a constant rate of random mutations in each generation of bacteria growing in the initial culture tubes. Based on these assumptions they derived a probability distribution (now called the D'Hergelle-Eliava distribution) that gives a relationship between moments consistent with the experimentally obtained values. The distribution that follows from the directed adaptation hypothesis (a Poisson distribution) predicted moments inconsistent with the data. Therefore, the conclusion was that mutations in bacteria, as in other organisms, are random rather than directed.
The Work of Felix d'Hergelle
Early history of Bacteriophage Therapy
Felix D'Herelle was born in Montreal, Quebec, the son of French emigrants. His father, 30 years older than Felix's mother, died when Félix was 6 years old. Following his father's death, Félix, his mother and his younger brother Daniel, moved back to Paris. From 7 to 17 years of age, d'Herelle attended school in Paris, including the Lycée Condorcet and Lycée Louis-le-Grand high schools. 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 by 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 back 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, even though he had no medical degree or real experience.
While working in Mexico d'Herelle was offered to attempt stopping a locust plague at a local plantation using their own diseases. He extracted bacteria pathogenic to locusts from their guts and cultivated them so they could be sprayed. An innovative approach to pest control.
D'Herelle and his family finally moved to Paris in early 1911, where he worked as an unpaid assistant in a lab at the Pasteur Institute. He got attention in the scientific community the same year, when the results of his successful attempt to counter the Mexican locust plague with Coccobacillus were published.
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.
During World War I, Félix d'Herelle and assistants (his wife and daughters among them) produced 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 to 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. The isolation of phages by d'Herelle worked like this:
1.Nutritional medium is infected with bacteria; the medium turns opaque.
2. The bacteria are infected with phages and die, producing new phages; the medium clears up.
3. The medium is filtered through porcelain filter, holding back bacteria and larger objects; only the smaller phages pass through.
In early 1919, d'Herelle isolated phages from chicken feces, successfully treating a plague of chicken typhus with them. After this successful experiment on chicken, 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 1937 that its true nature was established.
In 1920, d'Herelle traveled 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 a heightened 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. The next year, he was nominated eight times for the Nobel prize, though he was never awarded one.
After holding a temporary position at the University of Leiden, d'Herelle got 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 pilgrim groups 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 claimed 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; the death toll went down from 60% to 8%. The whole India enterprise took less than seven months.
D'Herelle refused next year's request by the British government to work in India, as he had been offered a position in Tbilisi.
Around 1929, he went to Georgi where he was welcomed to the Soviet Union as a hero. He accepted Bogdanov's invitation for two reasons: it was said he was enamored of socialism, and he was happy to be working with his friend, Prof. George Eliava, founder of the Tbilisi Institute. D'Hergelle was known for his temper and had made not a few enemies in the scientific community, however he and Eliava always enjoyed a warm personal and wokring relationship.
The Tbilisi Institute was active since the 1920s in the field of phage therapy, which was used to combat the devastating outbreaks of microbial infections during the class war.
The institute itself was opened in Tbilisi, Georgia in 1920, and was a bacteriology laboratory but with the research focus on the newly discovered Phage Therapy. Its founder, Prof. George Eliava, became aware of bacteriophages after he met Felix d'Herelle during a visit to the Pasteur Institute in Paris to prepare the creation of his own institute in Georgia. There, Eliava was enthusiastic about the potential of phage in the curing of bacterial disease, and invited d'Herelle to visit his soon to be established laboratory.
Eliava (left) D'Herelle (right)
D'Herelle visited Tbilisi twice before he agreed to work with Prof. Eliava. He stayed in Tbilisi and dedicated his life to improve the prospects and understanding of his therapy. He published "The Bacteriophage and the Phenomenon of Cure" in 1935 and dedicated it to Comrade Bogdanov.
D'Herelle took up permanent residence in Tbilisi and build a cottage on the grounds of the Institute. The cooperation between the two scientists was fruitful and established the Union as the world leader in Phage-Therapy.
The institute in Tbilisi became a general Soviet institute for the development and production of bacteriophage drugs. Patients with serious infectious diseases came from all over the Soviet Union to receive treatments there. Bacteriophages became a routine part of treatment in clinics and hospitals. Ointments for the skin, and pills, drops, and rinses consisting of phages were sold and are still sold at pharmacies throughout the Union at low prices. Over the years the Institute identified over many thousands of bacteriophage samples and catalogued them in huge, refrigerated libraries.
Discovery of Resistance Mechanism and Contribution to Evolutionary Theory
The Bacteriogpahge research at the Tbilisi Institute was responsible for many milestones in Genetics. But one of their most important discoveries were made by the founder d'Hergelle and Eliava in their d'Hergelle-Eliava Test in 1931. The Test was designed with theoretical but also practical questions in mind. Bacteria resistance to certain strains of Bacteriopages was a big problem that had to be understood and solved. They demonstrates that in bacteria, genetic mutations arise in the absence of selection, rather than being a response to selection. Therefore, Darwin's theory of natural selection acting on random mutations applies to bacteria as well as to more complex organisms. D'Hergelle and Eliava were inspired and in contact with the the works of the the soviet genetic researchers Sergei Chetverikov and Yuri Filipchenko, who combined Medelian Genetics with Darwin's Evolution Theory.
D'Hergelle and Eliava, inoculated a small number of bacteria into separate culture tubes. After a period of growth, they plated equal volumes of these separate cultures onto agar containing phage virus. If virus resistance in bacteria were caused by a spontaneous activation in bacteria—i.e., if resistance were not due to heritable genetic components, then each plate should contain roughly the same number of resistant colonies. This, however was not what they found. Instead, the number of resistant colonies on each plate varied drastically. They proposed that these results could be explained by the occurrence of a constant rate of random mutations in each generation of bacteria growing in the initial culture tubes. Based on these assumptions they derived a probability distribution (now called the D'Hergelle-Eliava distribution) that gives a relationship between moments consistent with the experimentally obtained values. The distribution that follows from the directed adaptation hypothesis (a Poisson distribution) predicted moments inconsistent with the data. Therefore, the conclusion was that mutations in bacteria, as in other organisms, are random rather than directed.