The Discovery of Bacteriophage

The first report about what we now recognize as bacteriophage was published more than a century ago.  In 1896, Hankin reported that something in the waters of the Ganges and Jumna rivers in India had marked antibacterial action and could pass through a very fine porcelain filter.  However, it was another 20 years before a British bacteriologist, Frederick Twort, actually isolated filterable entities capable of destroying bacterial cultures and producing small cleared areas on bacterial lawns (1915).  Twort did not further explore his finding.  Two years after Twort's discovery, Felix d’Herelle, a French Canadian microbiologist working at the Pasteur Institute in Paris, reported the same phenomenon.  For d’Herelle, there was no question as to the nature of his discovery: "In a flash I had understood: what caused my clear spots was in fact an invisible microbe... a virus parasitic on bacteria."  D'Herelle called the virus bacteriophage or bacteria-eater (from the Greek phago meaning to eat).

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Therapeutic use of phages in clinical settings  

In the period after his discovery, D’Herelle promoted the use of phages as therapeutic agents for the treatment of infectious diseases.  The first reported application of phages to treat infectious diseases of humans came from Bruynoghe and Maisin in France in 1921, who used bacteriophages to treat staphylococcal skin disease.  Phages have been used, since that time, for prophylaxis and therapy in the United States (early 1930s) and, for the last five decades, in eastern Europe and in the Soviet Union.
      The international literature contains several hundred reports on phage therapy, with the majority of the publications coming from researchers in the former Soviet Union and eastern European countries.  To give but a few examples, phages have been reported to be effective in treating skin infections caused by Pseudomonas, Staphylococcus, Klebsiella, Proteus, and E. coli, staphylococcal lung and pleural infections, P. aeruginosa infections in cystic fibrosis patients, neonatal sepsis, and surgical wound infections.  In the English language, the most detailed descriptions have come from the Institute of Immunology and Experimental Medicine of the Polish Academy of Sciences.  Briefly, phage therapy was used on 550 patients, at 10 clinical and hospital departments in three different cities (Wrozlav, Lubin, and Kamienna Gora).  The major infecting agents included Staphylococcus, Pseudomonas, Escherichia, Klebsiella, and Salmonella species.  Phages were administered orally, applied directly to wounds, or given in eye drops.  Reported success rates ranged from 75 to 100%, depending on the pathogen.
       Several reviews of the therapeutic use of phages have been published during the 1930s-40s and recently.  In a recent paper published in the Journal of Infection, the authors reviewed Medline citations (published during 1966-1996) on the therapeutic use of phages in humans, and they found that the overall reported success rate for phage therapy was in the range of 80-95%.  A comprehensive information package on the history of phage therapy has been assembled as a web-page at the Evergreen State College in Olympia, Washington.

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Therapeutic use of phages in animals

One of the most detailed reports (in the English literature) of the use of phages in veterinary medicine comes from H. W. Smith and R. B. Huggins in Great Britain.  In one of their early papers published in the Journal of General Microbiology, the authors reported the successful treatment of experimental E. coli infections in mice using phages, and noted the general superiority of phages over antibiotics.  In subsequent studies, the authors demonstrated that a single dose of specific E. coli phage was sufficient to reduce, by many orders of magnitude, the number of target bacteria in the alimentary tract of calves, lambs and piglets infected with a diarrheagenic E. coli strain, and to stop the associated fluid loss; all animals treated with phage survived the infection.  The authors also showed that diarrhea could be prevented in calves by simply spraying the litter in the calf rooms with an aqueous phage suspension, or by keeping the calves in uncleaned rooms previously occupied by calves whose E. coli infections had been treated with phage.  Another group of investigators in England performed several experiments in which they demonstrated the utility of phages in preventing/treating experimental infections with P. aeruginosa and Acinetobacter in mice and guinea pigs. The ability of Salmonella and E. coli phages to reduce colonization in/prevent death of experimentally-infected chickens also has been described.

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Safety profile

During the long history of using phages as therapeutic agents throughout eastern Europe and the former Soviet Union (and, before the antibiotic era, in the United States), there have been virtually no reports of serious complications associated with their use.  In the United States, phages have been used safely for monitoring humoral immune function in adenosine deaminase-deficient patients, and for analyzing the importance of cell surface-associated molecules in modulating the immune response in humans.  In the later study, the phage was injected intravenously into healthy volunteers, without apparent side effects.
     Phages have high specificity for specific bacterial strains, a characteristic which requires that therapy be carefully targeted (i.e., there is no analogy to the broad-spectrum antibiotics which can “kill anything”).  Therefore, phage therapy can be used to lyse specific pathogens without disturbing normal bacterial flora (i.e., it would not affect “colonization resistance” in cancer patients).  Phages pose no risk to anything other than their specific bacterial host: they are extremely common in the environment, are regularly consumed in foods, and have been shown to be unintended contaminants in a variety of medications, including vaccines commercially available in the United States.

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"For well over half a century, the most active center of research on phages as antibiotics was the G. Eliava Institute of Bacteriophage, Microbiology, and Virology, part of Georgian Academy of Sciences, Tbilisi, in the former Soviet republic of Georgia." 
Genetic Engineering News, Phage as antibacterial tool, October 15, 1998

The historical background of the institute is interesting.  George Eliava (after whom the institute is currently named), observed the bactericidal action of the water of the Mtkvari (Kura) river in Tbilisi in the 1910s.  However, he could not explain this phenomenon until d’Herelle’s work on phages was published.  Eliava spent 1920-1921 at the Pasteur Institute where he became acquainted with, and became a personal friend of, Felix d’Herelle.  The two friends had a dream to establish a phage research center in Tbilisi.  This dream, however, remained unfulfilled for over a decade, until d’Herelle visited Georgia and he and Eliava went forward with their idea.  The long-dreamed-of institute soon became a reality because of the strong support of Sergo Orjonikidze, the People’s Commissar (read: minister) of Heavy Industry in Stalin’s government.  The Bacteriophage Institute was established in Tbilisi in 1923, and a large campus on the Mtkvari river soon was allocated for its expansion.  D’Herelle spent several months in Tbilisi collaborating with Eliava and other Georgian colleagues (photo above), and intended to move to Tbilisi permanently (a cottage built for his use still stands on the Institute’s grounds; photo below, right).  However, in 1937, Eliava was arrested by “Cheka” (the predecessor of the KGB), pronounced a “People’s Enemy,” and executed.  Frustrated and disillusioned, D’Herelle never returned to Georgia.  However, the Institute survived and soon became a leader in developing therapeutic phage preparations in Eastern Europe, and possibly in the world.  

Currently, the Bacteriophage institute is a part of the Georgian
Academy of Sciences, and employs some of the most experienced people (in the field of phage therapy) in the world.  Intralytix currently is funding three projects at the Eliava Institute, with exclusive rights on the phage preparations developed under its auspices.

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