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The road to phage therapy

Nature volume 443, pages 754755 (19 October 2006) | Download Citation

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Viruses vs. Superbugs: A Solution to the Antibiotics Crisis?

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Macmillan Science: 2006. 256 pp. £16.99, $24.951403987645

The first evidence for a viral-like agent with antibacterial properties was reported by M. E. Hankin in 1896. Found in the Ganges river in India, it was temperature sensitive, capable of passing through a porcelain filter, and could reduce titres of the bacterium Vibrio cholerae in laboratory culture. Hankin suggested that it might help to decrease the incidence of cholera in people using water from the Ganges.

The viral nature of such antibacterial agents became clearer following the observation of agents capable of lysing bacterial cultures by Frederick Twort and Felix d'Herrelle in 1915 and 1917, respectively. It was d'Herrelle who named these agents bacteriophages and championed their use in treating infectious diseases. He and his colleagues introduced phage therapy throughout the world, with major efforts in India, Egypt, the United States and the Soviet Union. Unfortunately, these clinical applications were initiated before certain microbiological aspects of phage strains, such as their narrow host range, were fully appreciated. In addition, clinical investigations in the 1920s and '30s were based largely on anecdotal evidence — scientific and statistically relevant clinical trials were only introduced in the 1940s, primarily in the United States and Britain. The clinical use of phage therapy without the underlying scientific support needed to assure a high level of clinical effectiveness, combined with the development of antibiotics during the Second World War, served to marginalize the use of phage therapy in most Western countries.

There have been many reviews of phage therapy and some books, but few provide the historical details that Thomas Häusler introduces in this volume. For example, he mentions reports published in the journal Der Deutsche Militärarzt during the Second World War on a phage preparation known as 'polyfagin', which was produced by the German pharmaceutical company Behringwerke as a treatment for dysentery. And he reveals that the research of René Dubos on phage therapy in 1942 was supported by a committee of the US National Research Council that was “assigned the task of keeping the country prepared for war”. He also interviewed many of the researchers and business entrepreneurs who have been interested in developing phage therapy.

Troubled waters? Bathers in the Ganges were thought to be protected from cholera by phage. Image: STEVE BLOOM IMAGES/ALAMY

Much of this information will be useful for professionals as well as the general public. For example, I was interested to read of the progress made by Omnilytics (a company based in Salt Lake City) in the use and commercialization of phage for the treatment of bacterial spot disease in tomatoes.

However, like many 'popular' science books, the book often lacks a critical analysis of the information presented. For example, Häusler suggests that the spleen filters most phage from the circulatory system, whereas this task is largely done by the liver. He underplays the role of phage in causing human disease. He notes: “Prior to 1900, diphtheria was the most frequent cause of death for German children.” Two pages later he states that “phages are viruses that only attack bacteria”. He doesn't mention in this context that diphtheria toxin is encoded in a phage genome, so diphtheria is primarily a phage-associated disease. He also implies that the use of lysozymes to kill bacteria is new, but they have actually been used as food preservatives for decades. And there is no merit to his claim that lysin treatment, unlike antibiotic treatments, does not generate resistant mutants. Under laboratory conditions it might be hard to obtain the mutations needed to confer lysin-resistant phenotypes. But as most resistance comes from acquiring new DNA elements from nature, it is easy to see how the overuse of any lysin or antibacterial agent will select for those resistant elements that exist in nature, as has repeatedly happened before.

A more worrying aspect is Häusler's overuse of anecdotal cases. Although he states in the book's preface that the book “is not a health manual whose purpose is to testify to the efficacy of phages”, he refers to specific anecdotal cases in a way that suggests that phage therapy was indeed responsible for the reported clinical improvement. These treatments were often carried out in clinical settings that do not meet the current standards required for the certification of marketed pharmaceuticals. One of the cases, which is referred to numerous times throughout the book, involves an individual with a chronic bone infection who was treated by irrigation with solutions containing phage and by having phage-impregnated material placed in the open wounds. It would be interesting to compare such 'phage therapy' with the use of saline irrigations and sterile drains. Although Häusler acknowledges the need for the careful development of therapeutic agents, along with the need for adequate control experiments, there is a danger that this book might encourage some individuals with infectious diseases to use phage in such a way.

The development of therapeutic phage will need a commitment to meet all the scientific requirements for current pharmaceutical agents. An anecdotal approach, adopted by some of the investigators described in the book and widely used in clinical medicine in the early twentieth century, may retard rather then stimulate the acceptance of therapeutic applications. The encouraging results of animal experiments have demonstrated phage's capacity to rescue animals with life-threatening infections. Perhaps phage therapy, if carefully developed, could provide some much-needed antibacterial agents.

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  1. Sankar Adhya is at the Laboratory of Molecular Biology, National Cancer Institute, Bethesda, Maryland 20892, USA.

    • Sankar Adhya
  2. Carl Merril is emeritus at the Laboratory of Biochemical Genetics, National Institute of Mental Health, Bethesda, Maryland 20892, USA.

    • Carl Merril

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https://doi.org/10.1038/443754a

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