More about phage therapy
Bacteriophages are robust antibacterial agents. In this era of antibiotic resistance, alternative approaches to treat bacterial infections, especially those of the stubborn bacteria. Their use as therapeutic agents was not very popular during the trials conducted in the 1920s through 1950s. This was due to a number of inherent limitations - narrow host range, and rapid clearance from the body, etc. but the major one amongst them was the highly inadequate scientific methodologies used by practitioners at the time. In recent years, well-controlled animal models have demonstrated that phages can rescue animals from a variety of fatal infections, while non-controlled clinical reports published in Eastern Europe have shown that phages can be effective in treating drug-resistant infections in humans. If the efficacy of this therapy can be successfully proved, it might as well take its place as a stand-alone therapy for treating bacterial infections that are resistant to antibiotics. (Carlton, R. M., 1999)
The first steps of all phage therapy protocols involve some combination of phage isolation and phage choice. The procedures by which phages are isolated are similar regardless of the phage-choice model used and generally involve some form of phage enrichment. Some degree of purification is generally required following laboratory amplification. The simplest of phage purification protocols involve clarification of lysed cultures via either centrifugation or filtration. More stringent purification—generally used for more invasive applications of phages—involves either ultracentrifugation, a series of filtration and washing/buffer-exchange steps, or various forms of chromatography. (Abedon, S. T., 2011)
As far as the toxicity and safety of the phage therapy is concerned, it can be said that this therapy can be considered relatively safer. Phages clearly interact with non-target tissue to some extent. For example, at least some phages are taken up from the gastrointestinal tract into the blood and there is reason to believe that such uptake can be a consequence of specific phage-epithelium interactions, as also appears to be the case given phage interaction with the reticulo-endothelial system. These interactions with body tissues, however, do not appear to result in side effects.
Coming to the immune response aspect of the therapy, the immunology of phages has been a subject of study for well over a half a century, both in terms of the generation of humoral immune responses and the potential of immune responses beyond just humoral immunity to result in the inactivation of phage virion particles. It has been noted that phage administration could not initiate substantial anaphylaxis. Part of the apparent mildness of phage particles in their interaction with human tissue is that animals have been exposed to large numbers of phage virions presumably over the entire course of animal evolution, perhaps resulting in greater levels of tolerance than one observes with the application of novel—to us—chemotherapeutic drugs.
Though phage therapy is being looked up to as the new breakthrough in humanity’s battle against bacterial infections, it has several disadvantages that make it slightly challenging. Firstly, the success of phage therapy may be hampered by a lack of investment support from large pharmaceutical companies, due to their narrow spectrum of activity in antibiotics, very large costs associated with clinical trials of the variety of phages needed, and regulatory requirements remaining unclear. Intellectual property is difficult to secure for therapeutic phage products for a variety of reasons, and patenting procedures vary widely between different countries. Consequently, companies are more likely to invest in phage products for decontamination or veterinary use, rather than clinical use in humans. It is an ethical dilemma to pursue research on phage therapy because the side-effects of phage therapy are still not fully explored yet it can potentially save the lives of several patients dying with untreatable infections. The safety of this therapy is not something that has been ascertained yet. (Henein, A., 2013)
Another potentially serious concern that has been expressed of phage therapy safety is the ability of at least some phages to modify host bacteria in ways that could make them more pathogenic. In particular, it is generally important to avoid using temperate phages for phage therapy purposes it is able to display lysogeny, where phages incorporate their genomes into the bacteria they are infecting rather than immediately killing the host and producing phage progeny. The problem with lysogens is at least four-fold. First, bacteria that are lysogenically rather than lytically infected do not die as a consequence of infection. Second, bacterial lysogens tend to be resistant to the phage types that have lysogenically infected them, resulting in no bacterial killing even if subsequent phages of the same type succeed in infecting. Third, temperate phages often display lysogenic conversion, meaning that they modify the bacterial phenotype, sometimes in ways that result in increased bacterial virulence. Lastly, temperate phages are associated with certain forms of transduction, meaning that they can fairly readily pick up new genes from the bacteria they are infecting and then transfer those genes to subsequently infected bacteria—without killing those new bacteria. For each of these reasons one should avoid temperate phages as therapeutic agents, if that is possible. (Sulakvelidze A. and Kutter E., 2005)
Finally, there is a high possibility that the phage therapy would not be readily accepted by people. Creating market for phage products is a serious issue to be considered, as the research and formulation costs can be very high, and it is a concern if the investments cannot be recovered or profits cannot be made.
The first steps of all phage therapy protocols involve some combination of phage isolation and phage choice. The procedures by which phages are isolated are similar regardless of the phage-choice model used and generally involve some form of phage enrichment. Some degree of purification is generally required following laboratory amplification. The simplest of phage purification protocols involve clarification of lysed cultures via either centrifugation or filtration. More stringent purification—generally used for more invasive applications of phages—involves either ultracentrifugation, a series of filtration and washing/buffer-exchange steps, or various forms of chromatography. (Abedon, S. T., 2011)
As far as the toxicity and safety of the phage therapy is concerned, it can be said that this therapy can be considered relatively safer. Phages clearly interact with non-target tissue to some extent. For example, at least some phages are taken up from the gastrointestinal tract into the blood and there is reason to believe that such uptake can be a consequence of specific phage-epithelium interactions, as also appears to be the case given phage interaction with the reticulo-endothelial system. These interactions with body tissues, however, do not appear to result in side effects.
Coming to the immune response aspect of the therapy, the immunology of phages has been a subject of study for well over a half a century, both in terms of the generation of humoral immune responses and the potential of immune responses beyond just humoral immunity to result in the inactivation of phage virion particles. It has been noted that phage administration could not initiate substantial anaphylaxis. Part of the apparent mildness of phage particles in their interaction with human tissue is that animals have been exposed to large numbers of phage virions presumably over the entire course of animal evolution, perhaps resulting in greater levels of tolerance than one observes with the application of novel—to us—chemotherapeutic drugs.
Though phage therapy is being looked up to as the new breakthrough in humanity’s battle against bacterial infections, it has several disadvantages that make it slightly challenging. Firstly, the success of phage therapy may be hampered by a lack of investment support from large pharmaceutical companies, due to their narrow spectrum of activity in antibiotics, very large costs associated with clinical trials of the variety of phages needed, and regulatory requirements remaining unclear. Intellectual property is difficult to secure for therapeutic phage products for a variety of reasons, and patenting procedures vary widely between different countries. Consequently, companies are more likely to invest in phage products for decontamination or veterinary use, rather than clinical use in humans. It is an ethical dilemma to pursue research on phage therapy because the side-effects of phage therapy are still not fully explored yet it can potentially save the lives of several patients dying with untreatable infections. The safety of this therapy is not something that has been ascertained yet. (Henein, A., 2013)
Another potentially serious concern that has been expressed of phage therapy safety is the ability of at least some phages to modify host bacteria in ways that could make them more pathogenic. In particular, it is generally important to avoid using temperate phages for phage therapy purposes it is able to display lysogeny, where phages incorporate their genomes into the bacteria they are infecting rather than immediately killing the host and producing phage progeny. The problem with lysogens is at least four-fold. First, bacteria that are lysogenically rather than lytically infected do not die as a consequence of infection. Second, bacterial lysogens tend to be resistant to the phage types that have lysogenically infected them, resulting in no bacterial killing even if subsequent phages of the same type succeed in infecting. Third, temperate phages often display lysogenic conversion, meaning that they modify the bacterial phenotype, sometimes in ways that result in increased bacterial virulence. Lastly, temperate phages are associated with certain forms of transduction, meaning that they can fairly readily pick up new genes from the bacteria they are infecting and then transfer those genes to subsequently infected bacteria—without killing those new bacteria. For each of these reasons one should avoid temperate phages as therapeutic agents, if that is possible. (Sulakvelidze A. and Kutter E., 2005)
Finally, there is a high possibility that the phage therapy would not be readily accepted by people. Creating market for phage products is a serious issue to be considered, as the research and formulation costs can be very high, and it is a concern if the investments cannot be recovered or profits cannot be made.