Introducing Yesterday's Phage Therapy in Today's Medicine

Jean-Paul Pirnay; Gilbert Verbeken; Thomas Rose; Serge Jennes; Martin Zizi; Isabelle Huys; Rob Lavigne; Maia Merabishvili; Mario Vaneechoutte; Angus Buckling; Daniel De Vos


Future Virology. 2012;7(4):379-390. 

In This Article

Phage Therapy

Could (bacterio)phages, the viruses of bacteria, help fight antibiotic-resistant bacteria?[16–18] A virus is a natural biological entity, consisting in essence of a molecular assemblage of nucleic acids (the genome) surrounded by proteins, that behaves as a genetic replicative parasite. Lytic phages attach to receptors on the surface of bacteria, inject their genetic material through the bacterial membrane and take over the bacterium's transcription and translation machinery to synthesize new phages. Finally, the bacterial cell wall is destroyed (lysed), releasing the newly assembled virions to the environment, where they can invade new bacteria. Importantly, phages are able to infect bacteria regardless of their susceptibility to antibiotics. Wherever bacteria are present, there are bound to be phages, generally in an order of magnitude higher than bacteria. With an estimated unit number of 1031, phages are the most abundant biological lifelike constituents of our biosphere.[19–21] In fact, one could say that we live in an ocean of phages. But this does not automatically mean that all phages are safe at therapeutic concentrations. No phage-related nucleic acid sequence can be found in our genome, unlike the huge amount of human endogenous retroviral sequences, which make up 8–10% of the human genome.[22,23] Some phage-related polymerase gene sequences were identified in human mitochondrial DNA. It is common knowledge that mitochondria originated from Rickettsia-like ancestor bacteria that started a symbiotic relationship with prototype eukaryotic cells.[24] Phage DNA was likely introduced in the bacterial phase of the mitochondrion, at the time when the evolutionary split occurred between the prokaryotes and eukaryotes (endosymbiotic era), and does not constitute evidence for recent DNA exchange. Moreover, recent work suggests that even the eukaryotic nucleus itself is a viral import.[25] It is possible that phage sequences did enter the human genome, but were lost over time. In addition, entry into our germline may be irrelevant to the potential for causing harm, and we do not know how often phage DNA integrated into human somatic cells. One must also consider that the potential adverse effects of phages might not be caused by them acting as viruses. Researchers from the Hirszfeld Institute of Immunology and Experimental Therapy in Poland found phages to be constantly present in human and animal bodies,[26] where they were shown to modulate immune functions[27] and interact with cancer cells.[28] It is virtually impossible for a phage to enter directly into a eukaryotic cell system and subsequently multiply since it requires prokaryotic-specific cell wall receptors and biochemical machinery for its attachment and replication (e.g., prokaryotic polymerases and tRNAs). However, we should also consider indirect ways for phages to enter eukaryotes, no matter how far-fetched they may be. For example, theoretically, a phage could integrate into a plasmid, which could then transfer from a bacterium to a eukaryote.

According to most supporters, however, phage therapy has been proven safe through the massive application of lytic bacteriophages in humans in the past. We conclude that, although there are indications that phages are not harmful for eukaryotic organisms, more research is needed.

Today, a few laboratories and small and medium enterprises are developing phage cocktails or phage-based products for the treatment of bacterial infection.[29] This antibacterial therapeutic approach was first proposed by Felix d'Herelle almost a century ago. The first therapeutic application of phages probably occurred as early as 1919 in Paris, where d'Herelle used phages to treat patients suffering from bacterial dysentery.[30] Later, he founded the Laboratoire du Bactériophage in Paris, which produced five phage preparations for commercial use. They were marketed by the French company Robert et Carrière, which later was acquired by L'Oréal.[31] In the USA in the 1930s, pharmaceutical giants like Eli Lilly, Squibb & Sons (today Bristol-Myers Squibb) and the Swan–Myers division of Abbott Laboratories started marketing several phage preparations. Scientific uncertainties and the discovery and widespread marketing of antibiotics, however, relegated phage therapy to the history books in the western world. As such, the current 'knowledge' of the therapeutic effect of phages is mainly based on theoretical grounds, basic laboratory observations, animal models,[32–37] safety studies in healthy humans[38,39] and decades of empirical medical experience.[31,40–43] These empirical data were mainly accumulated in the former Soviet Union and its eastern European satellite states, with an important role for the Eliava Institute of Bacteriophage, Microbiology and Virology in Tbilisi (Georgia), several institutes in Russia and the Hirszfeld Institute in Wroclaw (Poland). Phage therapy remained a valid therapeutic component in France until the early 1990s.[44] Unfortunately, the historical clinical data are not taken into account by regulators because it has not been validated according to current western regulatory standards. The emergence of MDR bacteria has caused a renewed interest in phage therapy in western Europe and the USA, as illustrated by an exponential increase in phage therapy-related papers in the medical literature (Figure 1).

Figure 1.

PubMed search results for 'phage therapy' or 'bacteriophage therapy' across time periods.


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