Much has already been written about the history, successes, and failings of phage therapy. Most of the studies have focused on the use of lytic phages to destroy pathogenic bacteria 95,96
(). Clinically oriented phage research began very soon after the discovery of phages, with Felix d’Herelle using phages to treat bacillary dysentery in a number of human patients 8
. This optimistic start, however, led to a number of misconceptions and missteps, both scientific and political, regarding the use of phages. d’Herelle incorrectly assumed that there was only one universally efficacious strain of lytic phage 97
, though we now know phages exhibit exquisite host cell specificity. In the 1930s, pharmaceutical companies began distributing enormous amounts of lytic phages as generic antibacterial therapies, but in part because of the perceived universality of phages, they had very little knowledge of their product’s components.
Potential strategies for phage therapy
In retrospect, many of the commonly used phage preparations were destroyed by the organomercury preservatives added to the vials that contained them, or were contaminated with bacterial exotoxins secreted by the cultures used to generate them 98
. Inevitably these problems, along with manufacturing inconsistencies (the supposedly standardized strains of phages would change from batch-to-batch) led to distrust among the medical and scientific community.
The recent resurgence of phages as possible therapeutics has been driven by a number of factors. The alarming prevalence of antibiotic-resistant strains of pathogenic bacteria, combined with the inexorable spread of antibiotic-degrading enzymes, such as the New Delhi metallo-beta-lactamase (NDM-1), have led to calls for new therapeutic strategies 99
. From a practical standpoint, antibiotic discovery efforts have produced few novel compounds over the past decade 100
. Phages are a promising tool as they are easy to manufacture, have good host specificity, and can be readily genetically manipulated. Moreover, resistance to phages may develop more slowly than to antibiotics, though the reasons for this are multifaceted 101
. Phage resistance can occur spontaneously in cultures (as frequently as 1 in 105
cells), but there can be fitness costs associated with resistance. In contrast, many forms of antibiotic resistance cannot occur spontaneously, but instead require introduction of a foreign DNA element. In many ways, addressing bacterial resistance is much easier with phages than with antibiotics because one can isolate different phages, or phages may spontaneously mutate to overcome host resistance.
Perhaps a more interesting question, in the context of community dynamics and our growing understanding of the virome and microbiome, is whether we can produce more subtle phenotypic shifts in an ecological niche. Rather than destroy a single pathogenic member of a community, lysogenic phages could be introduced to promote a community structure that is beneficial to both the human host and microbial community members (). For example, one could expand the capacity of the gut microbiome to degrade dietary components102
. Similarly, phage could be used to introduce novel, beneficial traits to community members, such as those involving nutrient biosynthesis. In the latter circumstance, it may be difficult to introduce traits that are not purely beneficial to a lysogenic phage’s bacterial host, as the energetic effects of synthesizing an unnecessary protein impose a selection pressure.
Given the potential power and replicating nature of phages, a number of questions must be addressed before they can be more widely adopted including issues related to bio-containment 101
. Although phages are frequently sold as viruses that ‘can only infect bacteria’, their safety has yet to be completely defined. The intravenous administration of phage (e.g., in the case of bacterial sepsis) is particularly complex given the immunogenicity of some preparations and rapid clearance of phage particles by the reticuloendothelial system of the spleen 103
. It is tempting to assume that other routes of administration, such as oral cocktails of phage to target the human gut microbiome, would not have such effects. However, phage DNA is detectable by PCR and FISH in serum shortly after oral consumption 104
. Other studies have provided evidence of trans-placental passage of phage 105
. There is data suggesting that enzymes transcribed from phage DNA can be expressed in mammalian cells 106
, this finding has even led to attempts to use phage as gene therapy vectors 107, 108
Despite these concerns, we are exposed to millions of phages every day, including the ones from our own microbiota, without significant observable harm. In this spirit, it is interesting to consider the potential ‘therapeutic’ use of phages in the context of current efforts to apply microbiome-directed therapies 109
. Questions that can be asked include whether it is beneficial or detrimental for bacterial taxa being considered as candidate probiotics to possess or lack prophages or whether phages should be deliberately administered coincident with or preceding introduction of a probiotic consortium to help create niches that promote successful invasion and engraftment of the consortium.