Phage therapy needs to be beneficial for the patient. Potential side effects, such as: phages causing bacterial toxins to spread during lysis, phages mutating and then start harming good bacteria, and phages transforming bacteria to become more anti-resistant, should be addressed before phage therapy receives approval for human use. Along with these risks, other factors that should be considered when using phage therapy include which phage components are manipulated, the pathway of administration, and best practices for ensuring patient recovery. One main experiment that should be performed before phage therapy is approved for human use would investigate ways to make phage therapy the most beneficial and safe for use. With this in mind, I propose an experiment that specifically examines what would be administered to patients and would answer the question of what phage therapy design would ensure patients with the best recovery with the lowest amount of risk.
In Kuchment’s The Forgotten Cure, many phage therapy companies have designed different therapies to be administered. These companies therapies can be divided into the categories of whole-phage focused or “single biological entity” focused (98). Intralytix uses the whole-phage focused approach when they created a multi-lytic phage cocktail. The FDA opposed their work since they had no reliable method of ensuring only lytic phages were present in the cocktail. Also, the VRE cocktail was only tested on mice which are not immunocompromised to VRE, and company findings did not report the speed and the effects of mutations. Shifting towards component-focused therapies, GangaGen addressed the problem of determining whether the phage is virulent or temperate by removing the its endolysin, a protein responsible for cleaving the bacterial host’s peptidoglycan wall. Ramachandran, the founder of GangaGen, hypothesized that “without a ‘burst,’ no toxins or phages would be released into the patient’s body. The fewer the number of phages, the lower the chance that a virus would swap genes with a bacterial cell” (94). In 2001, an experiment was performed using phages without endolysins which resulted in inactive E. coli and no plaques. Another protein GangaGen looked into was tail proteins responsible for the initial hole allowing for DNA to be transferred into the bacterial cell. Their idea was to have the phages create the initial hole but not allow them to seal it back up. It was hypothesized since there was “no DNA going in to repair the hole, so it remains open, and eventually the cell dies because the membrane collapses” (110). Later, this phage tail protein was combined with lysostaphin, a protein that binds and kills bacterial cells, to create the drug StaphTame. Fischetti’s private company decided to abandon using phages for their enzymes.
With the creation of many different phage therapies, an experiment should look into comparing the effectiveness of therapies to each other. Each group would receive one of the following phage therapies: singled lytic phage cocktail, Intralytix’s multi-phage cocktail, GangaGen’s phage tail protein, StaphTame, Ramachandran’s endolysin-less phages, Fischetti’s phage enzymes, or no treatment, which would serve as a control. Also, the experiment should consider having an endolysin cocktail group to determine its effectiveness when compared to the edited phage tail proteins. Another set of groups should receive an antibiotic paired with one of the other therapies. Multiple trials would be performed on different organisms. Many control variables, such as the bacterial host used for infection and the way and rate of administration, would remain consistent among all groups to provide reliable results. This experiment would record the amount of infection and any side effects over the course of the experiment. The results from this experiment would reveal which therapy out of the ones mentioned in The Forgotten Cure would be the most beneficial and safest to use.
