Team:WPI-Worcester/Beyond-the-Bench
Beyond the Bench
Lysogenic Phage Therapy Safety Analysis
Phage therapy has recently been experiencing a revival, with dozens of studies being done on the therapy’s efficacy and safety. In his 1999 review, Richard Carlton identified several problems that needed to be overcome in order for phage therapy to become a viable option, and solutions to those problems. Like most research about phage therapy, this review referred to lytic phages. Lysogenic phage therapy, which we propose as an application for our research on biofilm self-inhibition, has been little discussed, and presents different problems to be overcome.
Several of Carlton’s problems and solutions apply to lysogenic phages as well: for example, excessive specificity can be combated by the development of phages that affect all or most strains of a particular species; and the body’s rapid removal of phages can be combated by the development (some of which has already been completed) of phages that exit the body at a slower rate. However, lysogenic phages present different concerns that must be addressed.
The most pressing concern is safety in humans, which is necessary in order to develop a viable treatment option. The effects of foreign proteins can be wide-ranging, from harm caused to natural flora to allergic reactions and adverse interactions with medications. Human intestinal flora includes potentially beneficial biofilms (Macfarlane and Dillon, 2007), so care would need to be taken to ensure that the phages selected for therapy were specific enough so as not to disrupt the natural balance of those beneficial biofilm-forming bacteria. Like Crevel et al. in 2002, we propose that antifreeze proteins that come from common food products are not dangerously toxic when consumed; however, there is very little data on the safety of undigested AFPs being released into the body. AFGP8 (not one of the proteins we tested) has been shown to be cytotoxic to human embryonic liver and kidney cells at sufficiently high concentrations (Liu et al. 2007), and a preparation equivalent to MaAFP, one of the proteins characterized through our research, was determined to have no toxic effects, and no adverse effects in individuals with allergies to the organism of origin (Hall-Manning et al. 2004). These widely different results are to be expected. Due to the hugely diverse structure of AFPs, generalization of such toxicity studies is unlikely to provide any useful insight. Instead, further research will be needed on individual AFPs in order to determine their safety for use in humans.
Another potential safety concern unique to our proposed lysogenic phage therapy would be the issue of modified DNA, by necessity, entering the environment. The transfer of genetic material from lysogenic phages (also known as prophages) to bacteria has been shown to have long-term effects: bacteria and their specific phages co-evolve, with phage DNA being responsible for much of their related bacteria’s genetic diversification. Some bacteria even require the presence of phages to cause certain diseases (Brϋssow et al. 2004). The long-term ecological impact of AFP-secreting bacterial cells in the environment is unknown and must be explored further.
References
Brüssow, Harald, Carlos Canchaya, and Wolf-Dietrich Hardt. 2004. Phages and the Evolution of Bacterial Pathogens: from Genomic Rearrangements to Lysogenic Conversion. Microbiology and Molecular Biology Reviews 68 (3):560-602.
Carlton, R. M. Phage therapy: past history and future prospects. (0004-069X (Print)).
Crevel, R. W., M. J. Fedyk Jk Fau - Spurgeon, and M. J. Spurgeon. Antifreeze proteins: characteristics, occurrence and human exposure. (0278-6915 (Print)).
Hall-Manning, T., A. M. Spurgeon M Fau - Wolfreys, A. P. Wolfreys Am Fau - Baldrick, and A. P. Baldrick. Safety evaluation of ice-structuring protein (ISP) type III HPLC 12 preparation. Lack of genotoxicity and subchronic toxicity. (0278-6915 (Print)).
Liu, S., Elisabeth von Wang W Fau - Moos, Jessica Moos Ev Fau - Jackman, Geoff Jackman J Fau - Mealing, Robert Mealing G Fau - Monette, Robert N. Monette R Fau - Ben, and R. N. Ben. In vitro studies of antifreeze glycoprotein (AFGP) and a C-linked AFGP analogue. (1525-7797 (Print)).
Macfarlane, S., and J. F. Dillon. Microbial biofilms in the human gastrointestinal tract. (1364-5072 (Print)).