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Kim Dueno “What the Phage?”

What the Phage?

There is an enormous world that goes largely unseen and unnoticed. The infinitesimal scale of this world is almost as difficult to comprehend as the galactic scale of the universe.  In and around us, entire generations of organisms are dying out or evolving into something new. The speed at which microorganisms can replicate and mutate puts science at a distinct disadvantage. In the time it takes to identify a pathogen, sequence its genome, and create a treatment, the microorganism may have changed. Instead of playing cat and mouse with the pathogen, there is a way to fight this battle with a different mentality altogether.

Bacteriophages (phage) are viruses that attack bacteria and are not harmful to the bacteria’s host (Tortora 360). Accounting for some of the smallest organisms on the planet, phages are miniscule. At a whopping 24 nanometers in size, these genetic powerhouses make up for their small size with their single-minded determination for replication. One of the most abundant and diverse organisms on the planet, they have crafted the genetic variability of virtually every other organism known to science (Clokie).

Made up of nothing more than a head with proteins, an inner core of DNA or RNA, and a hollow tail, bacteriophages are obligate intracellular parasites. This means that they cannot reproduce outside of their host organism (Tortora 363). Phages come in two known varieties. There are virulent phages and temperate phages. Virulent phages destroy the bacterial host by replicating until the bacterium bursts open. Temperate phages are the strong silent type. After attachment and deposit of genetic material, the phage stays inactive until an unknown trigger turns the phage into a virulent type (Lou). The full history of the phage is not completely known and surely goes back as far as the primordial ooze that started life on our planet.

For all intents and purposes, William Twort and Felix d’Herelle discovered bacteriophages at the same time. According to Duckworth, in 1915, in a meagerly funded lab, Twort made an accidental discovery. While trying, and failing, to grow viruses on sterile agar plates, he noticed peculiar behavior on plates inoculated with unfiltered small pox vaccine. While the small pox virus did not grow, the unfiltered fluid grew a micrococcus bacteria. The plates showed areas of bacterial stagnation due to an unknown reason. Although the phenomenon was well documented by Twort, he failed to make any conclusive statement about the mysterious agent that he named “the glassy transformation” (Duckworth 794).

Felix d’Herelle, a self-taught microbiologist on WWI French battlefields made and acted on one of the most important discoveries in biology. In his book, A Planet of Viruses, Zimmer discusses the amazing discovery made by d’Herelle. In 1917, sick and wounded French soldiers were dying due to a dysentery outbreak. Dysentery is an intestinal infection caused by the bacteria Shigella dysenteriae that caused diarrhea and dehydration that easily led to death during the 1900s (Tortora 300). d’Herelle noticed that some of the dysentery infected soldiers would seemingly heal themselves after five to seven days of initial onset of the illness. Curious as to why this was happening, d’Herelle took stool samples from the soldiers who were sick but able to get well and passed it through a filter. The filter was so small that the bacteria that caused the infection could not pass through. He then applied this clear fluid to cultured plates of Shigella dysenteriae bacteria. What he noticed were areas of clearing where the filtered fluid was applied. He concluded that there was something present in the filtered fluid that was killing the bacteria. He named this “material” bacteriophage, which means “eaters of bacteria” (Zimmer 34). With lack of options, d’Herelle tested the treatment on himself. After suffering no ill effects, he administered the treatment to those sick with dysentery. d’Herelle ended the outbreak of dysentery and is credited by many in the microbiological community as the founding father of the bacteriophage and modern biomolecular science.

This was only the first recorded use of phage therapy. A closer inspection of history may reveal phage use through the ages. In folk lore, there is a suspicious resemblance to unexplained mystic healing and documented cases of successful phage therapy. Take for instance the Ganges river in India, one of the most polluted bodies of water in the world. Millions pilgrimage to the Ganges in search of spiritual and physical healing each year. Yet, the instance of illness that can be directly connected to the river is statistically negligible. The reason for this is thought to be the great diversity of phages in the water (Koshy). Phages are literally everywhere just waiting to be found.

Langue de chien, langue de médecin- a dog’s tongue is a doctor’s tongue is a contemporary French saying. Consider Saint Roch, the patron saint of dogs. It is told that he was healed of the plague by a dog licking his wounds (Fliz). Also, folk stories of native Inuit people using frozen sled dog saliva to cure infected wounds appears to be more than just talk. A study of the diverse phage content of dog saliva lends credibility to these tales (Diep). It is not advisable to smear dog saliva on open wounds as a first choice for treatment. There is however, antidotally at least, a connection here that warrants further research.

The once isolated eastern European block was denied access to many pharmaceutical and medical advances during the cold war. Using relatively out of date equipment, phage therapy was crafted into an art out of sheer necessity. Now the world-wide leaders in phage therapy, countries like Georgia and Poland are proving that everything old will be new again (bell-bottoms and the Rachel hair style not withstanding!)

Head to any corner drug store in Georgia and you’ll find an antiseptic spray that is used like Bactine (Martin). The active ingredient in this spray is not benzalkonium chloride, however (Bactine). Unlike Bactine, alcohol, or traditional antibiotics, the use of phage therapy will not kill good bacteria. A bacteriophage cocktail can be purchase to self-treat bacterial infection such as Staphylococcus aureus. The narrow range of phages is a benefit, not a hindrance for most patients. If the infection is not staph, the patient may not improve but they will not suffer ill effects from the phage use nor will they contribute to the growing crisis of multi drug resistant organism (MDRO) infections.

Phage therapy has a long history of successful application for a number of ailments. According to The Phage Therapy Center website, simple infections like acne to serious MDRO infections can be treated with phage therapy. In affluent countries like the US and Canada, desperate patients and doctors are looking to these medically less advanced countries for answers. Zimmer recalls a story of an otherwise healthy 40-year-old man who was facing amputation of his leg. After years of painful treatments for a wound infected with a MDRO that included multiple surgeries and side-effect heavy antibiotic treatments, his last resort looked to be amputation. John was saved from this fate because of a courageous doctor. His doctor ordered a phage cocktail, presumably from Tbilsi, Republic of Georgia, that cured his infection, saved his leg, and gave him back his life. Patients and doctors should not have to resort to extensive travel or smuggling bioactive drugs into the US.

The variety of phages in nature are unknown but thought to be 10^9 (Phage Therapy Center). It is estimated that more than 6000 bacteriophages have been identified and categorized (Wittebole). Within this living natural pharmacy, cures for a multitude of diseases wait to be discovered. With such a powerful weapon in our biological arsenal, one has to question why isn’t phage therapy more prevalent in the USA? The fear of medically induced viral infections, use of genetically modified organisms, or the snail like speed and prohibitive bureaucracy of FDA approvals may have prevented the wide spread use of phage therapy in western medicine. Either that or capitalist driven greed that disregards humanities well-being for the almighty dollar. (I digress due to the fact that I wish this research paper to be about science, not conspiracy theory, but it makes you wonder…) Regardless of the reason, the current epidemic of MDRO infections is pushing doctors and patients toward alternative treatments for life limiting and life threatening infections.

Direct phage use is currently FDA approved for limited applications in the United States. Phage use is being employed in agriculture and farming. The use of phages to replace pesticides on crops and antibiotics in livestock continues to be at the forefront of agricultural science (Gill). Another important application is as a food additive to combat biofilms in lunch meat and in food processing plants to retard the growth of many dangerous drug resistant bacteria. Since mid-2006 an estimated 2500 people annually have been spared from illness or death from Listeria monocytogenes (Coughlan). The number lives that could be improved or saved if phage therapy was FDA approved is incomprehensible. The next logical step is to use phage therapy for human treatment.

The amount of time and money for phage therapy research coupled with the exhaustive FDA regulations required make phage therapy an option that may come too late for many. According to Merabishvili, “…the clinical application of bacteriophages for treatment of infections of humans in modern western medicine is stuck in a vicious regulatory circle. Under the current regulatory framework, bacteriophages do not exist because of the lack of clinical trials – yet to perform these trials one needs a regulatory existence.”

While there are currently no human FDA approved phage treatments in the United States, all hope is not lost. Prior to 2000, no human trials were FDA approved for phage treatment (Wittebole). Once that restriction was lifted, phage therapy research took off. There seem endless applications for phage therapy. By using the biology of other microorganisms, we could form an army of soldiers that follow the same rules as the enemy. An army with accelerated replication and genetic specificity could be utilized to target and destroy harmful pathogens, rogue immune cells and overzealous normal cells that have turned cancerous.

Consider the lytic (dissolving) nature of certain phages (Tortora 318). By genetically modifying a phage so it “infects” only scar tissue or tumors, this viral army of cleaners could remove damaged tissue and possibly reverse autoimmune damage or non-surgically remove tumors. This would seem to be a novel use of phages but really, it’s just capitalizing on what they natural do. This fighting fire with fire mentality has extensive applications in infectious disease therapies. Bacteriophages are built to sneak into a bacterium and turn its’ machinery into a virus replicating factory. When more of the viruses are replicated by the bacteria, they continue to seek out other bacteria and infect them (Cann 214). As a self-replicating “antibiotic”, bacteriophages seem to be designed by nature as a checks and balances implement that is foolishly not being utilized.

The future for phage therapy is uncertain at best. FDA approvals, GMO opposition and big pharma present obstacles that may be too great to overcome. What is certain however is that we cannot afford to ignore the abundant well of natural resources at our fingertips. There are no simple answers to the many issues surrounding bacteriophage use. However, fear of the unknown, lack of resources, or a capitalist agenda should not hinder this important research. Balance in all things is a motto that applies to all life no matter how great or small. When humans upset the delicate balance between organisms without fully understanding the implications, we are playing a dangerous game. Ultimately, we may be forced to look to nature for answers to many pressing men made environmental and medical crises.

Citations

Bactine, (2016) www.bactine.com/original

Clokie, Millard, Letarov, Heaphy, et al. (2013) “Phages in Nature.” Bacteriophage 1.1, 31–45. PMC. www.ncbi.nlm.nih.gov/pmc/articles/PMC3109452/

Coughlan, et al. (2016) “New Weapons to Fight Old Enemies: Novel Strategies for the (Bio)control of Bacterial Biofilms in the Food Industry.” Frontiers in Microbiology 7, 1641. PMC.

Diep, Francie (2013). Humans share microbiomes with their dogs, study finds. Popular Science. www.popsci.com/science/article/2013-04/humans-share-microbiomes-their-dogs-study-finds

Duckworth, D. (1976). “Who Discovered Bacteriophage?”, American Society for Microbiology, Vol 40, No 4.  p. 793-802, www.mmbr.asm.org/content/40/4/793.full.pdf

Filz, Gretchen. (2016). The story of St. Roch, patron saint of dogs and dog lovers. Get Fed. https://www.catholiccompany.com/getfed/st-roch-patron-of-dogs/

Gill (2016) Bacteriophage Ecology and Plants, The American Phytopathological Society,      www.apsnet.org/publications/apsnetfeatures/Pages/BacteriophageEcology.aspx

Los, Niedziolka-Jonnson, Leśniewski. (2016)  Phage Consultants.  www.phageconsultants.com/temperate-phages,16,pl.html

Koshy, Jacob. (2016) Testing the waters: Lab study healing power of Ganga, The Hindu. www.thehindu.com/news/national/Testing-the-waters-Labs-study-healing-powers-of-Ganga/article14416817.ece.

Martin, (2003) How Ravenous Soviet Viruses will save the world, Wired, https://www.wired.com/2003/10/phages/.

Merabishvili M, Pirnay J-P, Verbeken G, Chanishvili N, Tediashvili M, Lashkhi N, et al. (2009) Quality-Controlled Small-Scale Production of a Well-Defined Bacteriophage Cocktail for Use in Human Clinical Trials. PLoS ONE 4(3): e4944. doi:10.1371/journal.pone.0004944

Phage Therapy Center (2016), www.phagetherapycenter.com/pii/PatientServlet?command=static_more&secnavpos=0&language=0

Pires DP, Cleto S, Sillankorva S, Azeredo J, Lu TK. 2016. Genetically engineered phages: a review of advances over the last decade. Microbiol Mol Biol Rev 80:523–543. doi:10.1128/MMBR.00069-15.

Tortora, Gerard. Berdell Funke. Christine Case. (2016) Microbiology an Introduction.

Wittebole, X., De Roock, S., Opal, S. M. (2014). A historical overview of bacteriophage therapy as an alternative to antibiotics for the treatment of bacterial pathogens. Virulence, 5(1), 226–235. doi.org/10.4161/viru.25991.

Zimmer, (2011) A Planet of Viruses, University of Chicago Press.: Chicago, Illinois, USA.2011. ISBN: 978-0-226-98335-6