Ebola virus, HIV, SARS virus, and just recently, COVID-19 -- we commonly associate viruses with some of the deadliest infections in history. However, did you know that the next “wonder therapeutic” that could save the world may actually be a virus?
The Ganges, an ancient and historical river exalted in India and the world, was not only known for its sacred role in Hinduism but also in its miraculous healing property. For centuries, people were drawn to this river to seek for its miracle, while scientists were baffled by its inexplicable therapeutic quality. As early as 1896, scientists proved that the river possesses antibacterial property—that is, the water effectively kills disease-causing bacteria.1 In 1915, Frederick William Twort, a British physician, discovered an “invisible agent” that caused a similar antibacterial phenomenon. Later on, in 1917, Félix d’Hérelle, a French microbiologist, identified that this mysterious agent in the river is actually a virus which he named “bacteriophage,” literally a “bacteria eater.” 2
Bacteriophage, or simply phage, is a type of virus commonly visualized as a particle with head, tail and injector mechanism—much like a hybrid of a spacecraft and a spider. In reality, phages come in different shapes and types, but their unifying trait is that they only infect bacteria. They do this by injecting their genetic material into the bacteria, serving as the seed that creates progenies of phages which will eventually burst out of the bacterial cells. Knowing this, scientists found useful applications of phages specifically in combating disease-causing bacteria. Phages played a vital role during the Winter War of the USSR and Finland and have been used extensively to treat common infections in Europe and USA.3 Its success was also made known to the public with the publication of the Pulitzer Prize-winning novel “Arrowsmith” where the main character utilized phages to end the infamous plague. However, the fame and utility of phages were short-lived with the introduction of antibiotics for treating infections.
Antibiotics played a huge role in ending the reign of deadly infectious diseases. Unfortunately, with the rampant misuse of these drugs, we are now facing another dark age in our history—an age where antibiotics are not effective anymore. An age where a simple wound, cough or fever may cause death. This global threat is what we now know as the antibiotic resistance phenomenon. In fact, antibiotic-resistant organisms, commonly referred to as “superbugs,” are now reported in all parts of the world— this paved way for the scientists to revisit phages to survive the incoming onslaught of untreatable infections. The use of phages in various aspects of society particularly in medicine, industry, and agriculture is called phage therapy.
Superbugs meet Supervirus
The burden of antibiotic resistance in the world, particularly in Asia, has been drastically increasing in the past years, significantly in the healthcare setting. Antibiotic resistance caused treatment dilemma for physicians as experienced by Dr. Raul Destura, an infectious disease specialist and Deputy Executive Director of the Philippine Genome Center. “In the recent years, we have seen patients who are virtually resistant to all antibiotics, making the management of moderate to severe infection a huge challenge,” Dr. Destura recalled. For this reason, innovative and alternative ways of combating multidrug resistance in the healthcare setting serve as our future weapons. These include new antibiotics, new chemical entities or new biocontrol agents. Dr. Destura highlighted that using phages to control microorganisms within the human host seems to be the most promising option.
Dr. Donna May Papa, a pioneer phage researcher at the University of Santo Tomas, Philippines, and her research associate Ms. Tracey Gutierrez, agreed to this by highlighting the ideal properties of phages. “Phages are ubiquitous and can be easily obtained in any environment. In addition, phages are known for their [high] specificity. This provides a faster generation of phage preparations that are specific for [treating infections caused by] certain bacterial pathogens,” they mentioned.
Actual applications of phage therapy in humans were done in clinical trials. Scientists see this application as a promising future in human therapeutics since phages only specifically infect its target disease-causing pathogens and have fewer side effects than traditional antibiotics. In fact, in countries like Georgia, phage therapy is now routinely used to treat infections caused by superbugs, notably Methicillin-Resistant Staphylococcus aureus (MRSA), a common cause of serious untreatable skin infections.4 Cases of successful utilization of phage therapy are continuously reported in literature, holding on to phage therapy’s promise as an alternative to antibiotics. “It’s really an alternative to antibiotic treatment for patients with a failing fight with extremely drug-resistant infections!” Dr. Destura exclaimed.
Alarmingly, as a universal phenomenon, antibiotic resistance is not only limited to the healthcare sector; it also poses a significant problem in veterinary, agricultural and food industries. Fortunately, phages also have a universal property—they kill superbugs found in every environment.
Phage Therapy for All
Humans are not the only beneficiary of phage therapy. Researchers in the Philippines have found innovative and sustainable ways to apply phages for the treatment of infections in both animals and plants.
In one of the projects of Dr. Papa, her team successfully treated blood infection in the important aquaculture fish Tilapia using phage that specifically targets Aeromonas hydrophila, a common cause of fish sepsis. The team found that phage therapy performed similarly with the locally used antibiotics and is also safe for the fish.5 The use of phages instead of antibiotics also lessens the “antibiotic pollution” which poses a negative impact on aquaculture sites. Dr. Papa’s team also found useful applications of phages in the meat industry. Remarkably, they were able to use phages to significantly reduce the number of pathogenic Salmonella enterica in raw chicken meat locally.6 This application may help ensure that meat products sold to local markets are safe and within the acceptable standards.
In the agricultural sector, phage therapy is also gaining appreciation. “Bacteriophages may have two important applications [in agriculture]– one is in the management of plant diseases and the other is in food safety,” Mr. Johnny Balidion, a plant pathologist and researcher at the University of the Philippines Los Baños, elaborated. According to him, phages are promising solutions in treating the previously untreatable crop infections caused by bacteria, notably the soft rot disease of vegetables. Getting his inspiration from an experience in USA where phages are used to manage contamination in fresh produce, he served as one of the project leaders for a government-funded research on the potential use of phages as biopesticide for soft rot disease in vegetable crops.7 He sees phages as safer and ecologically-friendly alternative for chemical pesticides which are known to be unsafe for humans and the environment. “Eventually, we look forward to a bacteriophage-based biopesticide formulation that will significantly reduce soft rot disease incidence that will be available for use of the vegetable growers and farmers alike,” he added.
The Rise of Phage Therapy in Asia
The renewed interest in the potential use of phages in addressing the threat of antibiotic resistance provides a glimmer of hope in the upcoming dark age of superbugs. This reaffirmation for phage therapy is particularly important since we are seeing a continuous increase in the number and types of superbugs that will have a negative impact not only in human but also in animal and plant health. However, as with any new therapeutic agents, challenges in phage use are still evident. For instance, regulatory guidelines relating to phage applications in any sector are non-existent in most Asian countries. This roadblock prevents scientists from moving forward in applying phages as an actual therapeutic option.
Besides, only few researchers are specializing in phages. Hence, for Dr. Papa and Mr. Balidion, the field of phage therapy is the greener pasture. More things have yet to be discovered, especially in various Asian regions where the biodiversity of microorganisms are among the richest in the world. In particular, the fields of ecology and evolution relating to phages are promising areas to study. “Extensive research on phages from sediment, marine, freshwater, and terrestrial samples can be done in order to understand their ecology and host specificity,” Dr. Papa said. Meanwhile, Mr. Balidion also shared that long-term efficacy of phage therapy and phage resistance are fertile areas for exploration.
Lastly and most importantly, negative public perception of the use of viruses for treatment is still widespread. Hence, the full potential of phage therapy applications including its possible economic benefit is often neglected. “Educating people and communicating phage therapy benefits to the public is the key,” Dr. Destura mentioned.
Today, as the Ganges flows serenely, so are the millions of phages lurking in its waters. Just like a river realizing its fate in the ocean, there is a hope that phage therapy will also reach its full potential as the new and sustainable wonder therapeutic that will end the reign of antibiotic resistance in the different sectors of society. As the battle between superbugs and humanity rages on, may phages be our weapon and our battle cry be “Virus is the Solution!”
- 1.Abedon ST, Thomas-Abedon C, Thomas A, Mazure H. Bacteriophage prehistory: Is or is not Hankin, 1896, a phage reference?. Bacteriophage. 2011;1(3):174–178. doi:10.4161/bact.1.3.16591
- 2.Keen EC. A century of phage research: bacteriophages and the shaping of modern biology. Bioessays. 2015;37(1):6–9. doi:10.1002/bies.201400152
- 3.Moelling K, Broecker F, Willy C. A Wake-Up Call: We Need Phage Therapy Now. Viruses. 2018;10(12):688. Published 2018 Dec 5. doi:10.3390/v10120688
- 4.Kvachadze L, Balarjishvili N, Meskhi T, et al. Evaluation of lytic activity of staphylococcal bacteriophage Sb-1 against freshly isolated clinical pathogens. Microb Biotechnol. 2011;4(5):643–650. doi:10.1111/j.1751-7915.2011.00259.x
- 5.Dela Cruz-Papa DMA, Candare CMG, Cometa GLS, et al. Aeromonas hydrophila Bacteriophage UP87: An Alternative to Antibiotic Treatment for Motile Aeromonas Septicemia in Nile Tilapia (Oreochromis niloticus). Philipp Agric Scientist. 2014;97(1):96—101.
- 6.Avena MAC, Gumafelix RE, Mamuric GA, et al. The effect of storage temperature (4C) on the activity of isolated bacteriophage against Salmonella spp. isolated from raw chicken. Transactions of the National Academy of Science and Technology. 2013;35(1):98-x
- 7.Pelegrina LD and Nguyen MNR. DOST-PCAARRD Initiative to Use Viruses against Soft Rot-Causing Bacteria. Accessed from: http://www.pcaarrd.dost.gov.ph/home/portal/index.php/quick-information-dispatch/3076-dost-pcaarrd-initiative-to-use-viruses-against-soft-rot-causing-bacteria on November 2019.
Mark Carascal is a Registered Microbiologist and Science Research Specialist at the Clinical and Translational Research Institute of The Medical City, Philippines. His research interests include clinical and molecular microbiology, particularly focusing on ways to detect, characterize and treat multidrug-resistant pathogens.