Bacteriophages: the 100-year-old solution to AMR?
What has held phage therapy back given its vital curative potential? Zachary explains how research into these “bacteria eaters” has been hindered by Cold War rivalry and Big Pharma influence.
Down a small lane in Tbilisi, the capital of Georgia, the George Eliava Institute sits with its white-columned façade adorned with international flags, fluttering in the wind from the nearby Mtkvari river that flows down to the Caspian Sea. For some leading scientists in the field of microbiology, this site is considered to be a place of pilgrimage, owing to the exciting possibilities offered by the Institute’s area of expertise: bacteriophages.
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What are bacteriophages and why are they so interesting to scientists? Bacteriophages are viruses which work as “bacteria eaters”, as the direct translation of their full name indicates, but are often just referred to as ‘phages’. Remarkably, bacteriophages are thought to be the most abundant biological entities in the world. They infect bacteria much the same as how other viruses infect human cells—by attaching to their target’s cell surface and injecting their genetic material into the cell before replicating inside them. This eventually results in the bursting and death of their hosts and the propagation of the phages. Billions of years of complex coevolution between phages and bacteria have maintained this parasitic relationship, which now offers a vital alternative remedy to infections, tackling our reliance on our faltering mainstay: antibiotics.
Antimicrobial resistance (AMR), like climate change, is a sinister, creeping spectre, seeping into our modern day lives. It refers to the process whereby microorganisms, such as bacteria, adapt and lose their susceptibility to our medicines, such as antibiotics. Dystopian predictions of AMR’s impact no longer seem quite so hyperbolic, distant, or far-flung when multidrug-resistant infections are already complicating and exposing the limits of modern medicine. At least 50,000 people are currently thought to be dying annually in Europe and the United States alone from AMR infections. Disturbingly, it has been predicted that there will be 10 million deaths annually attributable to AMR by 2050, exceeding deaths attributable to cancer. Antibiotics have been instrumental in our success managing plagues, pandemics, and pathogens, but we are on the precipice of losing their incredible efficacy. And this is where phages come in—as vital alternatives against the growing threat of AMR.
“Billions of years of complex coevolution between phages and bacteria have maintained this parasitic relationship, which now offers a vital alternative remedy to infections, tackling our reliance on our faltering mainstay: antibiotics”
“Antibiotics have been instrumental in our success managing plagues, pandemics, and pathogens, but we are on the precipice of losing their incredible efficacy”
Different classes of antibiotics operate via different means, such as by preventing bacteria producing cell walls or new proteins, offering a ‘scattergun approach’ to infection therapy. In contrast, phages have very specific bacterial targets. By using the specific phages which target the bacteria causing us an infection, they can work as a far more precise and elegant route of treating infections than traditional antibiotics. Researchers have found and isolated phages from hot springs, wetlands, cold water and more: look for the bacteria you want to target, and you will find its phages. Once sourced and isolated, treatment (at its simplest) requires the application of the phages to the infection in need of a cure. Phages offer a completely different strategy of treatment compared to antibiotics, and could therefore galvanise our fight against current and future AMR bacteria and infections.
To understand more about phages, it is important to look back on their complex history. They were first discovered by a British microbiologist in 1915, but it was the independent discovery in 1917 by French-Canadian microbiologist Felix d’Herelle which led to their international recognition in the scientific world. Through his subsequent work, the clinical application of bacteriophages, ‘phage therapy’, became widespread in the Soviet Union. However, post-Second World War political fallout led to the decline in Western involvement, and the eventual collapse of the Soviet Union in the 1990s threatened to halt phage therapy altogether. Fortunately, the Eliava Institute survived, harnessing a small nest of phage therapy which continues today.
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Given phages were discovered over 100 years ago, and their potential to prevent deaths across the world, why aren’t they already a ubiquitous part of our medical arsenal? Soviet research quietly dominated throughout the twentieth-century, but was mostly published in Russian, Georgian, and Polish, limiting accessibility to Western scientists. Moreover, few clinical studies were produced which meet current standards of scientific rigour. Phage usage was more common as a means to an end in various other forms of biological research, playing a major role in discoveries such as that of DNA. Undoubtedly though, the discovery of antibiotics and their triumphant success was the greatest downfall for phages, resulting in disinterest and distraction from their curative potential.
However, with the increasing threat of AMR, international interest in phages has been truly rekindled, leading to many recent scientific achievements. Experimental phage therapy in mice has been used to treat bloodstream infections of Staphylococcus aureus, infections of burn wounds, and chronic chest infections with Pseudomonas aeruginosa. Early trials with humans suggest their safety in treating several conditions, including their use in leg ulcers and ear infections. The promising power of phages is further indicated by the exponential growth in published research, applications, and funding, with investment from the European Union, United States, and China.
“Given phages were discovered over 100 years ago, and their potential to prevent deaths across the world, why aren’t they already a ubiquitous part of our medical arsenal?”
So, what is still holding phage research back? The results from rigorous clinical trials in phage therapy remain limited, with praise often arising from success in small singular examples. Meeting pharmaceutical quality and safety standards is a significant stumbling block too. Bespoke, personalised phage therapy is likely the best way for phages to be administered given their specificity to certain bacteria, but the regulatory framework is particularly unaccommodating to this approach. The unique nature of phages makes passing them through the necessary bureaucratic and legislative hoops akin to trying to fit a square peg through the round, rigid hole of current standards. The adoption of new regulations specific to phages is likely to be necessary and is already being pioneered in Belgium.
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Poor industry interest in antimicrobials is also a challenge that needs to be overcome in order to fund the research that will deliver future clinical needs. From the perspective of pharmaceutical companies, why should they invest in drugs which quickly solve infections, are usually sold relatively cheaply, and—thanks to fears of resistance—need to be limited in their use? The natural availability of bacteriophages may be a factor too: it will probably make them cheaper and harder to patent, thus further reducing industry interest. The public should not be forgotten either: will there be reluctance to accept a therapy involving the administration of viruses?
Many questions still remain, especially around the biggest worry of all: resistance. It is known that bacteria in nature have the ability to develop some resistance to phages, but how big a limitation this will be for their clinical use remains unknown. Strategies such as using phage cocktails have shown promise at limiting the emergence of resistance, but much more research is needed.
Despite these hurdles, we must remember the human cost of AMR, which is best illustrated through individuals rather than statistics: from the elderly relative accursed with a chest infection, to the child who becomes septic from an infection that starts in a small scratch. Both are currently and readily treatable, but for how long? Phages offer hope, and a plausible answer. Only time will tell if national rivals can finally unite against common fiends of infectious diseases and the rising risk of AMR. The ancient biology of phages is an untapped potential solution to this global problem that urgently requires our research and interest.
Acknowledgments
I would like to thank Professor Martha Clokie of the University of Leicester for the inspiration for this article, upon providing a talk on phages to the University Public Health Society during 2021 Antimicrobial Awareness Week. I would also like to thank the committee of the society, in particular president Elena Perez Fernandez, for the encouragement and help in drafting this piece.
