Anca Segall, Dwayne Roach and Steffanie Strathdee recently published a perspective on phage-antibiotic synergy. They conclude that co-treatment with phages and antibiotics has the potential to extend the utility of antibiotics currently in use, though much basic and clinical work remains to be done before this can become a routine option for hospitals.
Amelia McKitterick and colleagues at UC Berkeley and the icddr,b in Bangladesh have published a new preprint on how Vibrio cholerae phage “satellites” (parasites of phages) adapt to their ever-evolving phage targets.—Provide comments on their preprint here!
PhagoMed, an Austrian phage therapy company, announced this week that it’s received 1.5 million Euro in additional investment!
Listen to Paul Turner of Yale describe his group’s phage research and phage therapy work (they’ve treated 16 patients so far!) on This Week in Evolution (TWiEVO), an ASM podcast. This one was recorded live at last week’s ASM Microbe conference. Fascinating insights! (Phage talk starts around 18 minutes in)
Submissions are now open to a new Bacteriophage Collection within the journal Microbial Genomics (a Microbiology Society journal). Here’s their tweet: #Bacteriophages are a key tool in biological research, and this new collection will bring together research focussed on the role of phages in #evolution of bacteria and #ecosystems, and large-scale genomic analyses that can inform new phage therapies. This collection will be guest-edited by Prof. Testuya Hayashi (Kyushu University, Japan).
The microbes that live inside our guts are mostly a mystery to science. We know they have an impact on our health and wellbeing that extends far beyond the gut but science currently doesn’t fully understand how or why. You can be part of this grand scientific endeavour to understand the microbes that live inside us all.
As a bioinformatician supporting this Programme, you will work with vast datasets of metagenomic sequence data (truly BigData) and will gain experience with cutting edge sequencing technologies, such as those from Nanopore and PacBio. At your disposal will be a massive OpenStack cloud computing system with hundreds of terabytes of disk space and thousands of computing cores.
You will be embedded within the core bioinformatics team for the Quadram Institute, so will be surrounded by experienced bioinformaticians, providing a friendly environment to enhance your skills. In this rapidly changing field you will have the opportunity to work with researchers on publishing new methodologies, which we make available as open source software on GitHub.
Required Special Knowledge, Skills, and Abilities:
40%: Maintain common laboratory and/or technical equipment, and train new users. Maintain common research supplies. Maintain laboratory safety records and protocols. Organize and update laboratory research protocols and research material stocks.
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5%: Other Duties as required
The phage community has an awful lot to be happy about right now. Thanks to the hard work of dedicated scientists, physicians, and advocates, phage therapy is increasing in popularity and prominence. These experts are on the front lines in the fight against the dramatically increasing incidence of multi-drug-resistant (MDR), extensively-drug-resistant (XDR), and even pan-drug-resistant (PDR) bacterial pathogens.
The nature of the rise of these pathogens—namely, the evolving failure of conventionally developed small-molecule drugs—has taken modern phage therapy on an unorthodox ride through a rugged regulatory landscape that was not designed to accommodate its unique qualities. High-profile stories like the world-famous “Perfect Predator” case and the genetic engineering of phages for personalized treatment have framed phage therapy in sharp relief, but medical regulations around the developed world have not yet kept pace with developments. This poses challenges to the short- and long-term evolution of phage therapy into a mainstream practice for the treatment of bacterial infections.
So how do we navigate this administrative quagmire to speed up and expand the delivery of phage therapy in the timeframe necessary to treat infected patients? In this piece, I will briefly discuss key parts of this infrastructure, how they help and hinder us, and a few tangible action items that we can support to benefit our field.
Many of the most high-profile cases of recent phage therapy have been enacted through “compassionate use”—the emergency review and approval to use unorthodox or unlicensed drugs or devices to treat patients for which conventional measures have failed. This reflects the contemporary state and purpose of phage therapy—a personalized, last-ditch effort to treat critically ill patients for whom antibiotics have failed or are failing fast.
The regulatory framework for compassionate use has been established in many countries. For example, the Food and Drug Administration (FDA) directly handles these cases in the United States, often hand-in-hand with emergency investigational new drug applications, tailored for specific patients. In contrast, the European Medicines Agency (EMA) delivers broad guidelines and regulations upon which member states of the European Union can craft their own specific policies. In recent years, the FDA has approved nearly all applications for compassionate use and has taken steps to streamline the process, but it still often takes a few weeks to file the necessary paperwork and wait for approval. As a result, the diligence, patience, and administrative support that this route requires likely puts large, wealthy teaching hospitals and clinical research centers at a substantial advantage over more rural, resource-stretched care centers that could benefit from greater access to alternative therapies.
We in the worldwide phage community, and the patients we serve, would benefit greatly if we worked together to share and expand the resources needed for compassionate use. Phage epicenters should share not just their phages, but also their legal and administrative resources, with clinical centers that are more hard-pressed to use this framework to their advantage. Doing so would let us connect with greater numbers of patients and bring phages to the attention of local government administrations whose cooperation is essential. It would also help us build the groundwork for long-term local and national policy changes in our respective home countries, thus compelling phage therapy into the fold of “conventional” modern medicine.
Much to our excitement, phage cocktails have been going through clinical trials all across the world, to assess their efficacy as prebiotics, antimicrobials, and immunogens. While clinical trials are intensive, time-consuming, and very, very expensive, they are the gold standard to which all new pharmaceuticals must be compared in order to be considered truly “adopted.” It is certainly good for our field that phages are running this gauntlet, but there are problems on the horizon that we can prevent with action now.
The most significant risk to the success of clinical trials of phages results from two key factors: their host specificity and their capacity to evolve. These introduce a bunch of variables that the contemporary regulatory infrastructure of clinical trials was not developed to address. Using heterogeneous cocktails addresses the host specificity issue (albeit to a more limited extent than most antibiotics), but it only amplifies the risk of fallout from the second factor: phages’ capacity to evolve. All kinds of messy legal arguments could ensue from the failure of a therapeutic that can mutate on its own, outside the explicit control of the clinician. And would a cocktail with 6 of the same 7 phages as a previously licensed one need to go through its own series of multi-million-dollar trials? Would all phages in a cocktail in clinical trials need to be rigorously screened for bacterial toxins that they may have picked up by transduction?
The existence of these variables foretells a new generation of medicine that much of our current regulatory systems are likely not prepared to face. We should also consider that compassionate use regulations could well become oversaturated if phage therapy really takes off around the world. For both these reasons, it is in our best interests to help shape the long-term future of this infrastructure, so that our work can be allowed to flourish while the patients we serve are still protected. Experts in the phage field should actively contribute their expertise to legal and political discussions that are necessary to enact these long-term changes. They could even team up with experts in oncolytic viral therapy and fecal microbiota transplant (FMT), whose fields are likely to face similar challenges.
Perhaps the entirely unconventional nature of phage therapy requires some entirely new ideas for its regulation. This idea has already been embraced through different mechanisms in several countries, as has been beautifully summarized in a 2018 mini-review by Lucy Furfaro, Matthew Payne, and Barbara Chang. The unsung backbone of each of these profound policy developments has been effective science communication and outreach to public officials. To enact substantial changes in medical policy, we need to get the attention of policymakers and their constituents through enthusiastic engagement that emphasizes the purpose and urgency of new systems to manage phage therapy. The more that we take the initiative to explain the value of our work to the public and to public servants alike, the more likely it is that we will receive support for new methods to distribute phages.
The sooner we start pursuing these concrete initiatives, the more robust the future of phage therapy will become.
For every issue of Capsid & Tail, we are committed to getting our facts straight, but we’re not experts in the information we’re bringing to you. If you feel that we’ve missed an important viewpoint, or if you have something to add, please reach out to us by emailing [email protected]. We’d love to hear from you, and we’d be happy to revisit topics we’ve covered (ideally with added information and viewpoints from community members like you!).
Lastly, please reach out if you’re interested in writing for us, or have suggestions for future issues!