Epilogue

We are really pleased to publish this special contextual issue of PHAGE, where the four articles show the importance of bacteriophage—or phage—research and applications across all three One Health Domains. The main focus of the articles is on human health, but the same considerations that have been unpicked apply to the use of phages in agriculture and in the environment. The articles reveal that despite the increase of interest in phages, there are multiple persistent conflicts within the development of phages that relate to the specificity of phage–host interactions and the way in which these organisms work.

They also highlight the complexities of standardizing the structures that are needed to study and share phages, and the uneven biases in phage accessibility. The latter point is largely due to the historic concentration of biomedical resources, associated intellectual property, and investment in the developed countries. Indeed, this lack of parity motivated me to work with Phages for Global Health, a not-for-profit enterprise established by Tobi Nagel and aimed at empowering academics from lower income countries to embed phage discovery and development into their own research programs.

Bacteriophages significantly differ from standard antibiotics in the way they target and interact with bacteria and could be used to treat or prevent bacterial infections. Because of this, they require specific considerations in all aspects of their development. As with so many things, it is important to not forget the past, and phages have both a rich and intriguing evolutionary history, of ∼3.9 billion years where they have shaped much bacterial evolution, population dynamics and physiology, and a studied history of ∼100 years. However, due to phages being considered less important than their bacterial hosts, and because they are technically difficult to study, our knowledge of them is often fragmentary.

Further compounding our scant phage knowledge is that the information that does exist from different facets of phage research is generally not considered as a whole. For example, insights from environmental studies of phages are little used to inform phages of medical relevance. Also strikingly, some research areas, such as phage typing, are often omitted from standard histories of phage research. Finally, the complexities surrounding the development of all anti-infectives are often not considered when discussing phages.

To address this fragmented nature of phage study and to unite historical, biological, and economic contexts, in this special issue of PHAGE, authors from many disciplines and geographies have come together to synthesize the multifaceted aspects of phage research. The resulting articles show parallels between the past and the present and provide thoughts on future directions that are needed to progress the field.

As was described in the Introduction section, each article was written by a multidisciplinary team assembled in part during a meeting at University College Dublin by historian Claas Kirchhelle and anthropologist Charlotte Brives. Titled Variable Viruses, the objective of both the meeting and this special issue was to critically assess the past, present, and future of phage biology while avoiding disciplinary silos.

If it was easy to develop phage products and widely disseminate them throughout the world, it would have been done so by now, and one of the questions as a phage biologist that I am regularly asked is that if phages are so useful, why can't they be widely accessed? This was also the topic of a recent UK Government Inquiry that took place in the House of Commons, in the Science, Innovation and Technology Committee on the antimicrobial potential of bacteriophages (https://publications.parliament.uk/pa/cm5804/cmselect/cmsctech/328/summary.html#). The inquiry took the form of written and spoken evidence and solicited expertise from academic, clinical, industrial, policy, and government perspectives.

The report that resulted from this inquiry outlined the complexities associated with developing a biological entity as a novel therapeutic, pointing out the problems that this causes in terms of production, formulation, and delivery and regulation. It also addressed the biological complexities and those associated with the economics of developing antimicrobials compared with developing pharmaceutical products that are taken for much longer periods of time. Several recommendations to the UK Government have been suggested to progress the challenges faced in the field. This included resourcing the work to undertake human clinical trials on phage efficacy.

The articles in this special issue were conceived of and written in parallel with the report—with neither directly impacting the other—but they would have made a perfect primer to the members of parliament who carried out the investigation, and indeed the report would have been a good starting point for the authors who wrote these articles. In the future, when asked why phages are not widely available, I shall recommend that my questioners enjoy a read of the report and read the set of articles in this special issue!

In doing so, they will receive a grounding of phage knowledge within the different frameworks. By bringing the context and setting associated with multiple aspects of phage biology into one place, these articles will engage phage scientists but also be of interest to people from any background who in understanding or addressing antimicrobial resistance (AMR), and to readers interested in structures within health care and beyond.

The first article by Brives et al., sets the scene for this special issue and the authors outline the ecological and evolutionary context of phages, and how we should contextualize them within this knowledge. Bacteriophages have likely been around for as long as bacteria, and the acute intimacy within their relationships with their bacterial hosts and associated with their environment at large means that not all phages can simply be repurposed to solve all of problems associated with AMR. Indeed, specific types of phages will be useful in different structures and settings.

Although understanding the natural biology of phages can inform the way that they are developed, such information is generally not used in clinical development. The authors provide examples of the disconnect between knowledge about phages' natural biology and applied research. In the context of viticulture, the authors discussed how phages interact differently when applied to, or associated with, living vines compared with the interactions that occur within the fermentation processes. They specifically highlight the fact that, just like in all environments, phages are naturally present in all of these specific parts of viticulture already. Indeed, the authors use these examples of complexities of the roles of phages within viticulture as a microcosm that epitomizes how we need to bring multidisciplinary inputs into phage development.

They make the point that by trying to force phages to do what we as humans wish, without learning what they naturally do, and how this could be most optimally adapted, is folly. The need to avoid reductionism extends to antimicrobial development. The authors stress the fact that although phages are being developed as antimicrobials, they are not simple compounds and thus should not be treated as such. We need antibiotics, and phages do have the potential to be developed to fill this need, but we must not ignore the very features of their biology that may prove to be most useful.

In the second article by Kirchhelle et al., we are reminded of the rich history that phages have in terms of mapping microbial complexity in what is known as phage typing. This application of phage use and associated history is generally not discussed within the “phage” literature as it is seen as being part of epidemiology and thus only considered from the bacterial perspective. The article starts by showing how phage typing was used actively for decades. The authors describe how the assay exploits the ability of phages to differentially attach to and kill specific bacterial strains within a species.

As the presence of phages can be easily assayed by looking for the death of the bacteria that they have interacted with, this meant that readily applicable and useful assays could be developed using phages, and this article relays their history specifically with respect to diagnosing and surveying dysentery and typhoid in the 1930s and 1940s, and later on, for nearly all bacterial pathogens. It is really fascinating to read about how many different variations and methods of typing phages were standardized and regulated by organizations such as the World Health Organization (WHO) and to think about how such thought can inform future standardization practices.

Often expertise in phage typing was not shared universally throughout the world and the authors highlight the importance of not repeating this mistake in terms of our current phage knowledge and availability. In a poignant reminder of our current geopolitical situation, the authors also focus on how political tensions can fracture research landscapes, but also highlight how science can transcend politics. During the Cold War, Soviet scientists used Western phages to devise their own system for phage typing but continued to read and cite literature from many other regions. Meanwhile, east European scientists regularly interacted with peers on the other side of the Iron Curtain.

Closely connected to phage typing, the authors also point out many neglected facets of the use of phages as rapid clinical diagnostics both pre- and postmolecular inputs as well as phages' potential for the mapping of AMR burdens in both high- and low-income contexts. They show that by neglecting this aspect of phage biology, we ignore decades of historical information on past microbial environments and phage–host interactions that could be exploited for current phage research.

In the third article by Resch et al., the authors describe the history and current knowledge on the physical collections of phages with a focus on those that are public and where the phages are accessible. Clearly the review could only be based on those collections that have been published, and the authors point out the bias this caused when drafting this article. They also express the many difficulties associated with procuring, maintaining, and disseminating phages. The authors beautifully contextualize phage collections in terms of all other microbial collections; they point out that phages were generally marginalized within the context of bacterial collections, in part because phages were seen as being somewhat niche, and therefore fewer resources were put into their collection and cataloguing.

The authors highlight that only the sets of phages that were used for bacterial typing were standardized as there was at this point a real need to ensure that the epidemiology was being interpreted consistently. Clearly the processes and difficulties surrounding the standardization of today's collections can benefit from the experiences of multiple researchers in the past who shared sets of these typing phages.

My own experience in helping set up our Phage Centre concurs strongly with the sentiment expressed in this article. It is difficult to obtain resources for systematized and sustainable collections and the curatorial aspects are of course not trivial. There is also often a strong pressure on researchers to ensure that their facility is financially self-sustaining, and it is currently unclear exactly how such sustainability will occur in the context of collections. It is clear, however, that compared with other biological organisms, there is less systematization—and more redundancy—in the way that bacteriophages are curated and maintained. Until recently it would have been difficult to carry out much of the genetic curation aspects of bacteriophage collections that are essential for their downstream usefulness.

The fourth article by Turner et al., takes us to the future, looking at where and how phages will be developed and used within modern mainstream medicine. The article highlights the scientific, logistical, and operational challenges that exist in translating phage research into practical products. The authors discuss the tensions between what is probably optimal from a scientific perspective in terms of a product and its potentially best way of selecting, combining, and delivering it, and what is possible within existing health care structures.

They also stress that because phages are perceived of as being “biological drugs,” they currently funneled down the developmental route of chemotherapy. There is also a fascinating section in this article on the many considerations of phage selection, potential improvement, and combination with other treatments, which impact efficacy when treating infection in its most common state—when the bacteria grow as biofilms.

The article also clearly discusses the issues surrounding how phage research is funded, who is funding it, and the implications of researchers from within different ecosystems such as academic and companies working alongside each other. There is also a very interesting section on how new interventions such as artificial intelligence and cell-free production of phages might impact further development. The authors offer insightful information on how phage innovators access commercial funding and, indeed, where information on commercial phage research is collated.

They then provide a detailed set of examples of specific phage products in development that are resourced by CARB-X, a nonprofit funder, with a focus on the Danish product and approach. The authors explore the concept of phages and IP within the context of IP strategies for other urgent diseases. Although many of these aspects are often discussed individually, readers will benefit from the merging of minds and knowledge that has brought many of these disparate topics together within one article.

In summary, the layers of complexity, which surround all areas of phage research, have been outlined throughout this journey from ecology to forgotten phage applications, past and present phage collections, and current economics. Perhaps most importantly, the articles highlight the importance of thinking across the social and biomedical sciences and making sure we do not repeat the mistakes of the past.

This is particularly important in the context of the global health challenge posed by AMR. Phages most likely can be a big part of the solution to AMR but developing them requires understanding their biology and they may not be suited to the existing pathways and architectures that exist for antibiotic development. Indeed, the articles here show that global cooperation and holistic thinking are needed to develop phages in an equitable and sustainable way.