Bacteriophages

Definition

Bacteriophages, or phages for short, are natural viruses that only use bacteria as host cells to multiply. During the multiplication process, they destroy the infected bacteria. Phages are highly specific: One type of phage usually only attacks a certain type of bacteria and leaves other microorganisms untouched. They are found everywhere in the environment – including in the human body – and are therefore harmless to people and the environment. They exist in an incredible variety, meaning they cover a broad spectrum of target organisms. 

In contrast to antibiotics, which have a broad effect and also kill “good” bacteria, phages function like a precision tool, targeting harmful bacteria while sparing the beneficial ones. 

Current applications and opportunities

Phages are considered promising candidates in the fight against antibiotic-resistant infections. In Switzerland, phage therapy is currently only possible within the limits of the experimental therapy guidelines of the Swiss Academy of Medical Sciences (SAMS), as it has not been officially approved by Swissmedic, the Swiss supervisory authority for therapeutic products. This means that phages may only be used in patients with a life-threatening health condition, or if all approved therapies have proven ineffective or unsuitable and the patient has given their consent to the treatment. While isolated accounts of successful treatments, for example for cystic fibrosis, urinary tract infections or infections of joint prostheses, show what this therapy can achieve, they also lead to media hype and exaggerated expectations. Belgium is a pioneer in medical applications thanks to flexible regulations. Portugal, the US and Australia are likely to follow suit. In Georgia, phages are an established form of therapy, but it is not subject to the degree of scientific monitoring required by our standards. 

In the food industry, phages are used preventively in production processes to eliminate potentially pathogenic bacteria. They represent an additional hurdle for pathogenic germs, which helps to ensure food safety. In these production processes, phages are used as an auxiliary material and not as an additive, meaning that they do not have to meet GMP standards. GMP stands for Good Manufacturing Practice, which is applied, for example, in the areas of food and pharmaceuticals. Around the world, the main way that phages are used is as a preventive treatment for foods against infestation with listeria or salmonella. A range of commercial phage products are already available in the US, Canada, New Zealand and some Asian countries. In Switzerland, on the other hand, phages that target listeria are only permitted as an exception in cheese production, but only with approval and under the supervision of the Federal Office of Public Health (FOPH). In the EU, there is no consensus among the member states for authorisation; the Nordic countries allow an exception for the use of phages in salmon farming and processing.  

The use of phages in agriculture is a potential alternative to antibiotics and other chemical pesticides. The advantage is that phages for agricultural applications do not have to be produced according to the GMP guidelines. A cocktail of phages – i.e. a mix of different phages – is intended to be used as a preventive measure in conditions known to promote infections. At present, there is a strong focus on the bacterium Erwinia amylovora, which triggers fire blight in fruit trees, and bacterial species that infect olive trees in countries such as Italy and Spain. While the preventive use of phages is approved in US agriculture, authorisation in the EU is limited to Erwinia amylovora; in Switzerland, phage applications are not permitted for crops grown in the open air. 

For modern medicine, phages represent an alternative to antibiotics, since they are less susceptible to resistance problems thanks to their high specificity – in other words, the narrow host range. However, it is important to understand exactly which pathogens are at play in the infection being treated. After all, this is the only way to achieve effectiveness. In the food industry, the use of phages promises improved product safety; in agriculture, they could at least partially replace chemical-based pesticides and thus represent a green alternative. 

Although the phages used today are certainly impressive, phage biology is still in development. This represents an opportunity for academic research to better understand and adapt the phages. We can also learn from the past, which has taught us that phages are the source of valuable tools such as restriction enzymes for molecular biology. Phage research is also an area that yields results with a high chance of commercialisation. Especially in view of the infectious diseases that are increasingly occurring as a result of climate change and demographic development, it holds great economic potential. Swiss research groups at both universities and university hospitals are doing pioneering work in basic research; however, commercialisation is lagging behind research – and this presents opportunities for start-ups to step in. 

Challenges 

Despite their enormous potential, phage applications face a number of challenges. This is because international clinical studies have not yet provided proof of medical efficacy. Until now, the precondition for clinical studies has been the use of GMP-compliant phages, which are expensive and complex to produce. For treatment to be successful, the phage to be administered must also be adapted to the bacteria that are causing the infection, which entails additional regulatory challenges. There is a lack of clear framework conditions and approval procedures for the medical application of phages in Switzerland; these exist for antibiotics, but not for their biological substitutes. Following the example set by Belgium and its progressive framework, as well as a clear commitment from political and economic decision-makers, should pay off for Switzerland. This is the only way to initiate projects that link basic research with hospitals and mobilise industry partners. Only then can phage therapy reach its full potential. 

At the technical level, modifying the phage genome to increase efficacy is a challenge. This is because for many phage species, completely synthetic production does not (yet) work reliably owing to the size of the genomes. In addition, the physical size of the phage particles complicates their application: There are numerous parts of the body they cannot reach, and they are only suitable for treating easily accessible systems such as the urinary system, skin, mucous membranes, bone surfaces, eyes and implants. 

Focus on industry

In industrial terms, phages are set to play a role primarily in production. They offer companies an easy way to implement flexible and green measures for improved hygiene and biological control. For pure users, a general understanding of hygiene and good manufacturing practices is sufficient. For companies that characterise the bacterial hosts and produce the phages, there are opportunities to be found in production and services. However, the demands placed on employees are higher here: Knowledge of microbiology and biotechnology at university level is a prerequisite. 

In Switzerland’s current training landscape, supply and demand are in balance. However, there are no in-depth study modules on phages. Nonetheless, if broad implementation of the technology were to be made possible, the limiting factor would be the number of apprenticeships in Switzerland. It would also be helpful to give students in the relevant disciplines a better understanding of clinical trials. 

International perspective

Compared to other countries, Switzerland is very active at the research level and there is strong expertise to be found in these research groups. Given the relatively large number of such groups, the opportunities for commercialisation have not yet reached their full potential. 

Country-specific regulations determine the use of phages in medicine, the food industry and agriculture. Some countries, such as Belgium, have a progressive framework for medical treatment, while others, such as the US, lead the way in preventive applications in the food industry and agriculture. Compared to other countries, it is advantageous for Switzerland that Swissmedic is open to the use of genetically modified phages – provided that phages are approved. 

Future applications

Four approaches are likely to shape future applications: 1) adaptation and modification of host range and efficacy, 2) phages as delivery vehicles, 3) development of reporter phages and 4) production of specific phage proteins. 

In the past, phages were isolated directly from nature and screened against the bacterial strain to be attacked, but nowadays, they are already being genetically modified. This makes it easier to bypass the bacterial defence mechanisms and increases effectiveness. At the same time, genetic modification can also alter the host range. For example, the well-researched phages against Escherichia coli can be modified to infect and kill bacteria of the genus Klebsiella. 

The phage can also be used as a delivery vehicle for foreign proteins. For example, its genome can be supplemented with lytic enzymes, which the host bacterium then produces and releases after infection, thus destroying bacteria in the environment. With such modifications, however, there are limits on how big the genome can be. 

Alternatively, it is possible to incorporate a sequence for luciferase, a light-emitting enzyme, into the phage genome. In this way, infected cells are marked and made visible, whether in the event of an infection or contaminated food. Essentially, the phage acts as a reporter. 

Phages are too large for direct secretion from the bacterium and therefore express endolysins to break up the bacterial cell wall. Such phage proteins can be produced in vitro without the phage and can be used, for example, in medicine for local applications such as acne creams. Because of their small size, these enzymes are also suitable for applications in tissues or the bloodstream. 

Bacteriophages are a natural, targeted and sustainable solution to some of the greatest challenges of our time. Whether in medicine, food production or agriculture, phages have the potential to supplement or even replace antibiotics and thus help to contain the global resistance crisis. 

Switzerland has the necessary expertise and research infrastructure to take a leading role in the development and commercialisation of phages. This requires clear regulation and targeted projects built on cooperation between universities, hospitals and industry.