Imagine if we had a self-replicating programmable smart bomb that could target specific pathogenic bacteria and kill them, while being entirely safe for the host. It turns out, such a thing exists – they are viruses that evolved to kill bacteria, and they are called bacteriophages. Bacteriophages were first discovered in 1896, and they were an early rival to antibiotics for the treatment of bacterial infections. In the former Soviet Union, Poland, and other Eastern countries there was extensive research into so-called “phage therapy” but in the West antibiotics won out and phage therapy never caught on.
But now phage therapy is gaining a second look, because a century later we have produced a dangerous level of antibiotic resistance. To some extent we may be coming to the end of the antibiotic era, as more and more multi-resistant strains of pathogenic bacteria emerge. This is a serious health problem that requires a multi-pronged solution. First, we need to minimize the emergence of resistance through best practices – not overusing antibiotics, using narrow rather than broad-spectrum antibiotics when able, and optimally completing antibiotic courses.
In addition we need to develop new classes of antibiotics that work through novel mechanisms. There may come a time when we need to retire classes of antibiotics, to allow for resistance to wane while we depend on other classes. Perhaps we can come to a sustainable long-term cycle.
Another possible solution is to take an entirely different approach to treating bacterial infections, and that’s where phage therapy comes in. The history of phage therapy is interesting, and there are a few lessons in there. Part of the reason phage therapy did not gain acceptance in the West is because the research was flawed. One early proponent, d’Herelle, did not use control groups in his clinical trials. He gave all the subjects phage therapy. This is a critical point for SBM – we often point out that, if the remarkable claims being made for a dubious treatment were in fact true, the proponents would be doing a disservice to humanity by not doing proper research to adequately prove it. The history of phage therapy, to some extent, bears out this concern.
But also it seems that the technology of the time was perhaps not quite ready for phage therapy. There were problems with purification, and contaminants could cause side effects at bad as the infection itself. Like antibiotics, some phages are lytic (they kill the bacteria) and some are not. Some early research unknowingly did not use lytic phages. It was also difficult to maintain stable lines of therapeutic phages.
The time, however, may be ripe for phage therapy. The technology to develop, quality control, and mass-produce biologics has evolved considerably, and the old problems that plagued phage therapy are entirely solvable. I liken this to the competition between electric and internal combustion engines. The gasoline engine won out a century ago, partly because of quirky contingency, but also partly because battery technology was very primitive. But now, with Li-Ion batteries, the time for electric vehicles is here. The same may be true for phage therapy.
In fact, with advances in genetic engineering, using a therapy that is potentially genetically programmable may allow for the rapid development of specific phages for specific infections. This is similar to the emergence of mRNA vaccines – once we develop the mRNA vaccine platform, new vaccines can be designed in a matter of days, because we are getting really good at engineering and making mRNA.
Where does the research stand? Some of the basic research is having to be repeated and updated, including preclinical and animal research. There are also some good clinical studies which support the safety and efficacy of phage therapy for specific infections. For example, a review of phage therapy for joint and bone infections concluded:
Together, the reports identified by this review suggest that appropriately purified phages represent a safe and highly efficacious treatment option for complex and intractable bone and joint infections.
Another review of phage therapy for superficial infections concluded:
This review strongly suggests that the use of purified phage to treat superficial bacterial infections can be highly effective and, by various routes of administration, is safe and without adverse effects.
A recent study also shows that using phage therapy in combination with antibiotics can be highly effective. The key is this:
We characterized two bacteriophages, ΦFG02 and ΦCO01, against clinical isolates of Acinetobacter baumannii and established that the bacterial capsule is the receptor for these phages.
The phages bind to the bacterial capsule in order to gain entry and kill the bacteria. Some of the bacteria did evolve resistance to the phage, however. They did so with loss-of-function mutations to genes responsible for the capsule. The bacteria without a capsule had no receptor site for the phage, so they were resistant. However, the capsule is what provides resistance to beta-lactam antibiotics, so those same bacteria were now susceptible to those antibiotics. The obvious conclusion here is that a combination of antibiotics and phage therapy can be very potent, because it would be extremely difficult for any bacterium to evolve resistance to both. This is the advantage of having different treatments that use wildly different mechanisms.
Conclusion: The end of antibiotics and the rebirth of phages?
At the same time that the antibiotic era is running into serious problems because of antibiotic resistance, we may be at the dawn of the era of phage therapy for bacterial infections. But phage therapy is actually over a century old, so what we are seeing is the rebirth of phage therapy with far more advanced technology for biologics in general, and genetic manipulation specifically. Further, the combination of antibiotic and phage therapy may be particularly potent.
But the history of phage therapy also tells us that we cannot get so caught up in the hype that we skip over careful and rigorous clinical research.