My last post discussed the disappointing results of a study of the effectiveness of phage therapy in animal models of diabetic ulcers. Although the authors reported improvement over sham treatment, the effects were only marginally significant - there was some reduction in bacterial load, but little or no effect on wound healing.
Well, that happens. Drug development is hard, and there are always going to be results that are less than stellar. The question is what has been learned, and can it be put to good use in improving the technology. Unfortunately the authors of the study did not ask this question, at least in print, so it is hard to tell if the study is a tiny step forward on the path to therapeutic development, or if it is just another random result that goes nowhere.
I'm sorry to say that this is where the vast majority of phage therapy studies go - absolutely nowhere. And given that phage therapy could have a real role to play in infectious disease therapy, it's tiresome and unacceptable. We really should be moving beyond the stage of reporting phage therapy results as mere phenomena. After all, there is more than a century of clinical and preclinical behind us, and you would think that phage therapy development efforts would be pretty sophisticated by now. But you would be wrong.
The thing that I find so appalling about this study is that the authors simply collected phage for the study from a convenient sewer. I'm sure they tested them for reactivity against a panel of clinically relevant strains grown in pure cultures in rich media to log phase and plated on agar plates in the lab. But these phage didn't do so well in the complex environment of a diabetic wound, causing only a slight decrease in the bacterial load. This shouldn't have been a surprise, but apparently it was.
Most bacteriophage genes are dispensable in the laboratory environment. That is, they can be mutated or deleted, and the phage are able to propagate just fine. The functions of these genes remain largely unknown, even to the present day. But we can guess, intelligently. My guess is that a large fraction help the phage adapt to less-favorable environmental conditions. They allow the phage to productively infect potential hosts by defeating a variety of host defenses, and to maximize their output of progeny in a host that is constantly warding off immunological, bacteriological, nutritional and environmental challenges.
If this is true - and it has to be true to some degree - then the notion of taking a phage that has adapted to sewer life or life in the gut, and expecting it to thrive in the environment of a wound is somewhere between naive and downright stupid. It doesn't advance the development of phage therapy, it discredits it. It is fundamentally unserious.
There are serious scientists who are interested in developing phage therapy. Steven Abedon's work is an outstanding example. But they are still a minority. I don't know how many times I have sat through presentations at a phage meeting that were just embarrassing, thinking "why did the organizers of this session pick this clown to speak?". But then the session leaders would get up to give their talk, and it would be just as bad, and I would have my answer.
So the question arises as to why phage science is so bad. There are a number of contributing factors of course. It is no longer the 8th day of creation. Molecular biology has "moved on" to more complex organisms, and funding has largely dried up. This has been true not just of phage biology, but microbiology in general.
Funding is surely a factor, but isn't the whole explanation. RNA science was a backwater in the 70's, but this didn't prevent brilliant science from being done by the likes of Noller, Woese, Spiegelman and others. Instead, I think it is the lack of funding combined with a low barrier to entry that makes phage science such a refuge of mediocrity. RNA science in the 70s and 80s was really hard - there was no way to synthesize RNA either enzymatically or chemically (except for very small fragments in very small quantities), and so getting enough material to do a study often required heroic efforts. But that didn't stop Woese from fundamentally reorganizing the Tree of Life, or Noller from showing that it is ribosomal RNA which directs protein synthesis.
That phage science hasn't made any paradigm-shifting discoveries since the 60s is hardly shameful - phage long ago secured their place in the Pantheon of model organisms. But it is scarcely credible that so little progress has been made in converting these model citizens of science into useful therapeutics.
Phage are everywhere and can be isolated, propagated and analyzed by very simple methods. That's what led professional physicists/amateur biologists like Delbruck and Crick to adopt phage as models of living systems. But it also means that just about anyone can find a new phage or alter an old one, stick it into some diagnostic or therapeutic model system, and show an effect that is statistically significant but functionally meaningless. This has been happening over and over since antibiotic resistance began to emerge as a significant medical problem, leading to an endless succession of review articles touting phage therapy as a new and emerging therapeutic alternative to antibiotics. That phage therapy keeps not emerging does not seem to make it any less new and promising to the writers of these reviews, nor does it abate the flow of such articles.
For translational phage science to improve, the first step is to call out the purveyors of mediocrity - to acknowledge that there is a problem, and that a higher standard is required. There is a real clinical need that phage therapy can fill, and enabling second-rate science benefits no one.
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