Phage therapy
Biologist Konstantin Miroshnikov on the discovery of bacteriophages, antibiotics and the prospects of phage therapy
In 1917, an article was published by Felix D'erell, a French-Canadian microbiologist, from the moment of which we count the very concept of bacteriophagy, that is, the discovery of bacterial viruses. The effect of the destruction of bacteria in culture, for some reason, was known before that. But D'erelle showed for the first time that this is the effect of a virus. And he called these viruses bacteriophages – eaters of bacteria.
They almost did not know how to fight against pathogenic bacteria then. Just ten years before, salvarsan was introduced into medical practice. This is an arsenic compound for the treatment of syphilis, very poisonous, but somehow coping. Here, the treatment was quite fast and effective. And in the 1920s there was a real explosion of applications of bacteriophages for the treatment of a variety of bacterial diseases in medicine, veterinary medicine, and crop production. Many articles quite convincingly showed such an application, but very little was known about bacteriophages. They didn't really know what they were, or how to cultivate them, or how to use them, or how sensitive they were, or how specific they were, or what ways to use them in medicine. As a result, there was an accumulation of negative or incorrectly interpreted results, that is, it was to a certain extent a false start.
In the late 1930s and early 1940s, when antibiotics were discovered in our current understanding - low molecular weight compounds that destroy microorganisms – the world medical community easily switched to them, because it was logical, it was simple, it was relatively cheap, it was universal. But for half a century of active use of antibiotics, a new problem has emerged: microbes have adapted to them. There were many varieties of pathogenic microorganisms that antibiotics did not act on, and several classes at once, up to the point that in general all antibiotics do not act on a specific pathogenic microbe. And therefore, for the last ten or fifteen years, discussions have been constantly taking place about what humanity can come up with and offer medicine as supplements and alternatives to existing antibiotics.
Among the possible methods, a return to phage therapy on a new scientific basis is considered, taking into account what biological science has accumulated over these hundred years. In general, phage therapy looks like a fairly scientifically sound logical method, although it is very difficult. Do not forget that all other methods that are supposed to replace antibiotics are various vaccines, nanoparticles, enzymes, and antimicrobial peptides – also not such simple compounds, it is more difficult to apply them, a fairly accurate diagnosis is needed. Making them is significantly more expensive than isolating antibiotics from natural producers. Here we can sadly state that the time for simple solutions is over. Any scientific development, any direction of scientific development requires certain efforts.
Let's talk about what requirements exist, what problems arise before the use of bacteriophages for medical purposes. Firstly, the bacteriophage should be described in sufficient detail. It is known that there are several infectious ways in which a bacteriophage can act on a bacterium. There is a so-called lytic pathway, when a bacteriophage inevitably destroys its host. There is a so-called lysogenic, or moderate, pathway, when, in anticipation of more favorable conditions for development, a bacteriophage embeds its genome into the genome of a bacterium and waits for favorable conditions. This is not very good, because it does not allow you to clearly predict how he will act. In addition, such an introduction of one's own DNA is fraught with the fact that something else unnecessary will be introduced. Accordingly, the bacteriophage must be lytic.
Now reading the genetic information contained in the bacteriophage is a purely technical and no longer prohibitively expensive way. And knowing the sequence of the bacteriophage genome, we can predict whether it is capable of a lysogenic pathway of development and should not be used in therapy, or whether it is professionally lytic and all paths are open to it. This is a purely scientific point, which we have already learned to solve in a fairly unified and fast way.
Then the problems of another plan begin. For example, bacteriophages have a rather narrow specificity. If antibiotics can act against all bacteria in general, or in extreme cases against gram-negative or gram-positive bacteria, then the bacteriophage acts very narrowly, not even against a taxonomic species, but against a group of narrower varieties of strains. There is a need for a more accurate diagnosis.
We take some kind of pathogenic bacterium, for example Staphylococcus. It has many group varieties, some of them get advantages in some conditions, in a specific geography, among a specific population group. Therefore, approximately in this geographical location, where there is an outbreak of staphylococcal infection, it makes sense to accurately determine the pathogenic agent and select bacteriophages specifically for it. Now great efforts are being made to rationalize this, so that these varieties of bacteria are not called Siberian Staphylococcus and not European staphylococcus, because this is not a biological characteristic, but a geographical one, and that's how Siberian differs from European. That is why some bacteriophages destroy one type with greater efficiency, while others destroy another. This is due to the receptors on the surface of the bacteria to which the bacteriophage attaches. Selection should be carried out specifically to specific strains, while trying to understand at the same time which receptors are used to attach bacteriophages. That is, this topic is being actively developed in world science. There is some progress. In general, there is hope that it will be possible to come to some reasonable unification of the selection.
Next, it is necessary to limit the areas in which the use of bacteriophages is advisable. If the bacteriophage can be applied directly to the pathogenic agent in the case of skin diseases, wound infections, rinses, enemas, and so on – this is one thing. But the most common and natural way of application is oral administration in the form of a pill or medicine. The problem is how the bacteriophage passes from the intestine into the bloodstream. The particles are quite large for this, and this should not happen, but it happens, and quite successfully. There have been reports on the successful treatment of bacterial diseases of internal organs by bacteriophages, for example, kidneys. Here it is quite possible that there is a difference in the permeability of the intestinal walls in normal and in pathology. But this is strictly individual, and it is difficult to catch any patterns here.
Usually, bacterial culture is used in the selection of bacteriophages, that is, liquid or on an agar Petri dish. In a living organism, the relationship with the victims is more complex. Bacteria are not in this form of suspension in the liquid, they usually form biofilms on the walls of internal organs, on the mucous membranes and behave differently. And it is difficult to penetrate the bacteriophage to this bacterium, which is protected by a layer of some biofilm polysaccharides. That is, the dynamics of the work of bacteriophages, ideally in culture, is quite different from how it behaves in a living organism.
It is believed that bacteriophages are not immunogenic, that is, the body's immune system does not respond to them. But when we use bacteriophages in medicine, there is about a million times more concentration of these bacteriophages. The same problem as with antibiotics. Antibiotics in nature, when bacteria compete with each other in some soil, and when an antibiotic is used in medicine, the difference is tens of thousands of times. The body's defense system is forced to react to this. You can achieve an immune response to salt, sugar, and anything that we usually eat without fear. Studies were conducted, and it turned out that there is some kind of reaction, but it is very insignificant and for a more or less healthy organism without pathology, without increased allergies and something else, it is unlikely that it will somehow interfere much. But again, you need to take this into account.
These problems concern science indirectly. Rather, they are connected precisely with the production, certification, approval of a particular drug in the form of a medicinal product, regulations on how to use it. This is terra incognita, which for some reason prevents the introduction of phage therapy as a medicinal method. There are groups of enthusiastic doctors all over the world who apply therapy quite successfully. This is not only in the territory of the former Soviet Union, where bacteriophages have always been regarded as an alternative to antibiotics, and above all in military medicine. Accordingly, we have a domestic school of phage therapy, there is a fairly good school in Georgia, Belarus. That is, from time to time there are reports that phage therapy has been successfully used. But this is also happening in Poland, Spain, Belgium, and the United States, where phage therapy is not considered a certified method of treatment, but nevertheless, in the case when traditional drug regimens are powerless, people are given the opportunity to be treated with anything. And in these cases, phage therapy regularly helps even in the case of very advanced diseases. Just a couple of weeks ago, an article was published in a very decent medical journal Antimicrobial Agents and Chemotherapy about the successful treatment of a very complex infection – acinetobacterium, resistant to almost all antibiotics. Not immediately, but with the help of bacteriophages, they coped with the infection.
That is, the accumulation of information that phage therapy is a good and fundamentally quite suitable method that requires a certain polishing, a certain bringing to mind, but nevertheless is quite worthy of implementation – such information is constantly there and is constantly accumulating. Why there is no shift in implementation is difficult to judge here.
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15.09.2017