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My enemy's enemy

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It has been a century since researchers first suggested the use of phages to fight diseases. Yet phage therapy remains in the realm of experimentation. The time has come to change that.

In 1919 a 12-year-old boy suffering from severe dysentery was admitted to a hospital in Paris. Felix d’Herelle, working at the Pasteur Institute in Paris at that time, suggested a novel therapy to treat the boy—phage therapy. This involved drinking a preparation of "bacteriophages", or viruses that infect bacteria. Doctors at the time were reluctant to administer this treatment. There was almost no evidence for its efficacy. No studies on possible side-effects. And most importantly, the existence of bacteriophages itself was still a matter of speculation. 

But the condition of the boy was worsening. In the course of the bizarre events that followed, d’Herelle and a few of his interns first themselves drank the phage preparation to prove its safety. As no side effects appeared, the preparation was administered to the young boy. His symptoms began to recede over the next 24 hours and the boy recovered soon afterwards. This trial of phage therapy was followed by many others, even before the existence of the phage was confirmed. 

D’Herelle first came to suspect an existence of a bacterial virus as a result of a serendipitous event—the type of chance incident that often steers scientific discoveries. In 1910, sisal plantations in Merida, Mexico were plagued by locusts. D’Herelle, at that time, was on a government commission to study the fermentation of sisal. This Canadian Frenchman had lived quite an unusual life. After barely completing his high school studies in Paris, he had given up on a formal education. He then became a self-taught microbiologist, with an immense interest in bacteriology. He had built a home laboratory for himself. D’Herelle studied microbiology from books, journal articles and whatever else came his way. 

While trying to fight the locust menace in Mexico, he noticed that the locusts were infected with bacteria, which caused dysentery in locusts. He isolated these infectious bacteria and then showed that they could be used to cause infection in healthy locusts. 

During these experiments, he observed that some of the bacterial culture tubes had "clear spots". The bacteria in these spots could not be grown any further. He filtered the contents of these tubes through a very fine filter to exclude the bacteria. When the filtrate was introduced in other tubes with healthy bacteria, all of them turned clear in appearance. D’Herelle suspected that this was a "virus" that infects the bacteria, which was killing its host. He christened this new class of viruses as "bacteriophages" meaning "bacteria devourers". He also coined the term "phagotherapy", the use of phage against the bacteria that cause infections in humans—the enemy of my enemy is my friend. 

D’Herelle published his claims in scientific journals but received little support except from Fredrick Twort who is known to have independently discovered the phage in 1915. D’Herelle’s eccentric character and lack of formal education were definitely a factor in this lack of recognition. But more importantly, at that time, there were no means of observing something that is one-millionth of a centimeter in size. Many scientists, instead, attributed the clear spots to a chemical secreted by the bacteria themselves which then, they claimed, passed through the filter and killed healthy cultures. It took another 30 years and the invention of the electron microscope for the world to be convinced of the existence of a virus that can infect bacteria. 

A century later, we know that viruses that infect bacteria, or phages, do exist. They are as omnipresent as their host bacteria themselves and much more abundant. This means that soil, water, plants and animals are laden with these phages. They can attack the target bacteria, hijack its cellular machinery to self-replicate, break open that bacterial cell and then infect a new one. But phages don’t go around devouring every bacteria in site. They are extremely choosy. A given phage targets some specific molecule on the outer surface of a bacteria, and infects only when this identification criterion is met. Obviously, bacteria try to evade this recognition and change the identity of the "target". Phages are no fools! They keep modifying the "identifier" as well and thus this bacteria-phage rivalry leads to an ever-lasting game of tug-of-war, or co-evolution in scientific terms. 

The first characterization of bacteriophage in 1945 opened up new avenues for phage therapy. Coincidentally, this was also the time when commercial production of penicillin had begun. This wonder drug was curing millions of people across the world. It had many advantages over the proposed phage therapy. Penicillin could act against many different bacteria. Phages, on the other hand, were known to be very selective about the bacteria they infect. Penicillin was easy to store and administer. The dosage could be standardized easily. On the other hand, phage culture, storage, and dosage were far from standardized. Little was known about the possible side effects of phage preparations. Together, these factors favored antibiotics over phages and the golden age of antibiotics began. 

More than half a century later, we are probably witnessing the end of this age. Prodigal use of antibiotics has unfortunately led to the widespread occurrence of antibiotic-resistant bacteria. Resistance has been reported to all available antibiotics, including the so-called "last resort" drugs: carbapenems. The current pace of spread of resistance could take modern medicine, some fear, to the pre-antibiotic era. This means that immunosuppressant therapies, common surgeries or even a simple wound might lead to an incurable infection and even death. We need to minimize the use of antibiotics to halt this spread. We need to accelerate the discovery of new antibiotics. 

Yet just one new class of antibiotics has been discovered in the past 30 years. So at the same time as we find new antibiotics, we need to look elsewhere for drugs. A recent report by the World Health Organization insists on the need for alternative agents that can control infections. Phage therapy is one such promising alternative. 

The advent of antibiotics, lack of confirmation for the existence of phage till 1940 and publication of a couple of influential reports doubting the efficacy of phage therapy, together, decelerated the research on phage therapy in the West. But in the former Soviet Union and Eastern Europe, researchers continued to evaluate the possibility of phage therapy. Many studies were conducted in the laboratory as well as on farm animals with encouraging outcomes. The leading Eastern European institute in phage studies, Eliavia Institute in Georgia, conducted one of the biggest clinical trials of the phage therapy. This trial involved more than 30,000 children. Preventive uses of phage therapy against bacterial dysentery were investigated in this trial. Children administered with phage preparations showed significantly lower incidences of infections. To date, Elivia continues research in phage therapy and many preparations are available commercially. They are administered either singly or in combination with antibiotics. Oral, topical, as well as intravenous administrations of phage preparations are known. 

Western medicine seems to have ignored these developments to a large extent, until recently, due to two reasons. Firstly published research articles were in Russian or Polish or Georgian, rather than English. Second, and more importantly, is what experts feel is a lack of rigour in the quality of trials in these studies: for instance the lack of placebo control groups. This poses a difficulty in the assessment of the results, and thus the efficacy of phage therapy is still largely doubted in the Western medicine. 

Sceptics also point out other potential problems. Phages infect the target bacteria, grow inside them and eventually burst them open. This can potentially release any harmful toxins the bacteria might possess. A large amount of such toxins can sometimes be more dangerous than the live bacterial cells themselves. Secondly, our own immune system might detect the phage and mount a response against them, leading to the failure of the treatment and further complications. Some infective bacteria reside inside our cells rather than out in the blood or on the stomach lining. How do we deliver the phages to these bacteria? Phage preparations are not as stable as antibiotics. This means that special care might be needed for delivery and storage. Co-evolution, the phenomenon previously introduced, demands continuous monitoring of the infective bacteria, and the generation of new phage preparations whenever needed. 

These obstacles are real but might not be insurmountable. More research can lead to sustainable solutions. Phage therapy offers many advantages. Specificity of the phage means little to no collateral damage i.e. microbes ordinarily resident in our body will not be killed as in the case of antibiotics. This could reduce the side effects commonly associated with conventional drug use. We also know that the resistance to phages evolves slowly in bacteria than resistance to antibiotics. More importantly, as phages can themselves evolve, it may be just a matter of weeks or months before the evolution of a new phage preparation that can kill resistant bugs. Phage cocktails are another alternative to counter the evolution of resistance in target bacteria. Many more sophisticated means of preparation, storage, and administration of phage preparations are at our disposal than d’Herelle’s time. 

In April last year, a 50-year-old man suffering from a severe infection of multidrug-resistant bacteria was admitted to the UC San Diego Medical School. As every antibiotic failed, the man slipped into a coma and was nearing death. As a last resort, doctors administered an experimental phage preparation intravenously. The man recovered completely. Of course, this incident cannot be compared with a full-scale clinical trial. But it definitely shows the potential of this therapeutic measure.

Development and approval pathways need to be designed. The US Food and Drug Administration has already sanctioned the use of phages in many foods as well as in agricultural and husbandry products. The European Union has started testing the efficacy of the phage therapy on the burn wounds in a project named Phagoburn. These are undoubtedly the first steps towards the possibility of a full-scale clinical use.

More research, more funding, and more awareness are imperative. Our enemies, multidrug-resistant bacteria, are alive and evolving. The arsenal we use against them probably needs the same attributes.


Who Discovered Bacteriophage? by D.H. Duckworth

Phages of life: The path to pharma by A. Forde and C. Hill 

The Epic of Phage Therapy by Alain Dublanchet and Shawna Bourne

"Phage therapy gets revitalized" by Sara Reardon

Bacteriophage Therapy by Alexander Sulakvelidze, Zemphira Alavidze and J. Glenn Morris

The Discovery of Bacteriophage and the d’Herelle Controversy by Milton W. Taylor

Shraddha Karve is postdoctoral scientist at University of Zurich. 

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