A therapy shelved for a century becomes an option for treating obesity and diabetes

There’s doubt about whether viruses are living beings, but their important role in life on Earth is clear. These tiny organisms, which make microscopic bacteria look huge, seem very simple: they are a piece of genetic material encapsulated in protein that hijacks the cells of other living beings to put them at the service of their own reproduction. It is estimated that sea viruses annihilate 20% of the ocean’s microbes every day and that they renew all of the planet’s phytoplankton in a week. According to an article published in Science Advances, that process of cell destruction and renewal releases about 140 gigatons of carbon into the oceans each year, almost four times more than the burning of fossil fuels.

These regulators of life play a similar role in the human body. Each of us contains over 10,000 species of bacteria, a balanced ecosystem that keeps us healthy, which viruses maintain. A century ago, bacteriophages were used to combat bacterial infections like the bubonic plague and cholera, but from the 1930s onward, the success of antibiotics shelved the viral treatment of contagious diseases almost everywhere in the world (they maintained prestige primarily in the Soviet Union). In recent years, the rise of bacterial resistance has reignited interest in phages, which have already saved seemingly hopeless patients.

This renewed interest in bacteria-killing viruses has also led to an appreciation of these organisms’ potential as regulators of human health. In an article published today in the journal Science, a group of researchers from Eran Elinav’s laboratory at the Weizmann Institute in Revohot, Israel, discusses the potential of phages in treating non-infectious diseases. Cancer, obesity, diabetes and neurological disorders are all influenced by imbalances in the population of bacteria that lives inside us, and phages may be a tool for restoring order. Elinav and his team have already conducted a study in which they proved that the oral administration of phage therapy to treat irritable bowel syndrome could control a strain of the bacterium Klebsiella pneumoniae in mice and alleviated the symptoms of the disease.

Fecal transplants work by introducing a healthy person’s balanced bacterial ecosystem into a sick person as a way to combat obesity or depression. Pilar Domingo-Calap, a researcher at the Institute for Integrative Systems Biology at the University of Valencia-National Research Council (Spain), explains that “studies show that, in such transplants, the viral part modifies the bacterial populations. Now, we have to study how to use these viruses as probiotics to improve the intestine’s bacterial population.”

Elinav’s team points out that one of the advantages of these treatments is that each type of virus specifically combats a certain type of bacteria. Once selected, the phages only attack the population of bacteria that is generating the imbalance, “thereby minimizing the damage to the surrounding microbiota.” This approach differs from antibiotic treatments, which kill harmful bacteria, but also wreak havoc on the good bacteria that do no harm and are necessary. Moreover, once the phage has entered the organism and begins to attack bacteria, the phage reproduces and causes it to explode, releasing new phages to continue the job each time.

While they fell out of favor with the advent of antibiotics that provided medical solutions intended for large population groups, phages now make sense in a world seeking personalized medicine. Treatment with these viruses must be designed for each individual by growing bacteria from the patient alongside potential phages, choosing those with a specific antibacterial capacity. “Metagenomic profiling could be used as a companion diagnostic to identify the dominant disease-contributing pathobionts in a patient,” the authors of the Science article note. Next, the most promising phages must be isolated. Phage biobanks would be useful in optimizing this process; phages could be organized by their effects, the bacteria against which they may be effective and their adverse effects.

When phages that fight a particular bacterium are not found in nature, synthetic biology — as in other fields of medicine — could be used to modify natural viruses and direct them against a specific target. That would also allow for introducing changes to adapt to the mutations in bacteria caused by treatments. The CRISPR system, now known for its use in gene editing, is one of the methods bacteria use to learn from their contacts with viruses and repel them. However, Domingo-Calap points out that “CRISPR is only one of the systems that bacteria have for blocking the entry of phages, and phages also have anti-CRISPR systems; they evolve and adapt.”

At this early stage of development, in addition to more basic research and the launch of more human clinical trials, Elinav’s group stresses the need for special regulation. “Because phages are live biological agents, they present numerous differences from traditional medications and so they merit tailored regulatory consideration,” they write. For example, when drug combinations are approved, as in the case for cancer treatments, evidence that each separate component is effective is required. “In the case of phages, such an approach would likely fail in many cases, given that bacterial resistance would develop against some or all individual phages when administered as sole interventions,” they say, explaining that combinations are necessary for success. With safety in mind, they believe that the use of these organisms as medicine for over a century and the fact that they infect bacteria, but not human cells, means that these treatments should be safe.

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