01/03/2012 - 04:57

Using microbes to fight microbes

Laura H. Kahn

Laura H. Kahn

A general internist who began her career in health care as a registered nurse, Kahn works on the research staff of Princeton University's ...

More

There are more microorganisms in and on our bodies than human cells. In fact, scientists estimate that microorganisms outnumber human cells by 10 to 1. These microbes cover our skin, nose, mouth, and gastrointestinal and urogenital tracts. Called the "human microbiome," scientists are investigating the relationship between these microbes and disease.

Microbes cause illness when the delicate floral balance in our bodies gets out of whack or when microbes invade places they don't belong -- such as the lungs, heart, kidneys, and brain. Sometimes, a disruption to our normal flora from the effects of medications can be as bad, or worse, than the infection being treated. For example, antibiotics, particularly in the elderly and chronically ill, can lead to clostridium difficile -- diarrheal infections, which can be life threatening and are increasing in frequency.

We rely on antibiotics to treat infections, and we assume they will always be effective and available. Unfortunately, that assumption is flawed. Antimicrobial resistance is spreading globally, and the pipeline for new antibiotics has largely dried up. Topping off the crisis: Shortages of antibiotics (and other medications) are threatening the quality of patient care.

The world needs a new defense against microbial diseases -- because antimicrobial resistance is not going away. Maybe it's time to resurrect a therapy not used in the United States since the beginning of the twentieth century.

A short history of bacteriophages. Discovered in the early 1900s, bacteriophages (or phages) are viruses that invade bacteria and destroy them. In 1925, Sinclair Lewis even wrote about using bacteriophages during a Caribbean island outbreak in his novel Arrowsmith. But the most imaginative science fiction writer would be hard-pressed to invent something as bizarre as bacteriophages. Phages look like alien spaceships that land on bacterial cells, inject genetic material, and then hijack the cell's reproductive machinery to make more bacteriophages. The result is that bacterial cells are destroyed in the process.

The story of the discovery of bacteriophages -- with several scientists claiming credit -- reads less like Sinclair Lewis or science fiction than a Cold War thriller. The journey of bacteriophages begins in Europe and leads to a Joseph Stalin- supported institute in the Soviet Union.

In 1915, Frederick Twort, a British bacteriologist, hypothesized the existence of an infectious agent that killed bacteria after observing micrococci on a Petri dish becoming glassy and transparent. The phenomenon became known as the "glassy transformation of Twort." His observation of bacterial colonies disappearing was similar to that of Alexander Fleming's when he discovered penicillin. Twort published his findings in Lancet but had to discontinue his studies due to a lack of funds.

Just two years later, Felix d'Herelle, a microbiologist at the Institut Pasteur in Paris, investigated an outbreak of severe hemorrhagic dysentery among hospitalized French soldiers stationed on the outskirts of Paris. He observed small, clear areas on agar plates where he had placed samples of the soldiers' filtered (bacteria-free) fecal specimens mixed with shigella strains isolated from the same patients. D'Herelle speculated that the clear areas were caused by viruses and coined the term "bacteriophage" (meaning viruses that eat bacteria). He claimed credit for discovering bacteriophages and received international recognition. But in 1921, Belgian colleagues published a paper contesting d'Herelle's findings and highlighting the work of Twort. So confronted, d'Herelle announced he'd actually discovered bacteriophages earlier -- in 1910, when he was studying locusts in Mexico -- but hadn't written it up.

The controversy surrounding the discovery, however, wasn't as damaging to bacteriophage science as d'Herelle's subsequent flawed studies. In 1919, d'Herelle conducted bacteriophage studies at L'Hôpital des Enfants-Malades in Paris. Treatments yielded remarkable successes, including the complete recovery of a 12-year-old boy suffering from severe dysentery. Unfortunately, in his zeal to treat patients, none of his studies included control groups (i.e., patients who didn't get phage therapy). Without comparison groups, it's difficult to prove efficacy even with high success rates. But d'Herelle wasn't the only scientist to omit this crucial component in bacteriophage studies.

In 1934, the American Medical Association published a report conducted by the US Council on Pharmacy and Chemistry that examined more than 100 bacteriophage studies. The report concluded that the majority of the studies were flawed and that d'Herelle had not proved bacteriophages exist. The report speculated that the agent causing microbial death was an enzyme. Seven years later, a sequel to this report concluded that the agent was a protein, possibly originating within the bacteria; it too had negative conclusions. These reports coincided with the arrival of antibiotic therapy; together, they drove nails into the coffin of bacteriophage research and development in the United States and Western Europe.

But, while the West turned it's back on bacteriophage therapy, Eastern Europe -- particularly the Soviet Union and Poland -- continued the work. So d'Herelle went east. In 1923, d'Herelle joined bacteriologist Georgi Eliava who had established the Eliava Institute in Georgia. Tragically, Eliava's affections for the same woman as Stalin's chief of police led to his arrest and execution (for being a "People's Enemy"); d'Herelle subsequently returned to France. But the institute continued -- with Stalin's support. At its peak, it became the world's leading center of phage therapy, employing hundreds of researchers and producing tons of therapeutic phage preparations per year.

Bacteriophages today. As global antibiotic resistance worsens, the West's interest in phage therapy has been rekindled. Bacteriophages have now been used to produce detection kits, treatments, and vaccines for many pathogens, including brucellosis, botulism, and anthrax -- classic bioterrorist agents. Recognizing the potential of bacteriophages, the Pentagon's Threat Reduction Agency, the US National Science Foundation, the State Department's Biotechnology Engagement Program, and NATO have collectively given millions to the Eliava Institute.

Granted, there are serious challenges with bacteriophages. They must be perfectly matched to the pathogen they're expected to destroy, which would make wide use of bacteriophages difficult. The use of broad-spectrum antibiotics against many types of bacteria has led to a shotgun approach to medicine in the United States. Practitioners typically treat empirically and don't identify the pathogen before starting antibiotic therapy. In medical school, students are taught to get a culture and identify the culprit before starting treatment, but in clinical settings, this is rarely done, largely because of time constraints. And bacteriophages would, by necessity, require more time in order to culture and identify the infecting bacteria for a specific therapeutic match.

Meanwhile, commercial use of bacteriophages has been resisted by the FDA: Since bacteriophages are living agents that evolve, safety trials will be difficult and expensive. The pharmaceutical industry, too, hasn't been eager to work with phages. Bacteriophages are naturally occurring and difficult to patent and market. But, perhaps if pharmaceutical companies invested in research to genetically engineer broad-spectrum bacteriophages -- phages that can infect many bacteria -- then they could be patented.

Besides, bacteriophage therapy has some real advantages over antibiotics. It typically produces no side effects. And if resistance develops, treatment can be readily adjusted using different phages effective against the resistant bacteria. Studies comparing bacteriophages with antibiotics in infections like Staphylococcus aureus in the lungs and pleura, have found phages to be more effective than antibiotics. Clearly, there should be many more rigorous clinical trials.

For now, phage therapy has been successfully used in both humans and animals, and it has prevented E. coli infections in calves, lambs, and pigs. It has the potential to treat infections across the species divide and might serve as a One Health solution (a movement that I support and participate in) to the controversial use of antibiotics in livestock.

Take two. Eastern Europe has a long, successful record using bacteriophages to treat infectious diseases. Bacteriophages have been dismissed as an old-style Soviet treatment, but they warrant a second look. The Cold War is over: It's time the United States and Western Europe investigate this potentially powerful alternative to antibiotics. The FDA should encourage research and development of bacteriophage therapy against antimicrobial-resistant organisms. Strategies to guarantee patent protection -- like genetically engineered broad-spectrum bacteriophages -- should also be explored so the pharmaceutical industry has financial incentives to advance the research.

We're all at risk of acquiring antibiotic-resistant infections. Antibiotics have served as an important treatment against infections, but they haven't provided the perfect ending scientists once thought they might. Their availability and effectiveness is waning. And even if new antibiotics are developed, bacteria will eventually develop resistance to them, too. We can no longer rely solely on antibiotics in our struggle to live with bacteria: We need a variety of therapeutics against infections. Bacteriophages may provide an important option, an alternative to treating bacterial diseases. It's certainly worth a shot.