It was widely reported that the waters of the rivers Ganges and Junna in India possessed astonishing antibacterial properties. Two enterprising scientists would eventually come to reveal and describe the filterable entities in the waters that could destroy cultures of bacteria. The French-Canadian Felix D'Herelle, a self-taught medical maverick then at the Pasteur Institute in Paris, discovered these bacterial assassins during World War I. British bacteriologist Frederick Twort would independently uncover their existence two years later. Both noticed a puzzling activity that produced clear areas in agar plates that were otherwise cloudy with flourishing bacteria. Something was destroying the bacteria. D'Herelle identified the minuscule marvel as a new type of parasite.
"In a flash I had understood what caused my clear spots was in fact an invisible microbe...a virus parasitic on bacteria," he wrote.
He named it bacteriophage, derived from two Greek words and meaning "bacteria devouring." Over time the word phage emerged as short term for bacteriophage. However, phage therapy proved more difficult than D'Herelle initially hoped for nevertheless, research on this topic continued in some enclaves of the world.
Phage therapy is a medical treatment that "uses bacteriophage viruses to kill the bacteria that are causing an illness or infection." It has had to overcome several obstacles before coming under the scrutiny of the Unites States medical community. Initially it was tried with many success stories for a variety of diseases and human phage therapy has been around for well over a century even ahead of the breakthrough of penicillin.
Early interest in phage therapy can be found among some of the 800 papers that were published on the topic between 1917 and 1956, but the results were disappointingly mixed.
"In some cases, a liquid containing the phage was poured into an open wound. In others, they were given orally, via aerosol, or injected. In some cases, the treatments worked well - in others, they did not." (Science Friday)
At first physicians and entrepreneurs were thrilled with the budding medical implications and leapt into applications with very little understanding of the scientific process or microbiology of phages. Eli Lilly had an active phage-production program in the 1930s. But many of the studies were anecdotal and/or badly controlled; some of the reported triumphs didn't make much scientific sense. Frequently, uncharacterized phages at unknown concentrations were given to patients without specific bacteriological diagnosis, and there were no references to follow ups, controls or placebos.
From Russia with gloves
When antibiotics became conventional therapy for treating illnesses, research largely faded in the West. In addition to the success of antibiotics, phage therapy has had to withstand the general disregard for Russian research and clinical practices. For quite some time Soviet biology was a pretty sad state of affairs, only in the last decade has it begun to get back on its feet. Around the time that phage therapy was emerging in the former Soviet Union a biologist Trofim Denisovich Lysenko suggested that crop yields could be enhanced rapidly by the inheritance of acquired characteristics.
Carl Sagan discusses the aftermath of Lysenkoism in his book The Demon Haunted World and how for three decades Soviet geneticists were forced into useless endeavors, removed from the field of genetics altogether, or castigated for their dissenting views. Outstanding scientists died in jail while crop improvement programs were botched all because Lysenkoism was favored by Soviet dictators.
Lysenko's ideas were greeted with a great deal of fervor. The enthusiasm was due not only to the fact that Lysenko promised immediate improvements of crop yields but also to the fact that Lysenkoism was supported by Josef Stalin, and then Nikita Krushchev. Even though Lysenko gained excessive power in his country his theory was destined to fail because the true mechanisms of genetic inheritance were denied for political reasons. With all genetic research in the former Soviet Union required to conform to Lysenko's Lamarckian views biologists who disagreed with him were either forced out of power or arrested and left to perish in prisons. It wasn't until Krushchev lost power in the mid 60's that Lysenkoism fell out of favor.
Old dogma, new tricks
In spite of the politicizing of genetics, phage therapy remained a successful and effective treatment in the former Soviet Union over the years. Used extensively in many parts of Eastern Europe as a natural part of clinical practice there are companies in Moscow and several other Russian cities today making phage preparations.
- Working independently, George Eliava discovered the minute creatures after collecting specimens from the Mtkvari River, which flows through the Georgian capital of Tbilisi. Eliava, head of the city's Central Bacteriology Laboratory, left a slide of river water containing cholera bacteria under a microscope for three days. When he returned, the germs were gone. Eliava surmised that something had destroyed them, and, like d'H'relle, he set about isolating the tiny bacteria killers. Eventually, the Georgian struck up a fruitful collaboration with his French colleague. They worked together at the Pasteur Institute in Paris and later at the Institute of Microbiology, founded in Tbilisi in 1923 and later renamed in Eliava's honor.
Since 1923 the Tbilisi Institute of Bacteriophages, Microbiology and Virology has been and still is the main center of research on the most dangerous bacterial strains. For years doctors there have used phages as therapeutic cures for infections ranging from cholera to typhoid fevers. According to various Georgian physicians:
- "Phage therapy is part of the general standard of care there, used especially extensively in pediatric, burn and surgical hospital settings. Phage preparation was carried out on an industrial scale, employing 1,200 people just before the break-up of the Soviet Union. Tons of tablets, liquid preparations and spray containers of carefully selected mixtures of phages for therapy and prophylaxis were shipped throughout the former Soviet Union each day. They generally were available both over the counter and through physicians. The largest use was in hospitals, to treat both primary and nosocomial infections, alone or in conjunction with chemical antibiotics. They played a particularly important role when antibiotic-resistant organisms were found. The military is still one of the strongest supporters of phage therapy research and development, because phages have proven so useful for wound and burn infections as well as for preventing debilitating gastrointestinal epidemics among the troops."
Since the 1940's antibiotics have been so overused, not just in medicine but also to advance the growth of farm animals, that many bacteria have become super bugs that have developed resistance to them. A growing chorus of experts predict that the treatment of diseases may be thrown back to the era before antibiotics when minor diseases were killers. One proposal being studied as a weapon against these super bugs is the use of phage therapy. There are a few drawbacks though. Phages will only target and kill specific bacteria cells that cause certain diseases, but since any given phage only attacks a single bacterium the good news is that it has no effect on human cells. In addition these super bug bacteria find it a great deal more difficult to render phages ineffective by their mutation tactics used against antibiotics.
During the early 1980's Britain and the United States began research applications with phage therapy in animals. The results in general have been very positive and correlate well with the clinical trial in terms of efficacy, safety and the significance of getting the biology of the host-phage interactions documented. This reinforces the confidence of the scientific community in Eastern European results. Many companies have concluded that phage therapy is well worth further study. Quite a few biotechnology companies have been established in the U.S. to expand upon bacteriophage-based treatments -- many of them drawing on the expertise of fellow researchers from Eastern Europe. Research and experiments into phage therapy may provide valuable co- treatments for future chemotherapeutic agents or other antibiotic methods.
Phages are among the simplest organisms on the planet. A milliliter of water can have up to a trillion phage. Carl Merril, chief of the biochemical genetics lab at the National Institute of Mental Health says they flourish anywhere bacteria can survive — in raw sewage, open water, humans and practically anywhere else. About a millionth of an inch in size, a fraction of most bacteria, phages become visible only under an electron microscope. These viruses that prey upon bacteria have a very simple structure - a DNA-filled head attached by a shaft to spidery "legs" that are used to seize the surface of a bacterium. Phage particles look a lot like a lunar lander. Its capsid head contains genetic material coded for the generation of more phage particles. The tail of these "smart weapons" identifies specific bacterial cell types then grips onto a bacterium and inserts its payload of genetic material into the bacterium's insides. The phage genetic material takes over the bacterial cell machinery and codes for the production of more phage. Once the bacterium is coded it starts to quickly manufacture "daughter" copies of the phage -- until the bacterium becomes jam-packed and bursts open, sending hundreds of new and active phage virus to infect other cells.
Antibiotics are either bacteriocidal which means they actively kill bacteria or they are bacteriostatic meaning they impede bacterial processes by halting or slowing growth By modifying their cell components to resist antibiotic interference, preventing uptake of antibiotic, or inactivating antibiotic molecules bacteria gain resistance to antibiotics. Bacteria can divide so quickly that they can create thousands in a matter of hours. As these exponential escalations persist, bacteria release toxins. For the most part the immune system keeps bacterial infections under control, but may be challenged by other diseases or a high load of bacteria. Antibiotics are used to control bacterial infections, but if the antibiotic-resistant bacteria load is high enough they can grow unchecked.
This is where the promise of phage therapy lies. Phages have several advantages over traditional antibiotics. One benefit is that phage multiply exponentially, just like bacteria. For example a small early dose of phage will multiply as it infects cells, lessening the need for continual dosages. Just like bacteria, phage mutates during replication. In effect the same methods that may lead to antibiotic or phage resistant bacteria, can manufacture new phage that can seek out and infect the altered bacteria. Traditional antibiotics wipe out useful bacteria, such as those that help digest food or compete with more dangerous bacteria and the specificity of phage decreases the chance that these useful bacteria are killed when fighting an infection.
More finicky than Morris the Cat.
Referring to the fact that such infections often lead to amputations in the West Elizabeth Kutter the director bacteriophage research at Evergreen State College in Olympia, Washington notes, "They basically don't cut off feet because of diabetic ulcers in Georgia because their staph phage works so well." At the present time scientists recognize that for phage therapy to be successful the bacteria causing the disease must be isolated, identified and then apply the specific phages that kill them. "A miracle of nature is that there seems to be a bacteriophage for every kind of bacteria," says Michael Shnayerson, co-author of "The Killers Within."
"This emerging alternative to antibiotic therapy is a small step towards nanomedicine therapeutically," says a research scientist for the Zyvex Corp, "after disappointments in early trials. Bacteriophages may be viewed as self-replicating pharmaceutical agents that can consume and destroy pathogenic bacteria when injected into infected hosts. A single E. coli cell injected with a single T4 phage at 37°C in rich media lyses after 25-30 minutes, releasing 100-200 phage particles; if additional T4 particles are added >4 minutes after the first, lysis inhibition is the result and the bacterium will produce virions for up to 6 hours before it finally lyses . Of course, medical nanorobots will not be self-replicating.
Wait a minute! Is this related to the Phage on Star Trek?
The writers of the show haven't developed the story line to that extent, many say no, but some say maybe. For those who may be wondering, the Vidiians are a group of aliens on the television program Star Trek Voyager who are badly affected with a disease called "the Phage." It's portrayed as a quickly progressive, adaptive and highly resistant disease that has laid waste to the Vidiian population. The disease is a necrotizing disease meaning it consumes bodies, obliterating genetic codes and cellular structures quicker than the race's medical science can keep up. Thousands die each day, and the only treatment is to replace organs — usually by harvesting from living victims.Similar to the results of the over used antibiotics leading the the evolution of antbiotic resistant super bugs. Writers could take the storyline of this phage as the consequences of super phage bug assassins run amok as The result could be gray goo or global ecophagy, synonymous terms referring to potential devastation of life caused by rampant bio-nanotechnological machines that break down organic matter to use as raw materials for replicating themselves.
The virus that cures
It's expected to be a slow-acting cure, and there is a long way to go before its use becomes a part of mainstream medicine. Laboratory trials use measured quantities of known bacteria, but real world applications are far more complex. Several concerns about phage therapy are on the horizon. One biomedical research facility lists a number of obstacles that phage therapy is expected to encounter:
- Pervasive fixation on chemical antibiotics within the clinical establishment;
- Resistance of the pharmaceutical sector, which is heavily invested in chemical antibiotics;
- Physicians' reluctance to forego wide-spectrum antibiotics in favor of the highly specific phages;
- Structural and functional reorganization required for a coordinated and responsive diagnosis-production-administration chain;
- Pervasive aversion within the biotech research establishment to revert to "archaic" microbiology;
- Need to constantly adapt and refresh phage preparations in response to pathogen evolution;
- Delay between clinical presentation and antibacterial administration;
- General disregard for Russian research and clinical practices;
- Concerns with bacterial evolution of resistance to phages; and
- Lack of a regulatory reference basis.
Tamarin, Robert H. Principles of Genetics, 6th Edition, 1999, pgs 6 - 7 .
Turns of Phrase: Phage therapy