The Good Virus

Do you mean to say you think you’ve discovered an infectious disease of bacteria, and you haven’t told me about it? My dear boy, I don’t believe you quite realize that you may have hit on the supreme way to kill pathogenic bacteria. . . . And you didn’t tell me! Well, sir, I wanted to make certain-- I admire your caution, but you must understand, Martin, that the basic aim of this Institution is the conquest of disease, not making pretty scientific notes! You may have hit on one of the discoveries of a generation. . . . May have, indeed. Martin Arrowsmith, the hero of Sinclair Lewis’s 1925 Pulitzer Prize-winning novel, Arrowsmith, goes on to use his discovery against a devastating epidemic of plague in the West Indies. Fiction, certainly, but it reflected the promise of the real thing. Arrowsmith’s infectious disease of bacteria was genuine, the handiwork of a newly discovered family of viruses called bacteriophages--bacteria eaters--that prey on other microbes. In the 1920s, with the age of antibiotics still in the future, bacteriophages looked as though they might be the longed-for magic bullet: a powerful, specific, long-lasting cure for disease. It hasn’t turned out that way. From time to time over the years, bacteriophages were used to stop bacterial infections, but neither consistently nor convincingly. Then, with the rush toward antibiotics in the 1940s, phage therapy was forgotten. Who wanted to fool around with live infectious viruses when you could pop a few penicillin pills and be as good as new? Western scientists bundled bacteriophage therapy into the dusty closets of history. Today it may be coming back. Some 50 years after antibiotics heralded the end of bacterial disease, their golden age is waning. Disease, of course, remains--it may even be on the upswing. More and more microbes are developing resistance to our arsenal of antibiotic drugs, and scientists are again searching for miracle treatments. Some are looking to the past, to the almost forgotten bacteria eaters. In fact, bacteriophage therapy has never really disappeared. In a corner of the world far from Western hospitals and labs, doctors and health care workers routinely use bacteriophage therapy to cure a wide variety of maladies, just as Martin Arrowsmith hoped. Or more to the point, just as Felix d’Herelle insisted. The checkered history of phage therapy begins with this irascible French Canadian bacteriologist at the Pasteur Institute, who in 1917 announced that while investigating an outbreak of dysentery in Paris he found something that did strange things to the bugs that caused the disease. When he forced the mysterious stuff through a filter and then poured the resulting fluid into test tubes filled with cloudy dysentery bacteria, the cultures suddenly became clear. Two years earlier, a British bacteriologist, Frederick Twort, had observed the same phenomenon, but he was unable to explain it. For d’Herelle, there was no question. In a flash I had understood: what caused my clear spots was in fact an invisible microbe . . . a virus parasitic on bacteria. He called the virus bacteriophage. It was a gutsy conclusion. Viruses had been discovered barely two decades earlier. You couldn’t see them, not even through the most powerful microscope then in existence; scientists had to infer them from available evidence. It strained the limits of turn-of-the-century credulity to suggest that tiny bacteria, themselves invisible except to the microscope, were at the mercy of even more diminutive microbes. But d’Herelle didn’t back down, and finally his persistence won out. tiny and deadly bacillus has enemies still smaller, announced the New York Times in 1925. While a typical bacterium measures about one micron across (a micron is one-thousandth of a millimeter, or one twenty-five-thousandth of an inch), a bacteriophage is only about one-fortieth of a micron, or one- millionth of an inch. And thanks to the electron microscope, today we can see them. Phages make up an outlandish fleet of spaceship-like creatures-- protein lunar landers with modular hollow heads, tunnel tails, and long, spindly legs, the better to grasp the slimy bacterial surface. A phage carries its genes inside its head and, upon landing on a suitable bug, uses the core of its tail to construct a channel into its prey’s interior; it then shoots the genes inside like a bullet through a gun barrel. Once there, the genes force the reluctant host to construct new phages, and within three-quarters of an hour as many as 200 new spaceships may burst from the microbe’s surface. These young phages drift off to infect more bacteria; the unfortunate host, blown to bits, rapidly dies. Which is why Felix d’Herelle suspected that these extraordinary bacteria eaters might function as our allies. Just as they destroyed disease-causing bacteria in lab dishes, perhaps they could destroy them in our bodies. It was a seductive notion then, and it is again, as bacteria gain the upper hand over antibiotics. Among the bugs now resistant to a wide variety of antibiotics are Pneumococcus, the cause of ear infections, meningitis, blood infections, and pneumonia; Staphylococcus, one of the most common causes of skin, wound, and bloodstream infections in hospitalized patients; Enterococcus, a frequent cause of hospital-acquired wound and urinary-tract infections; Streptococcus, the cause of strep throat, scarlet fever, pneumonia, and, most recently, gruesome flesh eating infections; and Vibrio cholerae, the cause of cholera. And tuberculosis is back. Antibiotic-resistant strains of the tb bacterium, Mycobacterium tuberculosis, have spurred a rise in the greatest killer of all time. Worldwide, a third of the population is infected, and 2 million to 3 million people die of tb every year. But even if antibiotic-resistant bacteria were not such a burgeoning threat, phage therapy would still be appealing. Antibiotics involve certain risks. They kill a wide range of bugs, not just their particular targets, and so rid the body not just of harmful microbes but of useful ones as well--bacteria that aid in digestion, for example. For antibiotic therapy to be effective, patients must diligently take multiple doses over an extended period of time. Slack off and you may find yourself battling a renewed attack of disease, this time borne by resistant bacteria. Antibiotics can cause intestinal disorders and yeast infections. Finally, some people are violently allergic to antibiotics. In such cases, the cure can be worse than the disease. None of these problems apply to bacteriophages. Phages prompt no allergic reactions and are notoriously finicky--they target only the bugs they’re supposed to. And if you miss a dose of phage, no problem. Because they reproduce within the bacteria they attack, they stay around for a few days before the body can clear them from the system. At least, that’s the idea. D’Herelle pushed it hard. Dysentery, intestinal disturbances, typhoid fever, infected wounds, boils, surgical infections, cholera, bubonic plague--d’Herelle treated them all with his bacteria eaters. And he wasn’t the only one. Researchers around the world experimented with phage treatment. In the 1930s the pharmaceutical company Eli Lilly listed phages among its biological therapies and offered them for sale. Phage therapy products were even licensed by the National Institutes of Health. But not all accounts were enthusiastic. Even reports of success were often suspect. In his rush to put phages on the map, d’Herelle didn’t bother to apply careful scientific controls by giving doses to some patients, withholding them from others, and comparing the results to determine whether phage treatment really was making a difference. Many other phage experiments similarly lacked persuasive standards and controls. Jim Bull, an evolutionary geneticist at the University of Texas in Austin, has made a point of reading the literature of the time. The reviews from the 1930s and 1940s, reviews of hundreds of studies done, showed that people tried phage therapy over and over again, and there was no consistent pattern, he says. Sometimes it worked; sometimes it didn’t. They didn’t know why. Bruce Levin, a population biologist at Emory University in Atlanta, agrees: It’s hard to evaluate how good phage therapy is. They didn’t run real controls. Now Levin and Bull are taking a new look at phage therapy in light of modern laboratory techniques, trying to see if it really is effective. It’s not that I necessarily think it’ll work, but at least there’s a whole tradition from which to start, Levin says. With all this antibiotic resistance, we have to try something. So in the spring of 1994, Levin and Bull dug out one of the few phage therapy studies done since the 1940s, a 1982 effort by British researchers H. Williams Smith and Michael Huggins, who found that bacteriophage did a much better job in mice than did antibiotics in treating lethal infections of E. coli bacteria. With graduate student Terry DeRouin and technician Nina Walker, Levin and Bull decided to try the experiment themselves. The team injected a dose of E. coli into the right thighs of 15 mice and a dose of phage into the left. Into 15 other mice they injected bacteria but no phage--these were the controls. The results were dramatic. The control mice died within 32 hours, Levin says. In the other mice the E. coli formed abscesses in their legs, but they survived, all 15 of them. Then the team compared phage therapy with antibiotic treatment. They injected 48 mice with E. coli, then separated them into groups of 12. Eight hours later they gave phage to one of the groups of mice, doses of the antibiotic streptomycin to two of the groups, and nothing more than a saline solution to the remaining mice, the control group. This time all the control mice died, and 16 of the 24 streptomycin-treated mice--two-thirds of them--also died. But only 1 of the 12 mice treated with phage died. Again, phage was by far the most effective treatment. Levin now wants to pit bacteria eaters against Staphylococcus and Pneumococcus. Bull is gearing up to loose them on Salmonella, the cause of typhoid fever and food poisoning. But none of the researchers are beating the drums for the promise of phage treatment--not yet anyway. We don’t want to give the impression that we think phage therapy is some kind of panacea, says Terry DeRouin. There are tremendous limitations. The biggest is that phages tend to be very, very specific for certain bugs. This is the downside of the viruses’ pickiness. Whereas an antibiotic can kill a variety of bugs, a phage will target one or at most only a few kinds of bacteria. If you don’t choose precisely the right phage, you’re out of luck. As proof, the team tried to treat the E. coli-infected mice with a different strain of phage; 9 of the 15 animals died. No one wants to see that kind of mistake in humans. So, in practice, the bugs for every illness, from the mildest case of diarrhea to a middling sore throat to worse, might have to be cultured and identified before phage treatment could be prescribed. That would be an expensive, time-consuming chore. Bull offers a cautionary scenario: My daughter had pneumonia a couple winters ago. She spiked a fever of 104 and just kept it there. We went to the doctor as soon as we could--about 18 hours after it started. They did a spinal tap on her, a blood culture, and they never did diagnose what it was. But they gave her a shot of antibiotic anyway, and within 6 hours her fever plummeted and she was okay. Well, we might’ve had to wait days longer to use a therapy that required us to know exactly what bug she had. It’s really hard to overcome that limitation. We literally may have to run out of wonder drugs before people start considering treatments like phage. What phage therapy needs is a startling success. Felix d’Herelle had the same thought. And he believed he could find his success in the 1,500-year-old city of Tbilisi, the capital of the Black Sea Republic of Georgia. In 1934 he spent six months in this river valley city collaborating with a Georgian microbiologist, George Eliava, to create what is now known as the Eliava Institute of Bacteriophage, Microbiology, and Virology. It was intended to be the world center of phage studies. Unfortunately, their dream could not come true due to the difficult political situation in the Stalin period, institute researcher Nina Chanishvili says. In 1921, three years before the formation of the USSR, Russia invaded Georgia. From then until the breakup of the Soviet Union 70 years later, any hopes the Georgian people might have had for a return to national autonomy were systematically snuffed out. In 1937, Lavrenti Beria, Stalin’s brutal lieutenant (both of them Georgian by birth), ordered Eliava to be arrested as a people’s enemy. Soon he was executed. D’Herelle’s grand hopes dissipated; he never returned to Tbilisi. But the institute survived, and since then, virtually unknown to the West, it has been producing phages for Georgia as well as for the rest of the former Soviet Union. The range of treatments is astonishing. Dys-entery, food poisoning, typhoid fever, burns, skin infections, throat infections, blood poisoning, and urinary-tract infections are just a few of the disorders being treated. If someone has an intestinal disorder, the person can drink the phage, Chanishvili says. If it is a skin infection, phage can be applied to the spot. We have developed aerosol and tablet preparations. Also, the institute has worked out a special phage remedy against staphylococcal infections. It is for intravenous use, directly into the blood. Phages are also used to kill bacteria that cause vaginal infections and sterility and to treat infection following lung surgery. They are used to clear up wound infections; as an antiseptic, to clean operating rooms and sterilize surgical instruments; and prophylactically. For example, they are routinely applied to incisions during surgery to forestall postoperative infections. Also, Chanishvili says, bacteriophage therapy has been used by military groups all over the former Soviet Union. They swallowed phage if they were going into an area where disease is common. (Among the infections prevented was bacterial gangrene.) And the onset of antibiotics hasn’t changed much. Phage therapy is very efficient, especially in combination with antibiotics, Chanishvili says. It retards the development of resistance. Irakli Pavlenishvili, head of pediatrics at Georgian State Pediatric Hospital, agrees. His hospital uses phage therapy to combat drug- resistant microbes. We had very big problems with antibiotic-resistant bacterial infections, he explains. They were resistant to amikacin, gentamicin, cephalosporin--third-generation antibiotics with a very wide range of action. But the same strains were very sensitive to phage. Phage gets very good results. Indeed, the results were so good that at the pediatric hospital it was standard practice to give every child phage. Immediately when a child arrived here, he or she was given phage for prophylaxis, Pavlenishvili says. It helped prevent the spread of salmonella, and also shigella and Staphylococcus, all dysentery diseases. That meant giving phage to as many as 11,000 children each year. The reduction in infection between 1987, the first year of the effort, and 1992, the last, was sixfold. And I can tell you that these phages are absolutely harmless, Pavlenishvili says. Even if you do not get clinical improvement, you do not harm liver, kidney, or any other function. And none of these bacteriophages harm normal microflora--only pathogenic microflora. The approach underlines the flexibility of phage therapy. Besides being able to prescribe specific phages for specific infections, doctors can also provide broadly effective doses, much like broad-spectrum antibiotics, by combining a variety of phages in one preparation. To extend the range of the remedies, we mix the phages together like a cocktail, Nina Chanishvili explains. Phage cocktails often include local strains, even those from specific patients, because those are the ones that have the best chance of stopping local bacteria. And, due to some extraordinary feats of surveillance, the researchers know precisely which strains of bacteria need to be stopped. In 1967 the minister of health issued a law requiring that we be sent all the pathogenic bacteria strains isolated in all the different republics of the former Soviet Union, says Teimuraz Chanishvili, Nina’s uncle, who has been the head of science at the institute for the past 36 years. We received 42,000 strains. And we were testing our phage remedies on these strains. It was exhausting laboratory work. But after several years of this, we built up quite an extensive collection of phages, which had quite a wide range of action. After that, we could anticipate pathogenic strains of bacteria and select an appropriate phage from our library. The principle of phage cultivation is simple--where you find bacteria, you usually find a predatory phage--but the reality is tricky and entails laborious work. The institute’s task involved nurturing its immense assortment of disease-causing bugs inside test tubes, culling the most lethal phages that attacked them, raising huge numbers of the viruses in bacteria farms, and cataloging and storing them for instant use. Teimuraz Chanishvili has elevated the procedure to an art. At its peak, in 1990, the institute had developed into a facility that was able to provide an enormous variety of phages for most needs, and to grow specialized phages quickly for difficult cases. That was the happiest time, Chanishvili says. We had good facilities and enough money to develop real research. There were limitations, however. Not every disease can be treated with bacteriophage. For pneumonia caused by Klebsiella infection, no specific phage exists--not yet, Chanishvili says. Phage cannot yet be used to combat tuberculosis or the sexually transmitted microbes gonorrhea and chlamydia. And because phages, like the bacteria they attack, are foreign to the body, they can provoke an immune reaction when introduced into the bloodstream. If you use phage for eyes, ears, and throat, swallow it to improve your internal system, or apply it on the skin, there are no problems, Chanishvili explains. But if you want to make injections, it can cause a reaction. The reaction consists of an antibody buildup that might eventually neutralize the phage--the patient experiences it as a couple of hours of mild fever. But it’s not necessary to let the process reach that point. You use the phage several days, then you must test whether antibodies appear, Chanishvili continues. If so, you simply change the preparation. In the case of babies, whose immune systems are not as developed as those of adults and older children, the reaction never even takes place. In contrast to antibiotic therapy, bacteria do not usually mutate to develop resistance to all the phages in a cocktail, but if they should, Chanishvili says, you can get new phages. And phages are much less expensive to produce than antibiotics. Bruce Levin, for one, is not convinced. I expect there is more inertia there than here. Institutions are less likely to die or wane even if they don’t work. I suggest caution until we can see some data. It is definitely time for outside scientists to go there and take a serious look at what they’ve been doing. Says Jim Bull, I’m skeptical. The same old problem: Sounds great, but where’s the proof? There are controlled studies, Nina Chanishvili insists. Indeed there are. But nearly all of them are in Russian, few of them have ever been seen by Western scientists, and perhaps few of them measure up to Western standards--that remains to be determined, if the West ever decides to look toward Tbilisi. But even if there were no studies, shouldn’t the experience of more than half a century count for something? Elizabeth Kutter thinks so. Kutter, who does research on phage molecular biology at the Evergreen State College in Olympia, Washington, has visited Tbilisi a number of times and collaborates with institute scientists on basic phage research. She has no doubt that something worthwhile is happening there. It’s not high tech, or biotech, so people in the West, the few that know about it, tend to distrust it. But they wouldn’t have been using it all this time if it wasn’t doing anything. It’s very much worth exploring. Nor does she have any doubt that phage therapy is likely to be a hard sell. It’s not as clean and tidy as antibiotics. You have biological species that mutate and get combined in various mixtures. Getting something like that through the fda would be interesting. In the meantime, Western medicine staggers on, struggling to cope with the explosive resurgence of infectious diseases. And bacteriophage therapy in Tbilisi staggers on as well. It’s no accident that the Bacteriophage Institute’s greatest success occurred some years ago. Since the breakup of the Soviet Union in 1991, Georgia has floundered in civil war and chaos. At its height, the institute housed some 700 researchers and technicians. Today the number may not reach 200. The sprawling campus on the bank of the Mtkvari River is crumbling. Water and electricity are available only a few hours a day. Corridors are gloomy, doors are padlocked, windows groan and slam in the wind. With the traditional demand from former Soviet Union clients disintegrating, facilities deteriorating, and government support virtually nil, phage production at the institute is intermittent, new research impossible. We are in a miserable position, says Nina Chanishvili. Today the institute has but half a life--but still it is existing. And still it may have much to offer us. Felix d’Herelle would have appreciated the irony--the West increasingly desperate for new treatments against bacterial diseases, and Tbilisi’s Bacteriophage Institute, the font of such treatments, increasingly desperate to just survive. He may have appreciated it, that is, when he wasn’t railing against the rest of the world for not paying attention.

The Good Virus

As bacterial diseases develop resistance to antibiotics, medical resarchers rediscover an older strategy: setting one microbe to kill another.

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