New York Times
A Stalinist Antibiotic Alternative
A hoary Soviet method for fighting infections may prove invaluable in an age of antibiotic resistance. Maybe that's why pharmaceutical companies are flocking to a remote laboratory in Tbilisi.
By Lawrence Osborne
In a barely heated ward for newborns on the top floor of the Georgian Republic Children's Hospital, Tamila Gogitidze carefully opens a glass ampul filled with amber liquid. The hospital, in the Degomi suburb of Georgia's decaying capital city, Tbilisi, is a spartan affair: its radiators are ramshackle, the electricity intermittent and the raw concrete heavy on the eyes. A few American posters of babies cavorting in cabbages seem direly out of place. The liquid trapped inside the ampul, meanwhile, can be identified from a box on the floor. Its label is Latin: Bacteriophagum Intestinalis Fluidum. Gogitidze, a nurse on the intensive care unit for newborns, cracks open the ampul, pours the liquid onto a teaspoon and prepares to administer it to one of her babies, a 3-month-old boy abandoned at the hospital a few days before by his impoverished family. He is screaming lustily.
''Look,'' Gogitidze says, holding up a tiny wrist. ''The parents made a kind of crude tattoo so that they can identify him later on. But for now, we must focus on his intestinal infection.''
The fluidum is tipped like any cough syrup into the boy's blubbering mouth. His face contorts into a horrible wince; I look apprehensive. But Dr. Tamar Gotua, head of the intensive care unit, takes my arm and says: ''We use them with almost all our children. Don't look so worried!''
It's hard not to feel worried in Georgia. After years of bloody civil war following the collapse of the Soviet Union, the republic is in free fall. Electricity runs for only part of the day; blackouts are a daily, if not hourly, occurrence. Nevertheless, in this dilapidated neonatal ward a possibly revolutionary medicine, one essentially unknown in the West, is being casually administered on a simple teaspoon: bacteriophages, or microscopic viruses that actually ''eat'' bacteria.
Downstairs in the same hospital, I talk with Dr. Irakli Pavlenishvili, head of pediatrics, in an office so cold that our breath mists. The doctor offers me some Greek brandy and warms his hands by a portable electric heater. We chain-smoke furiously. ''We've been using phages for years,'' he says briskly, looking up nervously at the flickering lights. ''There are no major side effects. They're a living, natural force, not a toxic chemical. I wish our electricity were as reliable!''
Today, the West is paying renewed attention to this unheralded therapy created behind the Iron Curtain. The reason: antibiotic resistance. Although drugs like penicillin have held killer bacteria at bay for half a century, the bugs keep genetically adapting to them, evolving into tougher, smarter variants of ancient adversaries. The systematic overuse of antibiotics by doctors, especially in the United States, has helped breed ''superbugs'' -- bacteria resistant to even the most potent antibiotics, like vancomycin.
Last year, The New England Journal of Medicine published an alarming editorial about superbugs. ''The outlook is rather grim,'' it wrote. ''The adaptive potential of the microbial world is such that for each new antibiotic that is introduced, several escape mechanisms are soon devised.''
Alexander Tomasz, a leading microbiologist at Rockefeller University, agrees: ''The miracle days of antibiotics are over. We simply didn't think enough about the evolutionary consequences of drug use.'' With leading medical researchers in the West looking anxiously for antibiotic alternatives, bacteriophage therapy is suddenly looking ''very promising,'' as Tomasz puts it.
''I'm convinced that bacteriophages will work,'' says Carl Merril, chief of the biochemical genetics laboratory at the National Institutes of Health. ''But there's the psychological obstacle of a new treatment coming from the former Soviet Union. It's unusual, to say the least.''
They may sound exotic, but bacteriophages are in fact among the most common organisms on earth. (The word derives from the Greek phagin, ''to eat.'') Viral predators only one-fortieth the size of the average bacteria cell, they swarm unseen around us, busily searching and destroying their favorite food: germs. In electron microscope images, phages show up as ghostly, spiderlike creatures with transparent box-shaped heads, rigid tails and a tangle of legs for gripping their prey. They are so tiny that a single drop of tap water may contain a billion of them.
How do phages kill bacteria? The answer is, with chilling efficiency. Latching onto the walls of a bacteria cell, the phage injects it with the genetic material stored in its very own head. Like a living syringe, it gradually empties itself into the victim and takes over its genetic machinery. Inside the helpless bacteria, bits and pieces of ''daughter'' phages begin to appear with sinister rapidity: rows of little heads, lines of tails, then legs. These different body parts assemble into miniphages, using the host cell as a kind of factory. As the phages multiply exponentially inside it, the bacterium's walls weaken -- then explode like a soap bubble. Scientists call this rather nightmarish process ''lysis.'' It is the flash point of a gigantic microbial war between phages and bacteria, in which humans are a mere side issue.
These deadly microscopic hit men were discovered independently during World War I by the English microbiologist Frederick Twort and the flamboyant Canadian biologist Felix d'Herelle, then working in a laboratory at the Institut Pasteur in Paris. It was d'Herelle who gave them their name in a 1917 paper that predicted a revolution in the treatment of infectious diseases.
D'Herelle first discovered bacteriophages while working in the Mexican state of Yucatan in 1910. He noticed them in the most unlikely of places: the diarrhea of locusts. During an invasion of these insects, d'Herelle collected sick specimens and observed their abundant stools. He concluded that the locusts were suffering from septicemia caused by coccobacilli bacteria. D'Herelle smeared some of the diarrhea onto plates of agar to grow cultures, but then noticed something odd. After a while, clear circular spots a few millimeters across had appeared in the agar, suggesting that something was munching away at the coccobacilli. What were these tiny bacteria-eaters?
Back at the Institut Pasteur, d'Herelle repeated the experiment in 1915 with stools taken from a Paris-based squadron addled with dysentery. In the excrement of the officers, d'Herelle again detected agents that consumed the bacteria spontaneously. Nature, d'Herelle boldly announced to the world, had provided humankind with a living, natural weapon against germs.
Phages were popularized by Sinclair Lewis in his 1925 novel ''Arrowsmith,'' about a young doctor who goes to the West Indies to use them against an epidemic of bubonic plague. ''You may,'' says one of the novel's characters to Martin Arrowsmith, who was inspired by the real-life d'Herelle, ''have hit on the supreme way to kill pathogenic bacteria!''
But it was not to be. Phages proved to be a hit-or-miss affair as a therapy. One problem was that there are hundreds of types of phages, and each type kills only one variety of bacteria. Predator and prey must be perfectly matched, a daunting process. What's more, there were early problems with purification. When phages burst out of the victim's cell, they leave behind debris that can contaminate the solution. This debris can prove fatal to humans, a problem that the purification technologies of the early days were unable to solve.
As a result of these difficulties, phages were quickly outpaced by a rival drug: penicillin. Although Eli Lilly actually manufactured therapeutic phages for the United States market in the 1930's, after World War II they were largely consigned to the margins of Western medicine -- even as they took center stage in DNA research, where their simple molecular structure made them an ideal tool for peering into the inner workings of genes. Sir Francis Crick and Max Delbruck, two architects of DNA theory, were phage researchers. Phage research helped unlock molecular biology at the very moment that they disappeared from the medical scene.
Yet there is a twist to this story. The aristocratic d'Herelle was a passionate Communist and admirer of Stalin. In 1934, he accepted an invitation from the Soviet government to join the Institute of Bacteriology in Tbilisi, recently set up by a young Georgian microbiologist named George Eliava. The Eliava Institute, as it became known, became the world's leading center of therapeutic phage research. One of its first successes was a powerful dysentery phage for the Red Army during the World War II. Over the ensuing decades, the institute began supplying precisely targeted phages to hospitals all over the Soviet bloc. The Eliava Institute became the largest phage library in the world, with a permanent ''museum'' of more than 300 phage clones.
''We've been perfecting bacteriophages as a medicine for over 70 years, just as d'Herelle said we could,'' explains Nina Chanishvili, a senior researcher at the Eliava Institute today. ''But has anyone been listening?''
On an icy December day, Chanishvili and I walk through the hilly Tbilisi district of Saburtalo on our way down to the Eliava Institute. The path winds vertiginously through plots of spindly pomegranate trees touched with snow. Clumped along the hillside are rotting Soviet-era apartment blocks. On the streets, the shops are lighted only with candles.
Nina's uncle, Teimuraz Chanishvili, has helped direct the Eliava Institute for a quarter of a century, and she, too, has devoted most of her life to phage research. But the last 10 years have been cruel. In recent years, she says, the institute's phage output has dwindled alarmingly. Virtually unpaid, the institute's workers now cling to a fading infrastructure. When high-tech equipment breaks down, they must work with improvised materials. Also, adds Chanishvili, ''because of the power cuts, we've lost about half of our phage library.'' (Phage cultures must be refrigerated.) Georgia's economic collapse has dwindled the demand for phages as well. Once the institute manufactured phage sprays, salves, ointments, tablets -- you name it. But now, even at $3 to $5 for a box of 10 ampuls, many of Tbilisi's sick simply cannot afford them.
The institute, however, still sits in its graceful park of cypresses overlooking the Mtkvari River, and over the wall I see the handsome cottage that Stalin had specially built for d'Herelle. It is still called ''d'Herelle's cottage,'' though it was later occupied by the Georgian K.G.B. Inside, the institute is a cavelike labyrinth of damp cement corridors, stairwells dripping wires and mournfully antiquated labs. The old fermentation vats that used to churn out phage preparations for the Soviet Ministry of Health stand abandoned in a room with no glass in the windows.
Upstairs, Chanishvili shares a cramped and unheated lab with a fellow researcher, Marina Tediashvili, and half a dozen young medical students. They are all women. They are all shivering. ''Of course,'' says Tediashvili, ''the men naturally move on to better things.'' Equipment is largely rudimentary. Among the centrifuges, water baths and piles of petri dishes stand dozens of beer and vodka bottles that the women use as containers for their solid agar. To melt the agar, they pop one of the vodka bottles inside an old Nescafe tin sitting on a hot plate. ''We like vodka bottles,'' Chanishvili feels obliged to explain, ''because they're so transparent.''
The interns spend most of their time on the tedious chore of planting phage cultures in the specimens of bacteria, turning each petri dish into a kind of phage farm. I watch as one of the women sterilizes the tip of an applicator in a Bunsen burner, drips a blob of phage solution onto a plate of E. coli and carefully closes the plastic lid. ''E. coli causes epidemics worldwide,'' explains Tediashvili. ''But these phages find E. coli tasty. They go through it like Oreos.''
Holding up an E. coli dish that has been incubated for two days, she points to a smattering of irregular, clear circles carved out of the agar. They look like the perforations of a shotgun blast. ''Isn't that beautiful?'' she whispers. A dish of salmonella is peppered with smaller, more regular bullet holes.
Chanishvili explains that she and her colleagues initially catch phages in gunky places where the creatures are known to thrive: sewage water, for example. They are then stored in a liquid broth kept in a refrigerator at 4 degrees Celsius. Oddly enough, they don't need to be fed with tasty germs to stay alive. ''Phages can live for months without food,'' Chanishvili says. ''Without additional germs to feed on, they cannot multiply out of control.'' If their numbers begin to decrease, however, a few bugs are thrown to them and they multiply again.
In the same wing, I am taken to see Amiran Meipariani, head of phage research. Meipariani has been here since 1946, at the height of the Stalin era, and his sardonic blue eyes seem to have seen it all. Like most Georgian doctors, he chain-smokes and shrugs frequently. His office is filled with disconnected Soviet telephones; on the wall hangs a faded portrait of Felix d'Herelle.
''As you can see, we've fallen on hard times,'' he says, shrugging. ''But it is now realized worldwide that an alternative to antibiotics should be sought and that the best one is bacteriophages. Perhaps it's a boon for us. Did you know that NATO is now interested in one of our inventions?'' His eyes light up puckishly. He is referring to a topical phage application invented by the Eliava Institute and known as a ''PhageBioDerm,'' a kind of bandage saturated with a cocktail of five to nine different phages that can treat infected burn wounds. It is the perfect military Band-Aid. Russian soldiers have used them in Chechnya. ''Of course, women and kids can use them in the kitchen, too,'' he adds with a sales-pitch smile.
The Eliava has a local patent on the phagoderm, which it manufactures itself along with the ''intestiphage,'' the 17-phage cocktail I saw being administered to the abandoned baby. All in all, the Eliava produces about 10 different phage applications that target about 15 different bacteria genera. By creating drugs that combine many phages at once, their administration can be simplified to a single dose.
Considering the difficulties involved in doing science in Georgia, the advancements made by the Eliava are remarkable. Chief among these has been the creation of an intravenous remedy to the deadly staph aureus bacteria, a strain that threatens to one day outpace vancomycin. According to the Eliava, it's been used successfully on dozens of patients.
In the past few years, the Eliava's skill has attracted the attention of Western entrepreneurs eager to harness the knowledge bottled up in Tbilisi's laboratories. But the Georgian scientists worry about this development as much as they celebrate it. Who will ultimately benefit from the commercial exploitation of their work? Will the Americans and Europeans simply steal their expertise and innovations? ''The local market has collapsed,'' says Meiparinai with a final shrug. ''But who will patent phages in the West? Who's going to make the millions?'' Then he corrects himself. ''The billions, I mean.'' Indeed, the worldwide antibacterials market is estimated to be worth $25 billion a year.
So far, the Eliava's experience of cooperation with American companies interested in phages has not exactly been propitious. In 1996, a Canadian venture capitalist named Caisey Harlingten came to Tbilisi, eager to talk to the Chanishvilis about their work. What happened next was, as Chanishvili puts it tersely, a ''culture clash.'' Although a start-up company that came to be named Phage Therapeutics was quickly set up in Seattle, the planned Tbilisi affiliate was closed almost as soon as it opened. ''Harlingten told me,'' says Chanishvili bitterly, ''that the American consumer would never accept a medical product from the Soviet Union.'' Meanwhile, Phage Therapeutics is busy readying Eliava-inspired medicines for the U.S. market.
''We gave the Americans access to all this background research,'' she goes on, ''and they simply walked away with it. They told us we were stupid at business. Well, that at least was true.''
That evening, I meet with Teimuraz Chanishvili at his home on Kazbegi Street, a lampless street of elegant 19th-century Russian houses. A Nabokovian charmer now in his 70's, he greets me at the top of the stairs in his dressing gown. ''Come and look at the TV,'' he says excitedly. ''The Americans have stolen my phage photographs!'' By one of those coincidences that even a journalist couldn't invent, there indeed is an American documentary about phages playing on the TV. Teimuraz's uncopyrighted images of phages float like extraterrestrial prawns across the screen. ''I didn't get a cent!'' he cries, shaking his finger at the screen.
Later, we have a calmer chat over chestnut soda, and he tells me the sad story of George Eliava. The man who established the bacteriophage's central place in Soviet medicine was not exactly rewarded for his efforts. When not doing brilliant science, Eliava was a handsome playboy who had the misfortune to fall in love with a woman also admired by Lavrenti Beria, Stalin's secret police chief. Despite Stalin's high regard for bacteriophages, it was Eliava's death warrant.
''Beria had Eliava shot in 1937 on a pretext,'' Teimuraz says matter-of-factly. ''That's the way it was back then.'' He adds with a chuckle, ''Thankless work, bacteriophages!''
As if on cue, the lights go out.
In the well-lighted laboratories in europe and the United States, however, the prospects for phages are glittering. In this country alone, at least three start-up companies are vying to be the first to push a phage therapy through Food and Drug Administration approval. In addition to Harlingten's Phage Therapeutics in Seattle, there are Intralytix in Baltimore -- a company with numerous Georgian expats on the payroll -- and Exponential Biotherapies on Long Island, a small biotech company run by Dr. Richard Carlton that expects to petition the F.D.A. to begin clinical trials on a phage drug this spring.
Big challenges face these companies. One pitfall of early phage therapy was that wild phages are expelled very quickly by the body's filtering system, often reducing their effectiveness. The immune system, in other words, treats them as foreign bodies. Can new technologies, however, pinpoint ''domesticated'' phages that can linger longer in the body? While the Eliava has had some success on this front, American scientists hope to do even better.
The work of Carl Merril has led the way. In the April 1996 edition of Proceedings of the National Academy of Sciences, the N.I.H. researcher published the result of some intriguing experiments with phages and mice. Essentially, he was able to selectively breed ''mutant'' phages that remained in the mice far longer than the wild variety. ''We altered the code proteins in the phages,'' Merril explains, ''to make them more durable.'' In the same issue, the Nobel laureate Joshua Lederberg of Rockefeller University wrote, ''This is an ingenious surmounting of one of the hurdles to the use of phage in therapy.''
It was Merril, recalls Carlton of Exponential Biotherapies, ''who told me that phages had been used as a therapy back in the 30's. What sometimes limited them, though, was this problem of making them stick around inside your body. But today, with genetic engineering, we can selectively breed phages that can last thousands of times longer.'' This represents a huge advance. After all, a single phage can produce 40,000 daughters in an hour; one hour later, the number increases exponentially to 4 billion. As Carlton puts it, ''It's the only drug that makes more of itself as it's actually being used!'' In recent experiments with mice infected with the E. coli bacteria, Merril reports, he cured every single animal with these long-life phages.
At University of Maryland labs used by Intralytix, Zemphira Alavidze, who also runs her own lab at the Eliava Institute, presides over the same array of petri dishes, jars of agar and phage phials. But the difference between Baltimore and Tbilisi is twofold. ''Here,'' she says, ''we have lots of mice to experiment on. And we can purify phage solutions using chromatography. Purification is much more tricky in Tbilisi -- and mice are just out of the question.''
Purification and in-depth animal testing are essential first steps toward commercializing phages in the painstaking medical culture of the West. Clinical trials involving human patients are yet to come. On this front, the Georgians are way ahead of the Americans. Indeed, the Soviet bloc's headlong experiment with human patients may well turn out to be the greatest contribution of the embattled Tbilisi doctors to the eventual medical use of phages.
Dr. David Shrayer, now a cancer researcher at Brown University, worked as a medical officer on the construction of the Baikal-Amur railroad in Siberia in the 1970's, where he says he regularly administered bacteriophages to Soviet construction workers. ''Even back then,'' Schrayer says, ''these Siberian workers were suffering from infections that were resistant to antibiotics. The phages worked splendidly. But here's the catch. D'Herelle and then the Soviets ruined the image of phages in the West by testing them on people without first conducting proper animal tests. Animal tests were expensive; patients were cheap. That was the tragedy of phages in the East. But it was also their trump card. We learned that they really work.''
The most exclusive private clinic in tbilisi is the plastic surgery unit within the Clinical Diagnostic Center, a stone's throw from the university. The contrast with the children's hospital couldn't be greater. A small vestibule sports a soothing green fish tank, while Tchaikovsky burbles on the sound system. Open just a year, the clinic serves the liposuction needs of Tbilisi's rich. Here I sit with the elegant Dr. Iva Kuzanov, Georgia's top plastic surgeon, looking at an album of post-op photographs. They are stomach-turning.
''This man was bitten in the nose by a pit bull. See how handsome he is now? This woman came to us from San Francisco for a sex-change operation. What do you think of her penis?''
''Marvelous,'' I say.
There is an alarm clock hanging from it. ''To prove the strength,'' Kuzanov says with a totally straight face. ''We amputated her finger and put it inside. Amazing, no?''
What is really remarkable about the clinic, however, is the frequency with which phages are used to counter surgical-wound infections in these complex (if bizarre) cosmetic operations. Many of Kuzanov's patients are from the West, he says. ''They come because of the low prices here.'' As for phages, Kuzanov claims, they've proved to be excellent for burn traumas or infections arising from accidents. He holds up a picture of a breast-reduction job. ''We treated her lesions with phages. Look, a perfect recovery.''
To see one of these phage patients for myself, however, I decide to call on the first person ever to have been treated with intravenous phages. His name is Prince Avtandil Chkheidze, M.D. He is a prince and a doctor. Chkheidze receives me in an imposingly austere office at his private clinic. Although it is freezing cold, he wears only a snappy maroon blazer. After first showing me a copy of his family's coat of arms, he hands me a more welcome glass of steaming Turkish coffee. ''So you want to hear about phages?'' he whispers like a character out of Edgar Allen Poe.
Chkheidze spins out his story. After graduating in 1976 from a Tbilisi medical school, he was posted to a gynecology clinic in Leningrad. Overworked and exhausted, he eventually fell ill with a severe lung infection. In time, he came to be additionally afflicted with a long-term purulent skin infection. Even though his hospital placed him in a top Soviet clinic with state-of-the-art Western medicine, its antibiotics made no difference. His skin infection worsened, and he begged to be allowed to return to Tbilisi. Once there, he asked his father, one of the city's leading doctors, to see if he could be treated with intravenous phages -- a procedure never carried out before. The risks were great. But unable to move and now dependent on crutches, Chkheidze didn't much care.
''At first,'' he says, ''my father was horrified by my proposal. Then Teimuraz Chanishvili told us he had a staph aureus phage already tested on animals. But he was afraid to use it on humans.''
They therefore had to find someone willing to administer the phages. In the end, Dr. Vakhtang Bochozishvili, a famous professor at the Sepsis Center in Tbilisi, agreed to do so. ''It was a bit of a conspiracy,'' Chkheidze says. ''I was the ultimate guinea pig.''
On the fifth day of treatment, the prince threw away his crutches and went to a late-night party with his friends. The taboo on intravenous phages, he notes, was shattered with one blow. ''On the seventh day I was completely cured. It was quite miraculous.''
The possible implications of this strange fragment of medical history are enormous. Chkheidze says that he would like to introduce widespread intravenous phages into his clinic. In fact, he claims, his clinic doesn't use antibiotics at all to treat infection. He also claims that during the last 10 years of the Soviet system, approximately 20,000 people were cured of chronic sepsis by phages, though it is hard to verify such statistics. As it is, he adds: ''I use them every day in my practice. They are excellent for pregnant women, extremely safe.'' He lowers his voice. ''I use them in vaginal suppository form. They are pure gold.''
But what of human patients in the West? This is a far more shadowy affair, since phages can be used only in extreme cases in which a dying patient's family gives explicit permission for their use. So far, such cases have been extremely rare. Last year, Nina Chanishvili was contacted by two Belgian brothers who had read about phage therapy on the Internet. Their 23-year-old sister lay dying of a severe post-measles viral infection of the brain. A trepanation in her skull to inject antibiotics, the brothers explained, had become infected with staphylococcus areus. Could Chanishvili treat the secondary infection with phages?
''I just had to go,'' she says. ''I brought the phages myself.'' According to Chanishvili, the secondary staph infection cleared up within days, though the girl remained mortally ill from her untreatable primary condition.
In another recent case, a woman dying of a Marfan-related heart problem in Toronto was treated for a staph infection by having a solution of phages sprayed directly onto her aorta. The infection was vanquished within 20 hours. (Two months later, the woman died of her heart condition.) Phage Technologies, which provided the medicine, hyperbolically hailed it as ''the first use of phage therapy in the West in modern times.''
Of course, one patient is far from the rigorous proof Western medicine requires; perhaps the staph infection would have cleared up on its own. Nevertheless, says Elizabeth Kutter, a leading American phage researcher at Evergreen State College in Olympia, ''what this shows is that phages are ready to be used in the West.''
The next international phage conference will be held this June in Montreal, d'Herelle's birthplace. It is difficult not to imagine the old Communist iconoclast smiling in his grave -- not to mention Comrade Stalin. ''It's strange to think,'' says Nina Chanishvili, ''that Stalin might be considered a medical benefactor of the 21st century!''
Feb 06, 2000