In the barely heated neonatal ward on the top floor of the Children's Hospital in the Republic of Georgia, Tamila Gugidze opens a glass ampoule filled with an amber-colored liquid.
By Lawrence Osborne New York Times
25/4/2000
In the almost unheated neonatal ward on the top floor of the Children's Hospital in the Republic of Georgia, Tamila Gogididze opens a glass ampoule filled with an amber-colored liquid. The hospital in Dagomi, one of the suburbs of Tbilisi, the crumbling capital of Georgia, is quite spartan - radiators tending to fall, intermittent electricity supply and bare concrete walls. Some American posters, where babies are seen jumping between cherubs, look completely out of place. The type of liquid trapped inside the glass ampoule can be identified by the box on the floor, on which there is an inscription in Latin: Bacteriophagum intestinalis phloidum. Gogididze, a nurse in the neonatal intensive care unit, opens the ampoule, pours its contents into a spoon and is about to give it to one of the children in her care - a three-month-old baby, screaming vigorously, who was abandoned in the hospital a few days earlier by his poor parents. "Look," says Gogididze, holding the tiny wrist, "the parents stamped a rough tattoo on it, so they could identify it later. But right now we have to concentrate on the intestinal inflammation that he suffers from."
The liquid is poured into the crying baby, similar to any other cough syrup. His face twitches. It's a disturbing sight. But Dr. Tamar Gotua, head of the intensive care department, grabs my arm and says, "We use this for almost all of our babies, don't look so worried."
It's hard not to feel worried in Georgia. After many years of bloody civil war, which broke out following the collapse of the Soviet Union, the republic is in a state of free fall. Power outages, for example, occur daily, if not hourly. And yet, in the dilapidated neonatal ward of the hospital in Dagumi, the babies receive a drug that is almost unknown in the West and that may turn out to be revolutionary. Bacteriophages: microscopic viruses that actually "eat" bacteria.
A few floors below the neonatal ward, I am talking with Dr. Irakli Pavlanishvili, head of the pediatric ward. The doctor offers me Greek brandy and warms his hands over a portable heater. We chain smoke. "We've been using pugs for years," he says quickly, looking nervously at the flashing lights. "There are no serious side effects. This is a living, breathing force, not a toxic chemical. I would be happy if it were possible to rely on our electricity supply to the same extent."
Today, doctors in the West are paying renewed attention to this little-known treatment, which was created behind the Iron Curtain. The reason: antibiotic resistance. Although for half a century drugs like penicillin have helped suppress the murderous bacteria, these are developing resistance against the drugs and becoming stronger and smarter than their predecessors. Systematic overuse of antibiotics, especially in the United States, has helped in the development of these "super bacteria", which are resistant to even the strongest antibiotics.
Last year the scientific journal "England Journal of Medicine" The New published an alarming editorial about the super bacteria. "The forecast is quite scary," he wrote. "The adaptability potential of the world of microbes is such that for every new antibiotic several ways of escape are immediately invented."
Alexander Thomas, a senior microbiologist at Rockefeller University, agrees. "The wonder days of antibiotics have come to an end. We didn't think enough about the evolutionary consequences of using drugs." In a situation where leading medical researchers in the West are anxiously looking for alternatives to the use of antibiotics, the use of bacteriophages suddenly seems "very promising", according to Thomas. Others also think so. "I am convinced that the treatment with bacteriophages will be successful," says Carl Merrill, director of the Biochemical Genetics Laboratory at the US National Institutes of Health (NIH). "But there is the psychological obstacle of using a new treatment that comes from the former Soviet Union."
Microscopic hitmen
They may sound exotic, but in fact bacteriophages are among the most common organisms in the world. The term comes from the Greek word phagin which means "to eat". These are viral predators, whose size is about one-fortieth that of a normal bacterial cell. They are everywhere around us, and are busy searching for and destroying their favorite food - bacteria.
In electron microscope images, the phages appear as ghost-like, spider-like creatures with a transparent box-like head, stiff tails, and numerous legs designed to capture their prey. They are so tiny, one flush of tap water can contain a billion phages.
How exactly do the phages kill the bacteria? The answer - effectively freezing blood. The phage adheres to the bacterial cell walls and injects into it genetic material that is stored in its head. Like a live syringe, it gradually empties itself into its victim and takes over its genetic machinery. Inside the helpless bacterium, fragments of the "daughter" phage begin to appear with frightening speed: small heads, tails and then legs. These various body parts become mini-phages, and use the host cell as a sort of factory. As the phages multiply inside it, the cell walls become weaker and weaker until the cell bursts like a soap bubble.
These microscopic "hired killers" were discovered during the First World War by the English microbiologist Frederick Tourette and the biologist Felix Darrell, who worked together at the Pasteur Institute in Paris. It was Darrell who gave them their name in an article he wrote in 1917 in which he envisioned a revolution in the treatment of infectious diseases.
Darrell discovered the bacteriophages while working in 1910 in the state of Yucatan in Mexico. He noticed them in an unusual place: in the diarrhea of the grasshopper insect. During a locust invasion, Darrel collected some diseased insects and examined their excrement. He came to the conclusion that they were suffering from blood poisoning caused by the bacteria coccobacilli. Darrel spread some of the diarrhea on the agar plates (a substance made from algae that swells in water and turns into a clear freeze) to grow a culture, but then he noticed something strange. After a while, bright circular spots with a diameter of a few mm appeared on the surface of the agar, which indicated that something was devouring the bacteria. What were these little bacteria gobblers?
Upon his return to the Pasteur Institute, in 1915, Darrell repeated the experiment. This time he used feces taken from soldiers of a unit that was stationed in Paris and suffered from dysentery. And again he noticed factors that devoured the bacteria without external intervention. Nature, Darrell declared, had provided the human race with a natural weapon against germs.
Pugs were popularized in Sinclair Lewis' 1925 book, Arrowsmith, about a young doctor, Martin Arrowsmith, who travels to the West Indies and uses pugs to fight the Black Death. "It is possible," says one of the heroes of the book to Aerosmith, whose character's inspiration came from Darrel, "that you came across the best way to eliminate pathogenic bacteria."
But that's not how things turned out. Handling the phages turned out to be quite haphazard. One of the problems was that there are hundreds of types of phages, and each of them only kills one type of bacteria. The predator and the prey must be absolutely compatible with each other. Moreover, early problems were discovered in the purification process. When the phages burst out of the victim's cell, they leave behind debris that can cause a fatal infection. The purification technologies that existed in the first decades of the century were unable to deal with this problem.
As a result of these difficulties, the use of phages was abandoned in favor of a rival drug: penicillin. Although the Eli Lilly company produced a bacteriophage drug in the 30s and marketed it in the United States, after World War II phages were pushed to the margins of Western medicine. In the DNA research, however, the phages played a central role: their simple molecular structure allowed the researchers a glimpse into the inner world of the genes. Sir Francis Crick and Max Delbruck, two of the architects of the DNA theory, were pug researchers. The study of the phage helped decipher molecular biology at the exact moment when phages disappeared from the medical scene. Or to be precise: from the medical scene in America and Western Europe.
Felix Darrell was an ardent communist and admirer of Stalin. In 1934 he received an invitation from the Soviet government to join the Institute of Bacteriology in Tbilisi, which had been established shortly before by a young Georgian microbiologist, George Alieva. Over the years, the Eliava Institute has become a world center for researching the medical uses of phages. One of his first successes was in the development of a powerful pug to combat dysentery, which was used by the Red Army during World War II. Over the following decades, the institute began supplying precise and targeted phages to hospitals throughout the communist bloc. The Eliava Institute has become the largest phage library in the world, with a permanent "museum" of over 300 phage clones. "We perfected the bacteriophages as a drug for more than seventy years, just as Darrel predicted we could do," explains Nina Chanishvili, a senior researcher at the Aliava Institute. "But did anyone listen?"
On one of the frosty December days, I walked with Chanishvili in the Savortalo district of Tbilisi, on our way to the Alieva Institute. The route winds through patches of thin, snowy pomegranate trees. Along the hills are heavily planted decaying residential neighborhoods from the Soviet era, and in the streets the shops are lit by candlelight.
Nina's uncle, Teymouraz Chanishvili, helped run the Aliava Institute for more than a quarter of a century, and Nina also devoted most of her life to phage research. But the last ten years have been brutal. In recent years, she said, the institute's phage output has dwindled alarmingly. The institute's employees, who receive almost no salaries, are currently clinging to a fading infrastructure. When the sophisticated equipment breaks down, they must work with improvised materials. Also, Chanishvili said, "because of the power outages, we lost about half of our phage library" (the phages must be kept refrigerated). The economic collapse in Georgia also reduced the demand for pugs. In the past, the institute produced all phage preparations imaginable - from sprays to ointments and tablets of all kinds. But today, even at the price of 5-3 dollars for a pack of 10 ampoules, many patients in Tbilisi cannot afford to purchase them.
The perfect military plaster
The institute is still located among handsome cypress trees and overlooks the Matakvari River. Beyond its wall you can see the beautiful cottage that Stalin built for Drel. It is still referred to as "Darrel's Cottage", although later it housed the headquarters of the Georgian KGB. From the inside, the institute looks like a cave-like maze: dank cement corridors, staircases with electrical cables dangling from them, and antiquated laboratories. The old fermentation tanks, which were once used to prepare phage preparations for the Soviet Ministry of Health, stand abandoned in a room whose windows have no panes.
Upstairs, Chanishvili shares a small, unheated laboratory with another researcher, Maria Tediashvili, and about half a dozen other female medical students. They are all freezers. "By the nature of things," says Tediashvili, "the men move on to better things." The equipment of the researchers is very basic. Among the centrifuges, water baths and stacks of petri dishes, stand dozens of beer and vodka bottles, which the researchers use as solid agar containers. To melt the agar, they put one of the vodka bottles into a "Miracle Coffee" tin can that is on a hot plate. "We like the vodka bottles," Chanishvili hurries to explain, "because they are so transparent."
The interns spend most of their time in boring work - planting phage cultures in samples of bacteria. Thus, each of the petri dishes turns into a kind of pug farm. One of the interns disinfects the end of a phage planting device with a burner, pours a drop of phage solution into a plate of E. coli bacteria and carefully closes the plastic lid. "This bacterium causes epidemics around the world. But these phages think the E. coli bacteria are very tasty. They eat them like they eat chocolate cookies."
The intern holds in her hand a plate of E. coli culture incubated for two days, and points to a group of transparent asymmetric circles formed in the agar layer. They are similar to gunshot wounds. "Isn't that wonderful?" she whispers Chanishvili explains that she and her colleagues trap the phages in dirty, sticky or greasy places, which the creatures are known to like to live in: sewage, for example. Then they are stored in a culture liquid kept at a temperature of 4 degrees Celsius. Amazingly, they don't need to be fed bacteria to stay alive. "Pugs can live for months without food," says Chanishvili. When the number of phages starts to dwindle, you give them some bacteria and they start multiplying again.
The director of the phage research department is Amiran Meifariani. Maypariani has been here since 1946 - the height of the Stalinist era - and it seems that his blue eyes have already seen everything. Like most Georgian doctors, he chain smokes and often shrugs his shoulders. His office is full of disconnected phones. On the wall hangs the faded picture of Felix Darrell.
"As you can see, our situation is not good," he says, shrugging his shoulders. "But now the whole world knows that an alternative to antibiotics must be found and that the best is bacteriophages. It might be an advantage for us. Did you know that NATO is currently interested in one of our inventions?" Meifariani refers to an ointment concocted by researchers at the Aliava Institute and known as a "phage-bio-derm" - a type of bandage soaked in a cocktail of five to nine different phages, which can treat burn wounds that have become infected. This is the perfect military patch. The Russian soldiers used it in Chechnya. "Of course, women and children can also use it in the kitchen," says Maifariani, his lips wearing a salesman's smile.
The Aliava Institute registered a local patent for the production of the "phage-bio-derm". He also produces the medicine "intesti-phage" - a cocktail of 17 phages, which is given to the abandoned baby. In total, the institute produces about ten different phage treatments intended for about 15 different types of bacteria.
Considering the problems involved in conducting scientific work in Georgia, the achievements of the Aliava Institute seem extraordinary. The most prominent of them was the creation of an intravenous treatment for the deadly bacteria "staph aureus" According to the researchers of the Eliava Institute, the treatment was successfully tried on dozens of patients.
In recent years, the Eliava Institute has attracted the attention of pharmaceutical companies in the West. But along with their joy at this development, the Georgian scientists are worried. Who will ultimately benefit from the commercial exploitation of their work? Will the Americans and Europeans reap the fruits of their hard work? "Who will earn the millions?" Mayfarian asks and then corrects himself. "The billions, I mean." He is right. The value of the profits of the global antibacterial market is estimated at about 25 billion dollars a year.
So far, the attempt at cooperation between the Aliava Institute and American companies interested in pugs has not boded well. In 1996, representatives of a Canadian venture capital fund named "Casey Harlington" arrived in Tbilisi. They longed to talk to Chanishvili about her work. Chanishvili succinctly defined what happened - "a cultural clash".
Although in a short time a start-up company was established in Seattle, "Fag Therapeutics" its name, but its planned branch in Tbilisi was closed shortly after its opening. "The Canadians told me that the American consumer would never agree to use a medical product from the Soviet Union," Chanishvili says bitterly. Today, Phag Therapeutics produces drugs inspired by the Aliava Institute, for the American market. "We gave the Americans access to all the research background material," Chanishvili continues, "and they just took it and left. They told us we were stupid in business. They were right, of course."
Fall in love with the wrong woman
Taimuraz Chanishvili, the uncle of Dr. Nina Chanishvili, told me the life story of George Aliava. The man, who established the central status of bacteriophages in Soviet medicine, was not rewarded for his very important work. Aliava was a brilliant researcher, but also a dress chaser. His luck ran out and he fell in love with a woman who was adored by Lavrenti Beria, the head of Stalin's secret police. Despite Stalin's high regard for bacteriophages, it was a death sentence for Alyeva. "Beria arranged the death of Aliava in 1937 under some pretext," says Chanishvili dryly. "That's how things were done then. Hard work, these bacteriophages", he adds with a smile. Then the lights in the room go out, as if obeying an order from on high.
In the well-lit laboratories of Europe and the United States, the future of bacteriophages looks bright. In the United States, at least three start-up companies are trying to be the first company to win the approval of the American Food and Drug Administration (FDA) for the treatment of phages. In addition to Phag Therapeutics in Seattle, Itralytix, a company that employs many scientists from Georgia, operates in Baltimore. "Exponential Biotherapies" operates in Long Island
These companies face many challenges. One of the problems that arose in the early phage treatments was that the unrestrained phages were expelled very quickly by the body's filtration system. In other words, the immune system treats them as foreign bodies. Do the new technologies have the power to create "domesticated" phages that can stay in the body longer? The Aliawa Institute has made several achievements on this front; The American scientists hope to be more successful.
Carl Merrill is the leading American researcher in the field. In the April 1996 issue of the scientific journal of the National Academy of Sciences, "Proceedings," Merrill described the results of studies done on phages and mice. He was able to make the phage mutations stay in the mice's bodies longer than the wild strains. "We changed the protein code in the phages," Merrill explained, "to make them more durable." In the same issue, Nobel laureate Joshua Lederberg wrote that "this is an ingenious overcoming of one of the obstacles that stood before the use of phages in medical treatment".
One pug can produce 40 thousand offspring per hour; One hour later, the number increased to four billion. "This is the only drug that multiplies while actually being used!" Says Richard Carlton from the company "Exponential Biotherapies." Merrill reported that in experiments done on mice infected with the E. coli bacteria, he was able to cure them all with the help of long-lived phages.
In the laboratories of the University of Maryland, Zamfira Alavidze, who also runs her own laboratory at the Aliava Institute, oversees an array of Petri dishes, agar jars and vials of phages. But the difference between Baltimore and Tbilisi is twofold. "Here", she says, "we have a lot of mice where we can do experiments, and in addition we can purify the phage solutions using chromatography. Carrying out the purification operations in Tbilisi much more
It's difficult, and there are no mice at all."
Purification and thorough experiments in laboratory animals are necessary first steps towards the approval of the treatment of phages in the meticulous Western medicine. Clinical trials in humans have not yet been done. On this front, the Georgians are ahead of the Americans, and it is possible that the early experiments carried out in the Soviet bloc on patients will ultimately prove to be the greatest contribution of the doctors in Tbilisi in the fight towards the medical use of phages.
Dr. David Schreier, a cancer researcher, worked as a doctor during the construction of the Baikal-Amur railway in Siberia in the 70s. At that time, he regularly treated the Soviet construction workers with bacteriophages. "Even then," says Schreier, "the Siberian workers suffered from infections that were resistant to antibiotic treatment. The phages worked wonderfully. But here lies the sting. Darrell, and later the Soviets, ruined the image of phages in the West by trying them on people without first testing them on animals. Animal experiments were very expensive; The patients were cheap. This was the tragedy of the pugs in the East. But it was also their trump card - that's how we learned that they really work."
The ultimate guinea pig
The most prestigious private clinic in Tbilisi is the plastic surgery unit at the Clinical Diagnostic Center, which is located near the local university. The difference between it and the children's hospital is very noticeable. In a small corridor stands a greenish fish aquarium, and music by Tchaikovsky emanates from the speaker system. In this clinic, which was opened only a year ago, fat is extracted from the bodies of the rich of Tbilisi.
Dr. Iva Kuzanov, the most senior plastic surgeon in Georgia, shows me an album of photographs of patients after surgery. The pictures are nauseating. "This man had his nose bitten by a dog. Look how handsome he is now"; "This woman came to us from San Francisco for gender reassignment surgery. What do you think of her penis?” "Wonderful," I answer. An alarm clock is connected to the pin. "We put it together to prove how strong it is," Kuzanov says dryly.
Kozanov and his colleagues frequently use phages to treat inflammation caused by these complex cosmetic surgeries. According to Kuzanov, many of his patients come from the West, because of the cheap prices.
Dr. Avtandil Chakhidze, physician and prince, is the first person in the world to undergo intravenous phage treatment. He met me in an impressive office in his modesty in his private clinic. Despite the freezing cold outside, he only wore a fashionable sports coat. He showed me a copy of the family crest, then served hot Turkish coffee.
After graduating in 76 from the medical school in Tbilisi, Chakhidze was assigned to a gynecological clinic in Leningrad. From too much hard work and exhaustion, he fell ill with severe pneumonia and at the same time with purulent dermatitis. Although the hospital where he worked arranged for him to be admitted to an important Soviet clinic that was equipped with advanced Western equipment, the antibiotic treatments he received did not improve his condition. The dermatitis worsened and he begged to be allowed to return to Tbilisi. As soon as he returned, he asked his father, one of the top doctors in the city, to see if he could receive intravenous phage treatment, a procedure that had not yet been tried. The risks were indeed enormous, but Chakhidze had no choice: he could hardly move.
The problem was that there was no one to perform the treatment. In the end, Dr. Vakhtang Buchozishvili, a famous lecturer at the Sepsis Treatment Center in Tbilisi, agreed to do so. "It was done somewhat secretly," says Chakhidze, "I was the ultimate guinea pig." On the fifth day of treatment, the prince threw away his crutches and went to a party with his friends. "On the seventh day I was completely cured. It was a miracle."
The possible implications of this strange piece of medical history are enormous. Chakhidze claims - and it is difficult to verify his claim - that in the last decade before the collapse of the Soviet Union, about 20 thousand people recovered from chronic sepsis thanks to the phages treatment.
But what about patients in the West? There, pugs can only be used in extreme cases where the patient's family gives explicit permission. So far, these cases have been very rare. Last year, Nina Chanishvili was called by two Belgian brothers who had read about pug care on the Internet. Their 23-year-old sister was dying as a result of a viral infection that affected her brain. Drilling in her skull, to introduce antibiotic treatment, became infected with staphylococcus bacteria. Can Chanishvili treat secondary inflammation in pugs?
"I had to travel," says Chanishvili. "I brought the pugs myself." According to Chanishvili, the girl recovered from the secondary infection within a few days, although she remained mortally ill from the primary illness she suffered from.
In another case, a woman who was dying in Toronto of a heart problem, and also suffered from inflammation, was treated with anti-inflammatory phages. Pug spray was injected into her aorta. The inflammation passed within 20 hours (but two months later the woman died of heart disease). The "Fag Technologies" company, which provided the drug, called the case "the first phages treatment done in the West in the modern era." It was excessive bragging.
It is understood that one patient cannot provide the solid proof that Western medicine requires. It is possible that the inflammation of the woman from Toronto would have passed on its own. However, says Elizabeth Cutter, a senior pug researcher at the Evergreen University in Seattle, "this proves that the pugs are ready for use in the West."
The next international pug conference is scheduled for June in Montreal, Darrel's birthplace. It's hard not to imagine the old communist smiling in his grave. You can also imagine Stalin smiling. "It's strange to think," said Nina Chanishvili, "that someone would regard Stalin as the darling of medicine in the 21th century."XNUMX
{Appeared in Haaretz newspaper, 25/4/2000{
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