Let the pugs win

They are human-friendly viruses that live in the city sewers and are able to easily eliminate the super bacteria that the antibiotics created themselves and against which they are powerless. The phage therapy, developed in Tbilisi during the Stalin era, is the leading candidate to replace the eroding antibiotics

An experiment on humans was conducted at the hospital in Tbilisi - Georgia. Was the penicillin of the 21st century invented in a damp laboratory in Georgia?

Let the pugs win

By Aviva Lori, Haaretz, Walla News!

They are human-friendly viruses that live in the city sewers and are able to easily eliminate the super bacteria that the antibiotics created themselves and against which they are powerless. The phage therapy, developed in Tbilisi during the Stalin era, is the leading candidate to replace the eroding antibiotics. The first western pharmaceutical company to market it will take a small step for a person and a big step for their bank account. Until then, take two more Moxifene Forte pills

How to make medicine from phages

The doctors are helpless: more and more bacteria are resistant to antibiotics. The race for the replacement is already underway. The entrepreneurs raise capital. Whoever reaches the finish line first will win the entire pot. It's billions.

Antibiotic resistance was discovered as early as 1947, shortly after it came into mass use, and over the years the situation has steadily worsened. "Due to overuse of antibiotics and uncontrolled use, antibiotic-resistant bacterial populations have developed," says Dr. Sergey Boyanover, microbiologist and researcher. "It is enough for a small percentage of the bacteria in a certain person, 2% to 5%, to become resistant - for them to spread in the human population and all people will be resistant to the same antibiotic and will not react to it. In the end, bacterial populations develop that cannot be treated with any antibiotic and this causes mortality. For many years there was hope that the antibiotic development process was endless, that new antibiotics would always be found for new forms of bacteria. But it didn't happen. Since the last antibiotic was developed, 30 years ago, no new antibiotic has been developed."

"50% of the time at every infectious disease conference is devoted to the growing resistance to antibiotics," says Prof. Zeev Handzel, an immunologist from Kaplan Hospital in Rehovot. Only about ten years ago, after the breakup of the Soviet Union, it became known in the West that at the Eliava Research Institute in Tbilisi, Georgia, an antibiotic substitute was developed back in the 30s that proved to be effective in treating infections. While the West was eroding antibiotics, it turned out that the Soviet Union always believed in bacteriophages, or phages for short.

Miniaturized space vehicle

Phages are viruses. But unlike viruses that need human tissue to reproduce, phages do not harm humans. They multiply inside bacteria only. Scientists believe that they are the oldest living creatures in the world. They resemble a space vehicle with six legs, which stick in front of the bacterium and insert DNA into it. This is how the phages multiply quickly. One bacterium, which is 40 times larger than a phage, can host 5,000 phages at the same time (a drop of water has an average of a billion phages). The end of the bacterium is known in advance: it is destroyed and the phages look for the next victim. Each bacterium has phages that are suitable for it and only they are attracted to it. Hence, wherever there are bacteria, there are also phages.

The phages were discovered at the beginning of the 20th century. William Tower, professor of bacteriology at the University of London, noticed in 1915, while working on cultures of staphylococcus bacteria that cause purulent wounds, that entire colonies of the bacteria were destroyed. He isolated the substance that caused the mass destruction and assumed it was some kind of virus. At the same time, the secret of the phages was discovered by Felix d'Harel, a Canadian researcher born in Montreal of French origin, who coined the term bacteriophages, which in Latin means bacteria-eaters.

D'Harel was born in 1873. When he was six years old his father died and he moved with his mother and brother to Paris. He cycled through Europe and then South America. When he was 24 years old, he returned to Canada and studied microbiology in a home laboratory he set up. Among other things, he specialized in distilling alcohol from maple syrup and later was invited to work as a bacteriologist in a hospital in Guatemala City. In his spare time he distilled whiskey from bananas. Then he moved to the Yucatan in Mexico and there, in 1910, he was first exposed to the strange phenomenon that phages generate. He collected locusts that in those days raided the fields in the Yucatán and examined the excrement of some of them who died of blood poisoning. He spread the faeces on flasks with the aim of growing a culture and then he noticed that after a while bright spots appeared on the flasks that gradually spread until the bacteria disappeared completely, like a magic wand.

D'Harel moved to work at the Pasteur Institute in Paris and in 1915 repeated the experiment. This time he used the feces of soldiers who suffered from dysentery. And again the bacteria disappeared as if they were not there. In 1917 D'Harel was officially recognized as the creator of the revolution. At first he successfully used phages to eradicate a typhus epidemic in poultry. From 1919 onwards treated phages in humans. In 1925, awareness of phages arose in the medical world. Everyone talked about the great hope. D'Harel received an honorary doctorate from the old Leiden University in the Netherlands and the Leeuwenhoek Medal, which Louis Pasteur also received in 1895, and continued his wanderings across the globe. He worked in Egypt in the sanitation department in Alexandria and used phages to heal pilgrims returning from Mecca and Medina. From there he moved to India and worked in the service of the British Empire, treating cholera patients in remote villages and reducing the mortality from 60% to 8%. When he returned from India, he was offered a professorship at Yale University.

In the 30s, the major pharmaceutical companies began to develop the new "wonder drug". But the invention of penicillin in 1928 and its introduction into mass use in the 40s made bacteriophages common. D'Harel, who died in 1949, was nominated 30 times for the Nobel Prize but never

Production of drugs from phages for mass consumption in Tbilisi in the 70s. The phages were the Soviet secret weapon against biological warfare

Didn't win it. America and Western Europe started to get addicted to antibiotics. Whereas the bacteria, the primitive organisms, learned over the years to get smarter about it. Each new antibiotic gave birth to strains of bacteria resistant to it. By way of simple evolution, the bacteria changed face and shape. Like humans and animals in nature, the weak were exterminated and the strong survived and took over the immune system.

Today, the scientists claim, humanity is standing before the super bacteria - the cocoon that rose from its creator - and is begging for its life. This is probably the beginning of the end of the antibiotic era.

To Stalin, in honor

The institute in Tbilisi started working in 1923. But it wasn't until 1926 that its founder, Prof. Georgi Aliava, became familiar with bacteriophages. He became friends with D'Harel during his visit to the Pasteur Institute in Paris. D'Harel is said to have been captivated by the communist idea. When Stalin invited him to the Institute in Tbilisi in 1934, he willingly accepted and stayed there on and off for about a year - and even dedicated one of his books, "The Bacteriophage and the Recovery Phenomenon", which was written and published in Tbilisi in 1935, to Comrade Stalin.

He even intended to move his permanent residence to Tbilisi and had already begun planning his cottage, which was gradually being built on the grounds of the institute (later the headquarters of the Georgian KGB was located there). But at that exact time, probably to his good fortune, his friend Aliava fell in love with a woman whom the head of the secret police also desired, and his fate was sealed. Alieva was executed and denounced as an enemy of the people in one of Stalin's purges. The frightened D'Harel fled for his life and never returned to Tbilisi. His book was banned for distribution in the Soviet Union.

When the Iron Curtain came down on Eastern Europe, the institute in Tbilisi became a Soviet-wide institute for the development and production of bacteriophage drugs inspired by D'Harel and Alieva. Patients with serious infectious diseases, from all over the Soviet Union, used to come there to receive treatments, which according to the reports were crowned with success. Bacteriophages were part of the treatment routine in clinics and hospitals in the Soviet Union. Skin ointments, pills and drops were and are still being sold in pharmacies throughout Eastern Europe at incredibly low prices, immeasurably lower than the price of antibiotics ("fractions of pennies for the medicine", says Dr. Boyanover), some of them without a doctor's prescription.

Dr. Eli Magen, an immunologist and allergologist from Kaplan Hospital and an internal medicine specialist at Barzilai Hospital in Ashkelon, studied medicine in Georgia. He explains the development and use of bacteriophages in the Soviet Union as the central government's need to maintain ambiguity and sow fear. "Like with us in the nuclear matter, the one who pushed them to develop it was the army," he says, "so that they wouldn't mess with you." to be afraid of them. It was the secret weapon against biological warfare in the Cold War era arms race. Straight and smooth".

In 1991, after Georgia refused to join the Commonwealth of Nations and a civil war broke out there, the center of Tbilisi was destroyed. Among other things, the Eliava Institute was damaged and decades of research went down the drain. Thousands of bacteriophage samples, identified over the years and cataloged in a huge library, were irreversibly damaged by frequent power outages. In the meantime, the Russians transferred part of the equipment to their domain and established factories for the production of bacteriophages in other places. The condition of the Eliava Institute deteriorated and it was on the verge of closure.

But in 1997, an article about the institute was broadcast on the BBC, which ignited a wave of media interest in the West. The headlines brought to the institute in Tbilisi doctors, researchers, scientists and especially agile entrepreneurs from around the world, who were determined to investigate the new wonder in depth. The shares of Georgian scientists whose names have been linked in some way to the Institute soared. Some of them migrated to the West as part of joint ventures.

These days it is known about several companies that are engaged in the research and development of bacteriophages: in Montreal, in New York, in Baltimore, in the state of Washington, in Vancouver, in Australia, in the Netherlands, in Tijuana in Mexico and two in Israel. The institute in Tbilisi also continues to exist, thanks to funding from various research funds in the West. Each company hopes to be the first to win the coveted approval of the American Drug Authority. The battle is over a market whose value is estimated at 25 billion dollars a year.

This market is now fed with amazing stories about the miraculous healing ability of bacteriophages. For example, the story about a woman from Toronto who underwent open heart surgery in 1999 during which she contracted an inflammatory infection that no antibiotic medication could overcome. Phage injected directly into her vein saved her life. Or a diabetic patient whose leg was about to be amputated, but it was saved thanks to phages treatment he received in Tbilisi.

Tuberculosis is making a comeback

Dr. Reuven (Robert) Aligar, senior surgeon at Kaplan Hospital, immigrated from Georgia, where he studied medicine and managed a surgical department at the Central Hospital in Tbilisi. "We used bacteriophages to heal wounds and infections after surgery", he says, "for each patient we would prepare the appropriate phages and the treatment afterwards was much more effective. If a wound from surgery takes a month to a month and a half to heal, with the help of the phages it took a week, a week and a half."

Why did the West hear about the phages only recently?

"Because the works published and the articles written in the Russian and Georgian professional magazines were written in Russian or Georgian. And in the West, if you don't write in English and don't publish in professional literature in English, things seem to not exist. And when everything was closed, the information did not leave the borders of the Soviet Union."

Dr. Magen visited the institute in Tbilisi last year, met with colleagues and saw patients. "People come there who have nothing to lose, whose situation is so dire that they are ready to do anything. I spoke with one of the senior professors. He told me about people who suffered from radioactive radiation in the back. They were carrying luggage from Russian bases and didn't know there was radiation there. Such wounds have a chance to be cured only by skin grafting. And here, they managed to cure them with the bacteriophages."

In the mid-80s, two Israeli researchers from the Technion, Prof. Yonathan Koon and Prof. Shimon Elitzur, founded a diagnostics company called Biolum. Kuhn and Elizur used bacteriophage technology to detect bacteria in food, industry and agriculture and hoped to succeed in the medical field as well. In the early 90s, the company stopped operating and these days Prof. Kohn, a researcher in the biology department at the Technion, is working on the secret development of a bacteriophage in the medical service. On the way to the big breakthrough, which he hopes to achieve soon, he enjoys royalties on bacteriophage preparations that have been successfully applied, within Biolum, and which include an international patent for testing salmonella in food.

"Bacteriophagy treatment is going to be a big hit," says Cohn, "the problem is very serious because all bacteria develop resistance to antibiotics within two or three years. Part due to excessive consumption and part due to use in agriculture, spraying, food, cattle, chickens and fish. There are antibiotics everywhere and we eat and drink them. Most of the viruses of the past, like polio, have been resolved and gone from the episode. It's not like that with the bacteria. And there are some, like tuberculosis, that are making a comeback."

why is it happening?

"Because of the increase in life expectancy and the erosion of the immune system. Now they are starting to see tuberculosis in old people and in people with AIDS. In the third world every year 15 million people are infected with tuberculosis and three million die from it. The scariest bacteria in Israel today is the predatory bacteria. He is resistant to everything. The story of antibiotics is over. If bacteria live in gasoline and can break down all kinds of synthetic substances, then obviously they can also break down antibiotics."

Not only tuberculosis endangers the world's population. Even just pneumonia, strep throat or an intestinal infection can end very badly, says Prof. Eitan Rubinstein, an infectious disease specialist from Sheba Hospital, who is on sabbatical in Canada and talks about the post-antibiotic era from there. "People with a poor immune system - such as those receiving chemotherapy, the elderly, people with burn wounds, infants, and those receiving many antibiotic drugs for a long period of time - are at high risk. The phenomenon has increased in the last ten years, partly because of overuse of antibiotics, and partly because of poor hygienic conditions and an increase in the number of patients in hospitals."

Prof. Rubinstein divides the world into three groups in which resistance to antibiotics is measured. According to this division, Israel is in the third group, whose situation is the worst, together with countries such as Greece, Spain, Portugal, Taiwan and Hong Kong. The situation will not change, in his opinion, if the issue does not receive comprehensive systemic treatment. "If it is decided that this is public enemy number one, then the preparation for it should be multi-systemic. We need to solve the problems in agriculture, in the food industry and in each and every one of the areas where antibiotics are used in an uncontrolled manner. I hope that the phages will enable this transition, with judicious and controlled use, so that what happened to us with the antibiotics will not happen again."

Prof. Eli Somech, director of the children's division and the infectious diseases unit at the Wolfson Hospital, offers a revolutionary idea: to take advantage of the properties of phages and use their mechanisms in the production of new antibiotic drugs. "It might be more appealing to the West than using the phages themselves. Ten years ago there was a feeling of security that every bacteria has its own antibiotic. Today it is clear that the bacteria are more and more invasive and this war ended in our loss. The bacteria lived millions of years before us and will probably live millions of years after us. Since the whole earth is a small village, the infections move from place to place and there is no good solution for this today."

Bunnies out of the hat

In the early 90s, the Israeli entrepreneur Asher Wilf, a former permanent officer in the navy, went to Russia and started doing business there. On one of the trips, he arrived in the city of Ufa in southern Russia and found a factory called "Immunoprefert" that produces drugs based on bacteriophages. He studied the subject and was sure he had discovered a gold mine. In 2000, he signed a collaboration agreement with you, for $100 in the first year and 10% of the royalties on future products. In return Wilf received exclusivity on the knowledge and technology of the Russian company. He raised money from a group of American investors and the chief scientist and founded the start-up company "Phage Biotech" in Kiryat Hameda in Rehovot.

"I thought we would transfer this technology to the West and upgrade it," he says, "2000 was a great year and I believed Tommy that the next big thing would be biotechnology. I recruited a professional team with the aim of establishing technological platforms that will later be used for wider applications in the food industry and agriculture." In order to prove the effectiveness of the preparations, about two years ago Wilf's professional team conducted experiments on rabbits in the laboratory at Hadassah Hospital. Dr. Alex Obolansky, a researcher in the ophthalmology department at the hospital, led the work. "We used a super-violent bacteria called Pseudomonas," says Obolansky, "it is active in plastic and destroys the cornea, as a result of using contact lenses. It's a bacterium resistant to all known types of antibiotics."

During the experiments, the eyes of rabbits infected with Pseudomonas were placed in a solution of bacteriophages and the inflammatory process was stopped. "We tested more than 20 rabbits and got pretty good results, we found a new phage that really destroys the bacteria, but we couldn't continue because we ran out of money. A rabbit costs more than NIS 500 and according to the law in Israel it is forbidden to use only one eye on each rabbit." Encouraged by the results, Wilf believed that the magic solution was within his reach. According to the forecasts he compiled in 2000, the market potential of these products in 2006 should amount to 10 billion dollars. In the meantime it is not happening. Wilf checked the chances of advancing the research and getting approvals from the American Drug Authority to market a drug based on bacteriophage, and quickly realized that this was not on the agenda anytime soon.

Why not, actually?

"It's a financial matter," explains Prof. Gerald Cohen, a molecular biology researcher of bacterial systems at Tel Aviv University. "The big companies didn't spend many years developing new antibiotics because it involves hundreds of millions of dollars. It's easier to sell what already exists than to make something new."

The big companies are not impressed that the process of isolating and producing bacteriophages, compared to the development of new antibiotic drugs (a billion dollars per drug), is relatively simple. Because phages come straight from the sources of municipal sewage. A sample of contaminated water is collected, the bacteria are destroyed while the phages are left alive. Then the necessary preparation is extracted from them and infused on a culture of the target bacterium. If the bacterium is gone, it means the phages have eaten it. All that remains is to extract a medical preparation from the specific phage and give it to the relevant patient. Then the phage should be dried and stored in the library for reuse, as needed. This is the modus operandi in Georgia and other places where bacteriophages are used.

"If a bacterium appears in a hospital that is resistant to all existing antibiotics," says Boyanover, "you go to the sewers of that hospital and you will surely find the phage there that will overcome this bacterium."

Every person carries in his body, always, both bacteria and phages. Why don't the phages regularly eat the bacteria in our body and rid us of infectious diseases?

"This is the main point in this whole story. Bacteria and phages make up a biological system that is in a certain balance. As soon as this balance is violated, let's say the properties of the bacteria change and its concentration increases rapidly, then the phages that are supposed to regulate the situation are not enough to do the job and the bacteria take over our body."

It works in shrimp

In addition to the ease of production, and the claim that, unlike antibiotics, there are no known side effects when using bacteriophages, there is another advantage: infinite possibilities. As long as bacteria exist in nature, bacteriophages exist alongside them. "Man lives from the age of zero to 120 in perfect balance with his bacteria and phages," says Dr. Magen, "but the Western perception treats man as if he exists separately from his natural environment, and it changes him all the time through drugs. No wonder Homo sapiens started getting new diseases."

The advantage of the bacteriophages is also their disadvantage. Because they are biological substances from nature, which change form, it is impossible to issue a single-value patent on them as is customary in the western pharmaceutical industry. And without a patent, no pharmaceutical company would enter into this kind of adventure. Prof. Handzel is optimistic and pessimistic at the same time: "In my opinion, it will eventually replace antibiotics, because the age of antibiotics is dead. The bacteria keep beating us. People are dying in hospitals today from infections for which there is no treatment. And it's only getting worse. The big companies are trying, but drug development is so expensive, and requires so much time and money, that we have no chance. The number of new drugs that manage to reach the market and pass the regulatory hurdle in the United States and Europe is decreasing all the time. The companies are afraid of complications, every time a new catastrophe is revealed. See Parashat and Yoks. It's a vicious circle."

Why don't the fags take off in the west?

"What is good for Russia is not good for the West. It is impossible to expect the US FDA to adopt Russian research and control methods. But I believe that eventually life will bend the regulators. People will start dying at an increasing rate and they will not be able to stand by and not flex their criteria. Today there are several companies in the US that are trying to break the way. The first company to succeed, everyone will run after it."

Boyanover is also optimistic: "The antibiotic crisis is so serious and dangerous that there will be no choice."

Wilf meanwhile moved on to a new venture: bacteriophages in the shrimp service in Thailand. "This is about aquaculture. Shrimp are raised in cages in closed ponds. Dealing with diseases is the bottleneck in animal husbandry. To overcome this, antibiotics are poured into the pools. It is common in Central America and Southeast Asia to prevent infections. There is a special bacteria called Vibrio, which makes names in fish. Today we are developing the bacteriophage preparations together with Mahidol University in Bangkok. It will be applicable next year - a supplement that will be sold to growers. We are also thinking about a product that will fit the cages in Eilat."

Most of all, the arrogance of science irritates Wilf. "We used to be sure that science would conquer and solve everything. Today it is already clear that the right solutions are ecological and natural and much less predatory than antibiotics. It is true that she had successes, but she worked on borrowed time, which may be running out." *

* The knowledge website was until the end of 2002 part of the IOL portal from the Haaretz group.