The story of hope, before we enter the era of

Viruses can fight resistant bacteria, which is a weapon that has been forgotten for decades.

Viruses can fight resistant bacteria, which is a weapon that has been forgotten for decades.

Dodge Pond is a beautiful freshwater lake on the outskirts of East Lyme town, in the New England district of Connecticut, USA. It is a natural home of green grouper and American herring, smaller creatures such as water fleas, algae and bacteria.

But there's something special, the Dodge Pond Lake is also a huge reservoir of viruses. It nurtures in that a population of OMKO1 virus , which in the future can become an extremely valuable resource for medicine and humanity.

That's because humans are entering an era of nightmares with antibiotic resistant bacteria, where even simple infections can cause 10 million deaths a year worldwide. Bacteria resistant to all types of antibiotics have been discovered in China, Europe, Canada, the United States and South Korea, causing irreversible infections.

But in early 2016, in an infection that seemed to have given up, doctors risked taking about 100 million OMKO1 viruses, cloning from Dodge Pond Lake into an 80-year-old man's chest, during the hour. minutes that his life has lost weight.

That touching story was told by a doctor before hundreds of scientists in a medical conference a few months ago. It opened up new perspectives, giving a tremendous boost to scientists, patients and anyone, before all of us soon faced a "post-antibiotic" period. " coming in the next few decades.

Picture 1 of The story of hope, before we enter the era of
Miraculous story begins from a beautiful lake in the suburbs of the state of Connecticut, USA.

Once harmless bacteria also become "assassins"

Dr. Ali Khodadoust is an ophthalmologist who works in New Haven, 40 miles west of Lake Dodge Pond. When we arrived at the Khodadoust waiting room, he was checking some papers with the secretary. Khodadoust's hair had strands erected like electricity. It was so white that it nearly blended in with the blue shirt he was wearing.

We entered his office. Khodadoust went slowly and was very cautious . "I can fall at any time," he admitted. That's right, with an 80-year-old man, constantly fighting to win his life for 4 years with a particularly dangerous infection. What you can imagine about it, about the existence of Khodadoust, is like "a thousand pounds of hair".

But ignoring the first impression of Khodadoust, he still seems to have good health. Certainly good enough to talk for 2 hours about OMKO1, about his illness, career dedication, countless years in the field of corneal transplants and training of young doctors.

During that intimate conversation, Khodadoust occasionally stood up, left the chair cautiously to lead us back to the hallway. That's where he can lecture on photos that have been faded but carefully framed.

They helped him recall the old work at Yale University, Johns Hopkins Institute as well as in Shiraz, an Iranian city where Khodadoust was born. He came back to build an eye hospital there. However, all were forced to stop after an incident 4 years ago .

" I was working in the operating room on Friday and Saturday I spent time jogging , " Khodadoust said. "At the end of that day, I felt my breath was unusually short and shallow. Both my brothers had a history of heart attack, so I wanted to check if that was the problem."

Unexpectedly, Khodadoust finally had to go to a coronary artery bypass surgery. His colleagues patched a part of his aorta. The entire operation went smoothly and Khodadoust was allowed to return home to recover.

Imagination will be a good result, but things then turn bad very quickly. For 48 hours, Khodadoust had a severe fever and rushed back to the hospital. When the surgeons decided to open his chest again, they discovered an infection that had broken down to the sternum of Khodadoust. His chest cavity at that time was awful, filled with blood mixed with infected pus.

Dr. Deepak Narayan was a member of the surgery at Yale New Haven Hospital that day. When he saw the scene, he knew exactly what happened to Khodadoust. There is an array of green moss on his aorta. It is an infection caused by bacteria, a very common bacterium called green pus bacillus (Pseudomonas aeruginosa). "You just have to look over, and you will identify them," Dr Narayan said.

However, the urgent task was not to find a way to fight bacilli. Narayan and other doctors have to do everything to regain Khodadoust's life, for as long as possible."His illness is so heavy - the heart really feels like breaking the operating table , " Narayan imagined that moment.

He and his colleagues had to take a piece of lung tissue to patch the heart for Khodadoust. The next job seemed to be "scrubbing" the entire chest cavity. Finally, when it was dry, they wrapped Khodadoust's heart with a fat film taken from his own belly. The incision was closed, but the doctors were skeptical about the prognosis that Khodadoust could tolerate.

Picture 2 of The story of hope, before we enter the era of
Green pus bacillus, which is present in Dr. Khodadoust's chest.

Now, when he recalls this time, what Khodadoust remembers is just a black space."There is a long, tight string that holds me with something endless , " he said. Khodadoust felt that he had been given two choices by someone. "Do you want to come back or not? Live or not? I envisioned my children, my wife. Water lights glistening in their eyes."

Khodadoust decided to return to life from that dark space."How can I?" , Khodadoust sometimes wonders. He came back to start a painful 4-year war, with drug-resistant bacteria in his own chest.

4 years living a non-human life

Khodadoust passes the surgery. But now, Narayan and the doctors continue to help him fight his infection. Green pus bacilli are harmless bacteria for healthy people. But ironically, it infects the surgery, when Khodadoust's immune system is weakening.

Khodadoust seemed to have been infected with a green pus from the aorta, which the doctors had implanted for him. At that time, green pus bacillus is almost death. It is like the terror of cystic fibrosis patients, blue pus bacillus that can lead to pneumonia and death shortly afterwards.

To avoid the worst, as usual Narayan and his doctors applied a dense antibiotic regimen to help Khodadoust fight against infection. But the bacteria has now become extremely resistant to drugs and cannot be defeated. They devastated Khodadoust's body, gouging out a hole that leaked out of his chest. You can see the bacilli have occupied the inside of the chest and overflow from the leak hole.

Khodadoust fought stubbornly for 3 months in the hospital, of course with more and more severe antibiotic episodes. He is allowed to go home when the situation is stable, but with a large infection still exists inside the body. Khodadoust must keep an infusion port in his chest, which is the way that every 3 times a day, a very heavy dose of antibiotics is pumped directly in only in hopes of keeping the bacteria from spreading further. That's good.

Picture 3 of The story of hope, before we enter the era of
The ophthalmologist Ali Khodadoust, who had to fight for four years with an infection in his chest.

But what comes will still come, bacteria are extremely resistant to drugs. Over time, they learned how to defeat the extreme antibiotic doses indicated for Khodadoust. He quickly became infected with blood and had to return to the hospital.

Dr. Narayan and his colleagues decided that they could do nothing about Khodadoust's chest. It has now become an inviolable zone of bacteria. If they intend to close the leak, or further open the chest wall to remove the infected artery transplant fragment, unfortunately, the infection may break and will immediately kill Khodadoust.

"They don't even dare to touch me," Khodadoust said . "I can't blame them either."

Khodadoust fell into a state of "limbo" between heaven and earth, according to doctors' soft words. In fact, he was dying badly in misery. "Life has no meaning to a pipe inside my chest. Every 8 hours, 8 grams of antibiotics will be transmitted through it," Khodadoust said. "This is not a human life."

Weapons of medicine have been forgotten

If every person in the world has a guardian angel that appears in life and death moments, that Khodadoust angel must be Benjamin Chan , a young scientist from Yale University. On one occasion to see Dr. Narayan, he suggested that if he wanted to give Khodadoust a "weapon" that had been forgotten by modern medicine. Viruses can be used to kill bacteria, when antibiotics become ineffective, that's exactly what Chan is pursuing in his research career.

Known as phage therapy , it was developed over a century ago and created another golden age in treating infections in the Soviet Union and Eastern European countries. There, antibiotics were banned and became extremely scarce during the Cold War.

Started in 1915, when Fredetick Twort, an English bacteriologist, observed the virus infecting bacteria. Then, Félix d'Herelle, a Canadian doctor, found that he could use this phenomenon to treat infections.

Viruses infect bacteria and rob their biochemical processes. The virus then multiplies the inside of the bacteria, to the point of overflowing and causing the bacteria to die from exploding. Viruses released after this process infect new bacteria and kill them according to the same mechanism.

Phage therapy works quite well, but doctors always need to be on the lookout and doubt about its safety. They use viruses to kill bacteria, but viruses are also impossible to trust, they can also cause illness.

It was time to ask for something new to solve the problem. And in the mid-1940s, Alexander Fleming was the one who found it. He discovered penicillin, the first antibiotic of humanity.

Antibiotics are chemicals, they are truly inanimate, do not live, do not evolve like viruses and are strictly tested to effectively control and side effects in treating infections. Antibiotics, not viruses, are things doctors can trust.

So phage therapy almost disappeared in most countries once they owned antibiotics. Only one area continues to study and use viruses to treat infections such as the Soviet Union and Eastern European countries. During World War II, phage therapy was used to save millions of Stalin's soldiers, while on the other side of the battle line, antibiotic pills were doing the same task.

Picture 4 of The story of hope, before we enter the era of
Images taken from an electron microscope, when phages attack a bacterium.

After the end of the Cold War, with the collapse of the Soviet Union and the system of Eastern European countries, countries were only given access to antibiotics, they also obviously noticed the superiority of chemical pills and abandon phage therapy. Only a small group of researchers continue to maintain their activities in the field of phage, typically at the Eliava Microbiological Research Institute in Tbilisi, the Georgian capital.

That work is maintained on a small scale, so phage therapy is only transmitted as a forgotten treatment. Until the 21st century, when antibiotic resistance became extremely popular and caused a series of unresolved drug resistance, the United States and Europe found a phage therapy. There were patients who had flown flights from the US to Georgia to treat the infection. There have been projects in the US and Europe funded for phage studies.

However, since then it has been only a short period of time, the researchers are very skeptical: Can the virus work in the same way on many different patients? Can bacteria develop resistance to the virus the way it has antibiotic resistance?

"You created the starting point of the problem," said Paul Turner, a virologist at Yale University. He has been studying phage for more than 20 years and initially found positive results.

In 2013, with his promising findings Turner expanded the scope of research. He himself hired Chan to work on the project. His job was to go everywhere to hunt for new viruses, which they could use to treat infections while antibiotics were disabled.

A bold plan

Hunting for viruses, or phage, is easy to say. They are everywhere on the planet, estimated to have 10,000,000,000,000,000,000,000,000 species of phage.

But what Chan wants to look for is not any virus, he wants it to be a species that can attack opportunistic bacterial infections, green pus bacillus. He also wanted it to be a mild virus that could collaborate with antibiotics and support them.

The logic that Chan uses is very simple: Green latex bacillus is an antibiotic-resistant bacterium by creating pumping channels, eliminating antibiotics from their intracellular environment. So Chan and Turner want to find a virus that can infect green pus bacilli by getting through pumping channels, then injecting their genetic material inside to gain control of the bacteria. The next thing is what you already know. They multiply and kill bacteria.

If such a virus exists, it can overcome the green pus bacillus in infection. The only way for bacteria to exist is that it must evolve to close pumping channels. Then we can re-use antibiotics and kill them again.

In summary, phage therapy and antibiotics will complement each other. Green pus bacillus does not die because antibiotics must die because of phage and vice versa.

Chan has started his scathing search by collecting soil samples, waste water and even manure. He deftly separated the viruses from them and put them into the experimental environment with the available green pus bacillus. In turn, the viruses infect and kill the bacteria, but they do not break through the pumping channel and close it.

Chan is constantly searching for new viruses, repeating experiments, failing and then searching again. He simply never gave up his job.

One night, Chan suddenly remembers a sample of water he received from Lake Dodge Pond a month earlier. He found some phage in it."In the middle of the night, I still tried to do the experiment and succeeded , " Chan said. Phage can attack green pus bacillus, precisely through its pumping channel. He named the virus OMKO1 , short for "short for outer-membrane-porin M knockout dependent phage # 1".

Turner was notified of the discovery, they immediately tested OMKO1 in the hypothetical environment. It works, but the next step is human testing. Turner also wants OMKO1 to be licensed by the US Food and Drug Administration (FDA). What they need now is a patient who agrees to treat humanitarian testing, in the case that their disease has been incurable.

"You know," Narayan told Chan . "I have such a patient".

Picture 5 of The story of hope, before we enter the era of
The mechanism that OMKO1 works in case of antibiotic-resistant infections.

Dr. Narayan provided Chan with an infectious bacilli in Khodadoust's chest. Chan infects it with OMKO1 and as expected, it worked to kill most bacteria. Even when he rechecked the surviving bacilli, their pumping channel against antibiotics was closed. He re-used the right antibiotics that failed to treat Khodadoust, this time, antibiotics worked.

Dr. Narayan was very happy, and he and Khodadoust completed the approval procedures from the FDA for a humanitarian trial treatment. Meanwhile, Chan developed specialized OMKO1 viruses to work more strongly on the bacteria of Khodadoust. He screened the best individuals to create a whole new generation of pure viruses.

This amount of virus is closely examined by another laboratory. In January 2016, Chan went to Yale New Haven Hospital with a very carefully preserved syringe, which contained OMKO1 viruses mixed with ceftazidime antibiotics and hope.

Only a small syringe, but it made Chan nervous to get sick. He did everything he could to ensure the treatment process for Khodadoust went well. But because it never happened before, the result is still unknown. Testing may go wrong. Viruses may not find bacteria, they may be washed away. In case they find bacilli and kill them, can Khodadoust die from anaphylaxis?

"I remember like printing a push-up shelf that they moved into the room. Above that was all the equipment for the worst case, in case we had to keep this man alive," recalls Chan. . "Oh my friend, this won't be any worse."

Narayan pushed the needle into Khodadoust's chest and it slowly deepened, deeply submerged, and then submerged further. He announced that the needle had touched the aorta. However, doctors suddenly discovered the vessel wall of Khodadoust had developed into a thick scar. The treatment was left on schedule for an hour only to explore whether they had a position on Khodadoust's chest that doctors could inject viruses and antibiotics into the infection. The result is zero."It was an extremely stressful time," Chan said.

At this time, Dr. Narayan and his surgical team had to risk the B plan. They decided to open the leak on Khodadoust's chest and put the virus in addition to the antibiotic in it. If you're lucky, phage can meet the bacteria here and find a way to attack the infection in the aorta.

The trick ended, but its success was put in a tight black box. Khodadoust returned home, continuing to use his antibiotics. He packed his belongings, booked a flight back to Shiraz. It may be the last days of Khodadoust and he wants to be with his relatives, in his native Iran.

Khodadoust had five weeks, before a small bone segment poked the fistula on his chest, causing him to bleed heavily. The Iranian doctors defied all risks to open Khodadoust's chest again. " They didn't have much choice - Khodadoust died clinically in 2 minutes, " Narayan said.

It has been 4 years since Khodadoust's chest was closed. The last time it was opened left a horrifying scene filled with blood and pus, the aorta had a moss-green infection. But this time, Iranian doctors were completely surprised that the inside was completely clean. They treated the injuries in Khodadoust's chest and replaced his new artery graft.

The infinite cord once again brought Khodadoust back to life. More carefully, the doctors took tissue from Khodadoust's chest to carry it out to test with the green pus bacillus. After that, the results were completely negative.

"You are in the eye of the storm and you cannot find any green pus. Clearly, something has killed them," Dr. Narayan said.

Between the summer days of 2016, Khodadoust left Iran and returned to Narayan's clinic. At this time, he no longer had a transmission port in his chest, nor used antibiotics to continue treatment. In other words, Khodadoust has completely recovered from infection during his 4 years.

"I can't believe it," Narayan exclaimed. "He looks so healthy."

The way forward

Picture 6 of The story of hope, before we enter the era of
Dr. Turner (the leftmost line of the last row) and Benjamin Chan (second from right to the last row) and colleagues in the lab.

The story is extremely emotional, about Khodadoust's miraculous fighting process with an unscathed infection, presented by Narayan in a medical conference a few months ago. He and his colleagues also published a study reporting on OMKO1 and the case of Khodadoust.

Narayan, Turner and Chan are very happy that Khodadoust lived and fought to overcome them all. But they also did not want to place a big promise on phage therapy, when there was only one test case.

"Just because we discovered that, doesn't mean we will save the world , " Turner said. "I can't be convinced 100%. I want to see more data."

Even so, the trend of phage studies has actually received a lot of attention, which is a sign that in the future, it may become a therapeutic routine used in medicine. In early 2016, the US National Institutes of Health (NIH) published a series of grants for the study of phage therapy. Researchers at NIH itself will also test OMKO1 on animals.

They will plan to use it to fight infection from the green pus bacillus on mice and the results will be officially announced next year. If the results continue to be positive, a small clinical trial will be conducted on humans. OMKO1 can be used with cystic fibrosis patients, to see the green pus bacillus that can cause lung infections can be defeated.

Khodadoust was a man who ventured ahead of all these steps, ready to trade his life for medicine. In exchange for that is a faint hope as he described: A thin rope in a pitch black space, a head connecting him to the other end is somewhere in endless.

"I did not regret that decision," Khodadoust said. He is grateful to all physicians like Narayan, researchers like Turner and young people like Chan who have been hard-headed to chase the tiny phages of billions of billion viruses on the onions. this planet.

Today, their work has truly saved Khodadoust's life. But tomorrow, it could be the door of hope for millions of others, who are life-threatening because of the soon-to-be antibiotic-resistant infection.