Attacking poison with poison, they used virus to treat diseases, and antibiotics have solved it

"To enter a new era of antibacterial, phage therapy is in front of you."

Bleak

骏 ‍ ‍ | Ling Jun

Source | "Medical Community" public account

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"Bacterial resistance" has become one of the world's largest public health crisis. A report pointed out that by 2050, the resistance of antibiotics will lead to 10 million people around the world's death and loss of 66 trillion pounds. In this case, the academic community has re -focused on a virus called phage. It does not infect human cells, but shows a strong sterilization ability after entering the human body.

In fact, phage was widely used 100 years ago, and then abandoned by humans. It is still only antibacterial therapy on the edge. But in any case, the abuse of antibiotics has provided an excellent opportunity for the refusal of the phage. Can the phage therapy after the return of the return of the human antibacterial pattern?

Before going to the Shanghai Smooth and Drug Research Institute in the suburbs, interns from other places will receive a strange request -bring a bottle of sewage from his hometown.

There are millions of bacteria from the pollution of a sewer or ditch, but like sheep and wolves on the grassland, a virus called phage is prevented from infinite proliferation. This ancient natural law inspires some scientists to use natural enemies in nature to fight infecting the human body.

"After infection with bacteria, some fierce phage can complete a cracking cycle in half an hour and copy more phage to sustained sterilization." Professor Zhu Tongyu, director of the Shanghai Smooth and Drug Research Institute, told the "medical community."

Sewage bottles in the laboratory of Shanghai Step and Drug Resistance Research Institute

In 2016, under the strong request of the infectious pathologist Steffanie Strathdee, the US Food and Drug Administration (FDA) turned on a green light for this unprecedented trial therapy. Her husband was depleted due to organ failure in the infection of superplant bacteria, but he re -reinforced the new life after approval of the injection of phage in three weeks.

This is like re -launched a shot of shots worldwide. As one of the most famous discoveries of modern microbiology, the pharmaceutical therapy that has been forgotten for decades will return to the school industry, and may lead humans to the dilemma of bacterial resistance in the future.

Super weapon against bacteria

"If the intestinal microorganisms do a genome detection, you will find many virus sequences. Most of them are phage and restraint bacteria to maintain human health." Dr. Wu Nannan, deputy researcher at the Institute of Fascus and Drug tolerance, said, the phage phage said, the phage phage It can inject their own nucleic acid into bacteria and reproduce a large amount, which eventually causes bacteria to rupture and die.

Caption: Pharmaceutical "capture" bacteria

On a diner divided into 8*12 grids, Dr. Wu Nannan introduced the approximate method of selecting phage:

"Put the bacteria you want to kill on the cultiv dish first, and then different phage on each grid point. There is a ring that represents the bactericidal ability of this grid. "

In the end, six kinds of phage passed the selection. Within the next ten hours, the researchers will perform the price verification again. The baying of the standard can be combined into a cocktail to treat the patient.

Just as not all bacteria are harmful to the human body, the number of phage in nature is as high as 1031, but only a few humans have excavated a small part for clinical treatment. "Through several years of collection and screening, our phage is currently more than 700 phage, which can cover more than 90%of clinical resistance." Professor Zhu Tongyu said.

In January 2018, the Shanghai Smooth Institute took the first patient, a super bacterial infection. In 2014, he breeds multiple drug -resistant pneumonia in infection in the urinary tract. In 4 years, he moved to the country for medical treatment. He had long -term hospitalization infusion. Drug resistance is strengthened again.

After the patient came to Shanghai, the stubborn infection was finally cleared after four treatments of phage treatment. Earlier, he even had a pain in his urine every day, but Professor Zhu Tongyu's team used the phage that could kill this super bacteria.

Just half a year ago, in August 2017, the Shanghai Institute of Bacterial and Drug resistance was formally established. Professor Zhu Tongyu is one of the sponsor. As a front -line expert in kidney transplantation and urology, he has been infected with bacterial infections for more than 20 years. He has seen a large number of patients who have been infected with drug resistance after surgery. A new therapy can bring clinical value.

The other two promoters were Professor Chen Liguang and Professor Guo Xiaokui. Professor Chen Liguang is the top scholar in the field of virus in the Tzu Chi Medical Center in Taiwan. As the Executive Deputy Director of the National Tropical Disease Research Center of Shanghai Jiaotong University, Professor Guo Xiaokui believes that in 1958, the Jiaotong University Institute of Immunium completed the first phage treatment in China. After nearly 60 years, it should be restarted.

The three of them were closed. Over the past four years, the Shanghai Stepper Research Institute has cured nearly 100 patients from all over the country. Most of them were infected by super bacteria, ineffective antibiotics, long -term hospitalization and even life -threatening, and returned to normal life after receiving phage therapy.

Shanghai Step and Drug Research Institute

In addition to 1200 kilometers, Professor Lu Hongzhou, Dean of the Third People's Hospital of Shenzhen and academic member of the Shanghai Efy Institute, also knows the broad prospects of phage therapy. In January of this year, Shenzhen Third Hospital and Shenzhen Advanced Technology Research Institute cooperated to carry out the first phage chic cocktail therapy of the hospital, which rescued an old man who suffered from inhalation pneumonia and infected three super bacteria at the same time. "A multi -phage can expand the antibacterial spectrum and reduce the bacterial phage resistance." Professor Lu Hongzhou said that the phage cocktail is one of the main development directions of the current field.

The darling of the global medical community

"The hospital's intensive care unit is using various high -end antibiotics every day." Professor Zhu Tongyu said, "To enter a new era of antibacterial, phage therapy is in front of you."

But the potential of phage is far more than the treatment of people infected by bacteria. "A phage is only aimed at one or a specific type of bacteria." Dr. Wu Nannan said, so it can be used to test whether different intra -hospital patients are infected with the same type of associated bacteria and then monitor the possibility of the sense of hospital sense.

Because it is not infected with people, the phage is also made into spray, which can be used in the ward, especially a large area of ​​infection wound ward for spray disinfecting. Even the aquaculture practitioners will spray specific phage in the fish pond to avoid adding antibiotics to the feed and reducing the opportunities of drug -resistant bacteria. Other scientists are also developing phage additives for food anticorrosive.

The impact of phage is so wide that some enterprises, institutions and health departments have shown great interest in it. In 2019, the three largest overseas phage therapy research in the business authorization of commercial authorization exceeded US $ 2 billion. The Shenzhen Institute of Life Sciences in Shenzhen also launched a global phage plan plan in 2020.

However, whether it is the Shanghai Efy Institute or other domestic and foreign institutions, neither promote the development of phage therapy from scratch.

In 1896, British bacteria scholar Han Jin observed a substance with antibacterial activity in the Ganges of India and found that it controlled cholera. It was not until 1917 that French microbiologist Dehler independently extracted the dysentery from the feces. Two years later, he first created phage therapy in human history and cured a child infected with dysentery.

The first phage treatment in my country appeared in 1958. At that time, 30 -year -old steelmaking worker Qiu Caikang was burned by 1800 degrees steel water, and the total area of ​​burns was nearly 90%. After the rescue of the shock section, copper green fake monosocopymal sepsis, antibiotics, plasma antibodies and other treatment attempts were not obtained. Satisfaction effect, life hangs a line.

The pioneer of China Microbiology, then Professor Yu Yan, director of the Microbiology Teaching and Research Office of Shanghai Second Medical College (now the School of Medicine, Shanghai Jiaotong University), thought of phage. At the beginning of the summer of that year, he organized more than 60 students to remove dung pits and sewage from the suburbs for a few days in a row. When the liquid finally infiltrated Qiu Caicang's whole body, his infection was slowly controlled, and this case also directly contributed to the start of the New China Burning Department and Plastic Surgery.

In fact, phage therapy was the darling of the global medical community in the early 20th century. Pharmaceutical factories are produced in large quantities of phage -made agents for different diseases. Residents in Europe and North America can easily buy pharmaceuticals in pharmacies to treat powder infection. Adsorption, invasion, replication, assembly, release ... Humans have continuously promoted the understanding of phage sterilization mechanism.

But penicillin's invention leads to human beings to another path against bacteria. After the large -scale production of penicillin in the 1940s, phage therapy was beaten into the cold palace, but the relevant basic research did not interrupt. From 1952 to 2011, there were six Nobel Prizes related to phage, which also directly promoted the development of disciplines such as virus, molecular biology, and synthetic biology.

Life -saving straw in the post -era of antibiotics

The phage therapy has been waiting for the time to come back until he returns to the academic field as a "rescuer".

In 2015, Patterson, a 68 -year -old American psychology professor in American psychology, infected Balman Bacteria during the tourism on the way to Egypt. Antibiotics are resistant.

This is the most unwilling to see the global medical community, especially for Patterson's wife Strasdi. "I started to realize that my husband's condition was much more serious than imagined. Modern medicine has used antibiotics."

Patson in a coma. Picture source: CNN

After the middle of the 20th century, the whole infection world is the world of antibiotics. But reality cannot be avoided -antibiotic therapy has encountered bottlenecks, and the effect is rapid attenuation, so that drugs used to treat infection in the past are increasingly increasing.

In a report by the WHO 2013, the carbonicochide antibiotic antibiotic antibiotic antibiotic infection was used as an example. The problem of drug resistance has spread to all regions of the world. And if you are infected with glyceland, you can easily treat penicillin in the past, but after the appearance of methamphetamine Golden Polyris (MRSA), penicillin has no effect.

In addition, in the 1980s, antibacterial drugs that were put into the use of urinary tract infections have currently lost effect on more than half of patients in many countries. In 2014, nearly 3.3%of the new cases of tuberculosis were anti -drug against a variety of drugs, and 20%of the recurrence cases were resistant to medicinal. According to the latest data released by "Liu Ye Dao", in 2019, more than 1.2 million people around the world died directly from antibiotic bacterial infections. This is the result of antibiotic abuse. Over the past few decades, not only clinicians have used to develop antibiotics for any patients -whether it is necessary to analyze from medical analysis, agriculture, fishery, and animal husbandry, antibiotics are used in large numbers. A study published in "Nature" in 2015 showed that from 2000 to 2010, global antibiotic consumption increased by 30%.

More and more super bacteria are born under the natural selection, and the development of new and efficient antibiotics may take decades. Once it is listed, it cannot avoid excessive use of global use and lead to failure again.

It is precisely because of high research and development barriers, huge investment, and short profitable windows, since 1987, the iteration of new antibiotics has been in stagnation since 1987. In the past 10 years, there are 7 companies that have successfully launched antibiotics in the United States, bankrupt or exit because of poor business.

"Ordinary infections will cause people to die again. If the trend continues, such as tube transplantation, cancer chemotherapy, etc., it will become more difficult." Dr. Chen Fengfuzhen, Director of WHO Director -General, said at the 2016 UN General Assembly. "It may even lead to the end of modern medicine."

In the era of post -antibiotics, modern medicine urgently needs to find another path against infection. For Strasdi, phage was the only life -saving straw at the time.

She persuaded phage scientists across the United States to search for natural enemies of Balman's non -moving bacteria in sewage, swamps, ponds and other places. Under the ethical terms of "use sympathy", in March 2016, for the first time, the FDA clinical use approved phage cocktail Injecting into the vein of her husband Patson, Patterson woke up from the deep coma 3 days later.

The therapist injected Patterson the first round of the sources of the bachelors: CNN

In 2017, this case was published in the journal "Antibacterial Drugs and Chemotherapy", and phage therapy once again set off a new wave. As of now, more than a dozen phage therapy pipelines around the world are being advanced.

Get rejuvenating phage therapy

The initial phage technology has a lot of room for improvement. When the academic community picks it up again, the development of related disciplines and engineering technology has rejuvenated phage therapy -decades of stagnation have not allowed research to start from scratch.

"At that time, the treatment of phage was drank or paved on the wound, and even the GMP production standards were not." Professor Zhu Tongyu introduced, "But the current purification technology guarantees the safety of the phage after entering the human body. The approach also increases its pertinence and effectiveness of sterilization. "

In March 2020, Zhu Tongyu and Wu Nannan's team used phage to treat 4 patients with critical re -crowned patients infection with Portobacteria infection. Related studies were published in the "New Inciture and Infection" magazine.

Some gene products encoded by phage, such as lobe, also have great antibacterial prospects. "It has shifted from a virus therapy that simply fights bacteria to a brand new biological therapy concept." Professor Zhu Tongyu said.

When scientists try to further analyze, edit, and even synthesize more powerful phage at the level of genetic level, the development of molecular biology and gene editing gives directions.

In 2020, Locus Bioscience, an American company, announced that the phage-pharmaceutical drug LBP-EC01 of CRISPR-CAS3 gene editing technology is incorporated into the clinical study of phase II/III. Target bacteria.

"Bacteria can be cut into phage through the CRISPR system in the body, so it produces resistance to phage, and strong specific specificity also causes the phage's antibacterial spectrum to be too narrow." solve these problems.

However, the CRISPR system is only one of the weapons of bacteria against phage. The research of other drug -resistant mechanisms is also the focus of scientific research in the Shanghai Efy Research Institute.

In 2016, Dr. Wu Nannan, who was born in a virus, returned from the science of Master Lyon, France, and joined the preparation of Professor Zhu Tongyu's team to participate in the research institute. From the professional team of more than 20 people to more than 20 people, the development of the institute requires composite talents with disciplines such as cell biology, molecular biology, infectious diseases, and virus.

Institutes of Shanghai Efy and Drug Resistance, researchers are conducting experiments

And when they tried to further popularize phage therapy towards clinical popularity, Professor Zhu Tongyu believed that he had to face the challenge of the inherent treatment concept of antibiotic era.

Although phage therapy provides an important direction for the dependence of antibiotics, its clinical awareness rate is not high like all new technologies. Over the past four years, scholars at the Shanghai Elysis Institute have tried to make this therapy be well known to more vast clinicians. In the research institute, some mature phage combinations are also made into fixed "drugs" to reduce the cost and time required for personalized therapy.

Plastic therapy, a door that was reopened

"The phage is not a picked out of the clinician. You need to identify it, gene sequencing, remove the internal toxins, including a complete set of complete GMP workshop preparation production processes, etc." Professor Zhu Tongyu emphasized that this is a system as a system Essence Institutes of Shanghai Efy and Drug Resistance, researchers are conducting experiments

As a microorganism, the production method of phage treatment products is very different from chemical and protein drugs, and standards cannot be fully applied. However, reality is that phage treatment is currently approved for clinical trials, and there are no regular treatment standards and preparation quality control standards at home and abroad.

Due to the historical safety of phage drugs, the FDA of the United States stipulates that when applying for clinical trials of phage drugs, there is no need to provide corresponding pharmacokinetic dynamics and toxicology research materials. The European Drug Administration (EMA) believes that any existing drug supervision path is not suitable for phage therapy and needs to be re -developed.

Similar to the "sympathy treatment" in the United States, the current development of domestic phage therapy is based on the Case-Series approval of the Ethics Commission. Some problems in front of the drug or therapy need to be resolved.

"For example, if we do respiratory tract infection, we need to know how the utilization and efficiency of different dosage channels are, and there may be any bad events." Dr. Wu Nannan believes that the process of clinical trials is high. "Before entering this stage, we need to enter this stage. Accumulate more detailed data. "

"Depending on the types of phage, the adsorption rate and incubation period are also different. How to grasp the best dose and time for treatment?" Professor Lu Hongzhou said that later industrial production also faces a lot of challenges, such as what technology to use to purify the phage batch phage To meet safety standards.

In any case, the door of phage therapy has been reopened.

On May 3 this year, "Nature · Communication" stated that the phage's therapy was successfully cured for the first time. Ten days later, "Cell" posted a post that the phage that was transformed by genetic engineering for the first time was cured for the first time, which had been cured for the first time. The patients had to endure the pain of the lungs in the patients. On August 4th, "Cell" posted again, proved that the phage of Crabobacteria, which is orally, can alleviate inflammatory bowel disease.

Scientists have recently discovered a giant phage that has never been seen. It has a different "partition" that can protect the core genetic material to avoid "counterattack" from bacteria. Related research on August 3rd on August 3rd Published in the top issue "Nature".

Perhaps human beings have to spend decades or even a century in order to understand the history of evolutionary evolution of the struggle between 4 billion years in nature and bacteria in nature. But when he returned to the field of modern medicine, Professor Zhu Tongyu had hope for the application of phage therapy. "To do more research in the field of phage structure biology transformation, to form a standard industrial system, and to benefit more patients." He said, "This is our work."

references:

[1]No antibiotics worked,so this woman turned to a natural enemy of bacteria to save her husband's life，https://edition.cnn.com/2022/07/08/health/phage-superbug-killer-life-itself -Wellness/index.html

[2] How can we prevent antibiotics from drug resistance, https://www.bbc.com/ukchina/simp/vert-fut-40717441

[3] The previous life, this life and the future of phage treatment, https://baijihao.baidu.com/s? ID = 168476613004276543WFR = Spiderfor = PC

[4] Research and investment recommendations for phage drug industry: In the industry cooperation over 3 billion yuan, can it rescue humans from resistant bacteria? https://www.vbdata.cn/42895

[5] Paired by 10 tons of steel water, the burning area is 90 %. https://xw.qq.com/cmsid/20211029a04kie00

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Source: Medical Community

Editor: Ling Jun

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