Novel coronavirus pneumonia, why is the new drug development process so difficult?

 Novel coronavirus pneumonia, why is the new drug development process so difficult?

Laboratory tests have shown that the antibiotic can effectively kill many of the worlds most troublesome pathogenic bacteria, including some strains resistant to all known antibiotics. Researchers paid tribute to Kubricks classic sci-fi film 2001 Space Odyssey and named the molecule halicin (the artificial intelligence system in the film is called Hal 9000). In addition, using other machine learning models, the researchers found that the molecule may be less toxic to human cells.

How will this new antibiotic affect modern medicine and human health? There is still time to verify.

Since penicillin was discovered, antibiotics have become the cornerstone of modern medicine. But in the world, the resistance of bacteria to antibiotics is increasing rapidly, and the abuse of antibiotics makes some pathogenic bacteria become immortal super bacteria, which has become a public health problem in recent years. Who has warned that countries around the world abuse antibiotics, making once treatable diseases difficult to cure. Taking Streptococcus pneumoniae as an example, the proportion of penicillin resistant Streptococcus pneumoniae has increased from 21% in 1995 to 25% in 1998. For this kind of pneumonia, which was once the easiest to treat, human beings will face a difficult situation. Researchers predict that if new drugs are not developed as soon as possible, 10 million people will die each year from drug-resistant bacteria infection by 2050, the British journal Nature reported.

However, in the past few decades, few new antibiotics have been developed, and their structures are similar to those in the past. In addition, the current methods for screening new antibiotics are expensive and time-consuming. And the endless arms race between disease and drugs continues to this day, the problem of antibiotic resistance has not been solved.

Novel coronavirus pneumonia is becoming more and more serious in this case. Novel coronavirus pneumonia is not effective for the treatment of severe pneumonia and severe diseases, but also for many light and ordinary patients. Novel coronavirus pneumonia, which was warned by Woodk, chairman of the China EU Chamber of Commerce, warned in February 18th that if the outbreak of the new crown pneumonia could not be resolved as soon as possible, it would continue to impact the supply of the pharmaceutical industry, and the world would probably face the problem of drug shortages such as antibiotics.

Recently, the novel coronavirus pneumonia emergency approval 5 new drugs for the new crown pneumonia clinical trial, effective drug research and development is still facing many difficulties and unknown.

Donald R. Kirsch is an old pharmacist with 35 years of experience in drug research and development. In his book pharmacist Hunter, which he completed in cooperation with the writer ogi ogas, he narrated all kinds of twists and turns and accidents in drug research and development with his own experience. Antibiotics, anesthetics, insulin, contraceptives, antidepressants The emergence of each new drug has a hard work unknown to the pharmacists. They expose themselves to known or unknown risks, and repeatedly screen and trial and error in countless compounds, which makes it possible to treat diseases and save lives. Sometimes the discovery of drugs is purely a matter of luck, whether before or after the development of modern science.

To this end, Kirsch compared the drug developers to the Librarians in the novel Library of Babel by Borges, an Argentine writer. They spent their lives trying to find drugs that could change the fate of human beings. At the same time, the fear that they could not find in their hearts would follow. However, in this Babel library, there must be some books containing philosophy and wisdom that can change the fate of mankind. These books are called truth. Most librarians can only see the disordered letters, but some of them finally find the truth with luck and perseverance.

Pharmacist: people who discover new drugs, by Donald R. Kirsch and ogi ogas, translated by Tao Liang, China CITIC publishing group, June 2019.

The probability of successful drug development is only 0.1%

By Donald R. Kirsch and ogi ogas

In the fog of prehistory, everyone was a herbalist. The ancestors, who were plagued by parasites and were full of small problems, would chew the roots and leaves of any trees they found by chance, hoping that those plants would just alleviate the pain, but also praying that they would not die. Relying solely on luck, people in the Neolithic Age discovered some substances with medical effects, including opium, alcohol, Ophiopogon, juniper, frankincense, fennel, and birch fungus.

Around 3300 B.C., a starving, cold and seriously injured man stumbled between the peaks of the Italian Alps of iztar and finally fell into an ice crevasse. He lay there quietly in freezing conditions for more than 5000 years, until in 1991, hikers accidentally found his body. They named the body Oates. Austrian scientists melted the ice age body and found that his intestines were infected with Whipworms. At first, scientists thought that Oates and his contemporaries had nothing to do with the parasite. However, the subsequent discovery overturned the idea of scientists.

There are two skins in Oatess bear skin, each of which is covered with a white ball. These strange globules are the fruiting bodies of birch porous bacteria, which have antibacterial and hemostatic effects, and contain oil like substances that can kill flagellates. The fungi wrapped in the skin of Oates are likely to be the first medicines to be found in the world. Drugs during the ice age are not very effective, but at least they are useful.

The fungus found in Oates illustrates a simple truth of human medicine Hunting: the prescriptions of Neolithic Age did not come from ingenious innovation or rational exploration, and there was no great man like jobs who invented insect repellent through his vision and insight in the stone age. On the contrary, the discovery of drugs only depends on luck. Before the development of modern science, the discovery of drugs completely depends on trial and error.

What about today? Pharmaceutical giants such as Pfizer, Novartis and Merck have spent billions of dollars to build advanced drug research laboratories. You may think that the blockbuster drugs are the products of drug engineering projects. Rigorous scientific demonstration and careful planning have replaced the repeated trial and error process, but this is not the case. Despite the great efforts of large pharmaceutical companies, the main technology of drug hunting in the 21st century is no different from that 5000 years ago: painstakingly sampling and experimenting with a large number of mixtures in the hope that one is effective.

The process of drug research and development may be circuitous, completely unexpected, or both. A professional herbalist is like a professional poker player: he has enough knowledge and skills to turn the game at the critical moment, but he can never get rid of the influence of the quality of the card on the game.

The professor who taught me pharmacology once told me that 95% of the time, patients dont get much help going to the doctor. In most cases, either the patients body does not need the doctors intervention, and then he recovers himself, or the disease has developed to the point where there is no medicine to cure, and the doctor has no way to do it. He believes that only in 5% of cases can doctors treatment play a decisive role. The 5% probability seems to be very low, but it is much higher than the success probability of drug developers.

Only 5% of the pharmaceutical R & D projects reported by the R & D personnel can be approved by the management. Of these approved projects, only 2% can develop drugs approved by the FDA, that is to say, the probability of successful drug R & D is only 0.1%. The challenge of drug research and development is so great that it has triggered a crisis in the field of medicine.

Each FDA approved drug costs an average of $1.5 billion and 14 years, and large pharmaceutical companies are increasingly reluctant to spend huge R & D costs, because most of the money they spend ends up in the water. Recently, Pfizer executives told me that they are considering whether to completely withdraw from the field of pharmaceutical research and development and only buy ready-made drugs developed by others. Pfizer is the worlds oldest, most talented, most funded and largest pharmaceutical company, and even wants to give up research and development, which shows the difficulty of developing new drugs.

Why is it so much more difficult for Pfizer to develop new drugs than to send humans to the moon or to develop atomic bombs? The moon project and Manhattan Project use mature scientific equations, engineering principles and mathematical formulas. Of course, these projects are also complex, but at least the researchers have clear scientific planning and mathematical guidelines. The researchers of the moon project know the distance between the moon and the earth and how much fuel is needed to reach the moon. Scientists at the Manhattan Project know how much material can be converted into enough energy to destroy the city, according to the formula e = MC.

However, in the field of pharmaceutical research and development, it is necessary to repeatedly screen trial and error in countless compounds, and there is no known equation or formula to use. Bridge engineers can clearly know the maximum load-bearing capacity of the bridge before the official ground breaking, but medical researchers can never know the efficacy of the medicine before patients take it.

In the mid-1990s, Ciba geigy (now affiliated with Novartis) calculated the number of compounds that could become drugs in the whole universe: 3 u00d7 1062. When we describe the characteristics of numbers, some of them are relatively large, some of them are huge, and some of them are too large to be imagined by human beings, almost reaching infinity. 3 u00d7 1062 is the third case. Suppose that in order to develop effective drugs to treat breast cancer, 1000 compounds can be tested every second until the suns energy is all burnt out, and only one corner of the 3 u00d7 1062 iceberg can be tested.

The story written by Argentinian writer Borges is suitable for describing the difficulties of drug development. In the novel Library of Babel Tower, Borges conceives the universe as a library composed of countless hexagonal rooms, which extends infinitely in every direction. Each room is full of books, each book contains randomly combined letters, and no two books are the same. Occasionally, there is a meaningful sentence in the book, such as there is gold in the mountains, but according to Borges, there is a meaningful sentence in countless meaningless and disorderly stacks of letters.

However, there must be some books in the library that contain philosophy and wisdom that can change the fate of human beings. These books are called truth. In Borges story, the librarian shuttles through the library, hoping to find the truth. Most librarians spend their whole lives in the library and get nothing, only seeing disorderly letters. But some administrators have found the truth with luck or perseverance.

Similarly, every possible drug is hidden in a corner of the huge compound library. Some compound may kill ovarian cancer cells, another can inhibit the deterioration of Alzheimers disease, and another can cure AIDS, but it is also possible that these drugs do not exist at all, and there is no way for human beings to obtain accurate information. Modern drug developers, like the librarian in Borges story, spend their lives searching for compounds that can change the fate of human beings, and need to overcome the fear they cannot find.

In fact, the root of all problems lies in the human body. Our physiological activities are not as fixed as rocket propulsion or nuclear fission. The human body is an extremely complex molecular system, and the relationship between various parts of the body changes in many ways, and each individual has its own characteristics. As for the physiological activities of human body, we only know a small part of them, and we still cant describe how most of the molecules in the body work. Moreover, each individual has its own unique genetic and physiological characteristics, so each individual operates in a slightly (or very) different way.

In addition, although we know more about cells, tissues and organs, we still cant predict exactly how a given compound will react with a human molecule. In fact, its impossible to know for sure whether a disease has what pharmacologists call a protein that can be treated with drugs or a target that can be treated with drugs, that is, a specific protein in a pathogen that reacts to a chemical agent.

There are two conditions to develop an effective drug: one is the right compound (i.e. drug), the other is the right target (i.e. protein that can be treated with drug). Drugs are like a key, which can turn the protein code lock to start the physiological engine. If scientists want to have an impact on human health in a specific way, such as slowing down depression, relieving itching, treating food poisoning or improving health, they must first find the target protein in the human body that will affect the physiological process, or the target protein in pathogens that will hinder the physiological process.

The process of systematically searching for compounds is called screening by pharmacists. The prehistoric method of screening was to pick every berry or leaf that had not been seen before, and then smell it with the nose, or crush it, or eat it directly. Our ancestors have been screening in nature in this way until 1847, when they first screened in a more scientific way to find a drug - ether. At that time, ether was used as an anesthetic for surgery, but there are several obvious disadvantages of ether, one is that it will cause irritation to the patients lung, the other is that it has the possibility of explosion. So doctors have been looking for new compounds that are similar to ether but work better to avoid these problems.

Chemical formula of ether

Ether is a volatile organic liquid, and Scottish doctor James Young Simpson and two colleagues decided to test each of them. Their screening process is simple: open a bottle of test liquid and inhale steam. If nothing happens, mark the liquid as inactive. If you lose consciousness after inhalation, mark the liquid as active.

Of course, this screening process certainly does not meet the safety standards of modern laboratories. Benzene was a volatile organic liquid widely used at that time, and Simpson must have tested benzene, but now we know that benzene is a carcinogen, which will cause permanent damage to the ovary or testicles when inhaled into the body.

This method of screening is indeed imprudent and reckless, but on November 4, 1847, Simpson and his colleagues tested chloroform. When three people inhaled the compound, they immediately had a pleasant feeling and then lost consciousness. When they woke up a few hours later, Simpson knew they had found an active drug sample.

To test the results, Simpson insisted that his niece inhale chloroform while he watched. The girl fainted. Fortunately, she woke up after that. Now we know that trichloromethane is a powerful cardiovascular sedative. If it is used as an anesthetic for surgery, the death rate will be very high. Although the method used is dangerous, Simpson discovered the 19th century blockbuster drug by inhaling various chemicals in his living room, which is unlikely to be used again now. But Im not sure I tried to find new drugs in the back of a Volkswagen van in the 1980s.

You may think Im making drugs, or why do you want to develop new drugs in a van? Thats not the case. My first job was working for an antibiotic research and development team. The most common way to find antibiotics was to screen every microorganism in the soil. So Ive been looking at all kinds of soil, trying to find useful microbes, but also to make money.

One weekend, I volunteered to drive a Volkswagen van to Delmarva Peninsula to screen soil samples from Chesapeake Bay. The van is my Mobile Lab with sink and gas lamp. My team recently discovered a new antibiotic called monoamines, so my mobile lab is called monoamines car.

When people know that I am a drug researcher, they usually ask me the following questions with a slight disdain:

Why are medicines so expensive?

Why are there so many side effects?

Why is my illness incurable?

In fact, the answer to all three questions is related to the fact that the process of drug development is extremely difficult, because at some key points, repeated trial and error is always needed, which is the same as that of cave dwellers thousands of years ago. We still cant master enough knowledge of human physiology, and there is no mature theory to guide us to find the compounds that human beings are eager for in a rational way.

Golden age and earth age of antibiotic research and development

Great scientific discoveries are often unintentional rather than intentional. For example, biologist Barbara McClintock initially focused on why corn grains have different colors, but finally found transposons, the genetic factors that can move. Similarly, when neuroscientist Stanley prussiner was a resident, a patient with Creutzfeldt Jakob disease, a neurodegenerative disease that usually causes death, came to the hospital. At that time, the pathogen of the disease had not been found, and no one knew the cause of the strange disease. To help patients as much as possible, bruciner eventually discovered prion, a new protein-based pathogen. McLintock and bruciner both won the Nobel Prize for their unintended research results, and Waxman was no exception.

Selman Abraham Waksman was born in a small city on the edge of Kiev. Later, he immigrated to the United States, studied at Rutgers college in New Jersey, and obtained a bachelors degree in agriculture in 1915. The growth of crops depends on the interaction between crops and soil, including microorganisms in the soil. Waxman was interested in this interaction, especially in fertile soil, so he began to study the soil and the microbes in it. The microorganism in the soil will degrade the organic matter which falls on the ground and transform it into the nutrient substance needed for plant growth. Waxman hopes to improve crop yield by studying soil microbiology.

Selman Abraham Waksman (1888-1973), a Ukrainian American biochemist and microbiologist. Waxman discovered streptomycin and other antibiotics, first used streptomycin in the treatment of tuberculosis patients, and won the Nobel Prize in physiology or medicine in 1952.

Knowing the fact that penicillin is extracted from a very common fungus in the soil, Waxman immediately began to study whether there are other microorganisms in the soil that have the same antibiotic effect. A group of microorganisms that Waxman has studied for many years is called Streptomyces, which has a high content in the soil. The fragrance of soil from the newly turned soil comes from this kind of microorganism. In 1939, he planned to test whether the bacteria could kill bacteria, especially penicillin, the immortal tubercle bacillus.

How to cultivate and isolate microorganisms is a field that Waxman is good at, but he doesnt know how to test it safely with tuberculosis bacteria. In theory, he could, of course, like Flemings test of penicillin, first grow the tubercle bacillus, and then put it in the Streptomyces to see if the Streptomyces could kill the tubercle bacillus. But he is concerned that large-scale cultivation of TB bacteria is too dangerous, which may lead to infection of the entire laboratory staff.

Waxmans ultimate solution is to find a bacterium called Mycobacterium smegmatis to replace the tubercle bacillus. These two kinds of bacteria are very similar, but Mycobacterium smegmatis is harmless to human body, and the cultivation speed is faster, which is conducive to the experiment. Waxman hypothesized that substances that kill Mycobacterium smegmatis also kill TB. Fortunately, his hypothesis is correct.

In 1940, Waxmans laboratory found the first candidate antibiotic: actinomycin. Actinomycin can kill a range of pathogens, including tuberculosis, but when tested in animals, Waxman found that the antibiotic was too toxic to be used as a drug for humans. In 1942, he found another candidate antibiotic: Streptomyces, which is also highly bactericidal, and after testing in animals, animals did not die, at least in the first place.

But later, Waxmans team found that Streptomyces could gradually damage the liver function of animals. Short-term use had little effect on animals, but long-term use would lead to death due to renal failure. Antibiotics work best when bacteria are growing. If bacteria are dormant, such as in spores or cysts, antibiotics are ineffective.

In general, the faster the bacteria grow, the better the bactericidal effect of antibiotics. Unfortunately, as a highly evolved bacteria, the growth rate of tuberculosis is extremely slow, which also means that it will take a long time to take antibiotics to completely kill the bacteria. Therefore, Streptomyces is not suitable.

Despite two blows, the indomitable scientist is confident that his team will find the right medicine. They went on to test Streptomyces griseus, found in chickens windpipes in 1943, which produces antibiotics that also kill a range of bacteria, including tuberculosis. After testing in animals, they found that the antibiotic was not toxic, and they called it streptomycin. In 1949, Merck began mass production of streptomycin, the first drug to cure tuberculosis, and sold it worldwide, saving millions of lives.

In the United States, poor immigrants have a very high probability of contracting tuberculosis, and most people will die within five years of getting sick. At the end of the 19th century, the best way to treat tuberculosis was to bask in the sun and breathe the fresh air from the mountains. Many sanatoriums have sprung up all over the country, especially in the Rockies. One of the most famous sanatoriums is the Trudeau sanatorium in the small town of salanak Lake in the north of New York. Ironically, the sunshine is not good and there are no mountains around, but it doesnt matter. In fact, the sun and air are not helpful for the treatment of tuberculosis.

The emergence of antituberculosis drugs has made a qualitative change. Patients dont have to wait for miracles in the sanatorium. They can go home safely and have treatment. Now the treatment of tuberculosis is cocktail therapy, just like the treatment of AIDS, isoniazid, rifampicin, pyrazinamide and ethambutol are taken together, as long as the dosage is appropriate, tuberculosis will be cured.

Waxmans discovery has opened a new door for the pharmaceutical industry. Pharmaceutical researchers have been digging the earth around the world, hoping to find new bacteria killing microbes from the earth, and also opened the so-called golden age of antibiotic research and development. Many of the antibiotics currently used were found in the golden age, including bacitracin

(1945), chloramphenicol (1947), polymyxin (1947), aureomycin (1950), erythromycin (1952), vancomycin (1954), etc.

Benzathine penicillin, developed by Florey and chain, proved to doctors, scientists and the public that antibiotics can completely eliminate pathogens in the human body, make all symptoms disappear, and ensure that the bacteria will not be transmitted to others. This is the Holy Grail of the early 20th century in the field of pharmaceutical research and development. It is a special medicine for curing infectious diseases. It also ushered in the mud age of pharmaceutical research and development. Major pharmaceutical companies have sent teams to search for treasures in the mud. But penicillin brings a vexing problem. When the pathogen bacteria are attacked by antibiotics, they will change their own properties and make the drugs invalid, just like bacteria put on a new set of armor to defend the drug weapons.

The first report of penicillin resistance appeared in 1947, only four years after the mass production of penicillin began. And penicillin is not the only drug that fails because of resistance to pathogens. The resistance to tetracycline, another antibiotic, appeared 10 years after its appearance. Erythromycin was used for 15 years, gentamicin for 12 years and vancomycin for 16 years. At first, scientists were confused about why the panacea failed one by one, and soon realized that it was the evolution of pathogens.

The discovery led to a battle in the pharmaceutical world, an endless arms race between disease and drugs. The process of the arms race is consistent: the researchers found new antibiotics, which had a good bactericidal effect for a period of time, but soon the chromosome of the bacteria changed and the drugs failed.

Pharmacists usually change the structure of antibiotics slightly to kill the mutated bacteria, but soon the bacteria changed again, and the improved medicine also failed. Up to now, scientists still havent solved the problem of antibiotic resistance. Many bacteria that produce drug resistance gradually become fatal. The pharmaceutical industry has no way to deal with it. It seems that it goes back to the era before the invention of penicillin, including Staphylococcus aureus, Neisseria gonorrhoeae, Pseudomonas aeruginosa, Escherichia coli, Streptococcus pyogenes, etc. Mycobacterium tuberculosis has also mutated, one of which completely invalidates the standard TB cocktail therapy.

Bacterial infection is still a high-risk disease, but in the 1980s, many large pharmaceutical companies abandoned the development of new antibiotics. Why abandon this market with clear demand? Because antibiotics are unprofitable, pharmaceutical companies prefer to develop and produce drugs to treat chronic diseases, such as high blood pressure or high cholesterol. Patients have to take drugs for life day after day to generate huge sales. But if you take antibiotics for up to a week, the patient will recover, and the pharmaceutical company wont make much money.

Whats worse, because doctors all know the problem of drug resistance, the newly developed antibiotics will have the same problem sooner or later, so doctors will not easily prescribe new drugs for patients. Only when patients are seriously infected with bacteria that have developed drug resistance, will they let patients take new drugs. This is a wise way to preserve the effectiveness of antibiotics, but so the sales of new antibiotics will be lower u3002

In 1950, almost every pharmaceutical company had an antibiotic R & D team. By 1990, most American pharmaceutical companies had marginalized their antibiotic R & D projects and even cut off the antibiotic R & D team completely. But in the same year, due to the outbreak of Staphylococcus aureus and other resistant bacteria, the scientific community renewed interest in antibiotic research and development. But pharmaceutical companies remain indifferent and continue to reduce investment in antibiotic research and development projects. In 1999, Roche completely terminated the antibiotic research and development project. By 2002, Bristol Myers, Squibb, Abbott, Lilly, Aventis and Wyeth had completely terminated or largely eliminated their antibiotic research and development projects. Pfizer was one of the few pharmaceutical companies still insisting on the development of antibiotics at that time, but it also closed the antibiotic research and development center in 2011, which means the end of the mud era. Today, 15 of the worlds 18 largest pharmaceutical companies have completely withdrawn from the antibiotic market.

I should be the youngest group of people who have worked for the antibiotic project of a large pharmaceutical company. My experience of driving a van to search for soil samples in Chesapeake was for the antibiotic project. The earth age is coming to an end. I havent found any new antibiotics in the earth, but even if I can find them, I dont think I can enter into the stage of commercial production. I will only be put on the shelf by my boss.

Now, things are in jeopardy, according to Janet Woodcock, head of the FDAs Center for drug evaluation and research, the world is facing a huge crisis due to the lack of new antibiotics, and its not good now, and it could be worse in five to 10 years.. More than 23000 people die of bacterial infection every year in the United States, more than people die of AIDS every year. Antibiotics could easily kill these bacteria, but bacteria have developed resistance.

Alexander Fleming made one of the greatest inventions in human history: a special medicine that can cure many diseases. Unfortunately, the drug will fail and must be renewed as the bacteria mutate.

This article is selected by authorization of CITIC from some chapters of herbalist Hunter, which is abridged and modified compared with the original content.

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