As a mage, I just want to pursue the truth

Chapter 272 Biological Small Molecule Drugs (ask for monthly tickets!)

The pressure of doing R&D under Zheng Li is enormous because he knows this industry so well.

The boss is the person who knows the most in the entire R&D field. You cannot fool him about the R&D progress, R&D difficulty and R&D ideas.

For example, Li Wanqing didn't dare to fool Zheng Li at all. He always reported on his work based on the actual situation, including what he had done, what he had not done, and how the progress was.

Among them, Kechuang Biopharma has two small molecule drugs that will undergo clinical trials this year. The project leader of one of them is Wang Jinsong, who is considered to be a relatively early researcher in the company's field of innovative drug research and development.

He and Cheng Gang are alumni, but not from the same class.

When Kechuang Biopharma went public, its prospectus stated that it aimed to develop original drugs. After the company was successfully listed, Wang Jinsong joined Kechuang Biopharma.

He had been at Merck before, from Merck's headquarters in New Jersey to Merck China.

The reason I came to Sinovation Biopharma is that there is almost no room for upward movement in Merck.

As for Kechuang Biotechnology, Cheng Gang is in charge. Kechuang Biotechnology has a very new history, abundant cash flow, and the founding team seems ambitious and has many opportunities.

So after leaving Merck, Wang Jinsong joined Sinovation Biopharma, where he was responsible for the research and development of small molecule drugs.

After joining the company, you will select a topic and then start a research and development project.

Wang Jinsong originally thought that Zheng Li didn’t know much about the research and development of small molecule drugs.

First of all, we need to popularize a concept, that is, drug research and development is divided into many fields, mainly divided into chemical small molecule drugs and biological macromolecule drugs.

Endorphins are biological macromolecules and substances that exist naturally in living organisms. It was only Zheng Li who developed the manufacturing process for endorphins.

Biological macromolecules have larger molecular weights and more complex structures, with molecular masses generally ranging from 1500 to 150000.

The molecular weight of small molecule drugs is generally between 200-700.

Historically, from the discovery of penicillin in the 1982s and s until , all drugs in the modern medical sense were small molecule drugs.

Penicillin is also a small molecule drug.

The first truly large molecule drug was launched on the market in 1982.

The reason for this phenomenon is that the means of determining the structure of small molecules only require nuclear magnetic resonance hydrogen spectrum and carbon spectrum and LCMS to achieve relatively good results.

The methods for measuring the structure of large molecules are often more complicated.

The measurement of biomolecules requires higher precision and sensitivity than that of small molecules.

Of course, this does not mean that the research and development of biological macromolecules is absolutely higher than that of small molecule compounds.

The most important means of modern small molecule drug development is screening.

To screen, first you need a sieve, and secondly you need a library with enough things for you to screen. Then you need to know what these things in the library are and what they look like. Finally, you need to be able to mass-produce the things you screen out.

In recent years, new methods have also emerged. The small molecule drug research and development of Ke Chuang Biotechnology adopts new technical means.

But historically, especially in the 90s when the pharmaceutical industry was booming, screening methods were the mainstream.

Screening refers to experiments based on various disease indicators, where small chemical molecules are put into corresponding experiments to see which ones are effective.

The so-called library refers to the molecular library, which was created due to the rapid development of organic synthesis methods in the 1970s and 1980s.

A large number of complex, stable, heterocyclic molecules that were originally difficult to synthesize began to appear in large quantities.

The advancement of detection methods such as nuclear magnetic resonance and mass spectrometry has led to the successful separation of many natural products, which in turn has promoted the synthesis of other types of molecules.

Therefore, by the 1990s, there were millions of different types of small molecules in the molecular libraries of various pharmaceutical companies.

The development of biotechnology during this period has led to the discovery of some important disease indicators and targets.

These discoveries enabled biopharmaceutical giants to use the millions of small molecules they had to screen these diseases and targets, leading to an explosion of new drugs in the 90s.

The gap between China's biopharmaceutical companies and the world's pharmaceutical giants was mainly widened during this period.

While others are doing targeted analysis, China is making slow progress in this area.

There is a piece of data that can indirectly prove this, that is, in 1985, China began to implement a new drug registration method.

From 1985 to 2008, China approved only five new class I drugs in a total of 23 years.

Wang Jinsong first heard the name Zheng Li in Nature when he was still at the Merck headquarters.

At that time, many people inside were discussing the laboratory preparation method of endorphins that was developed by a Chinese.

Wang Jinsong was amazed by the ingenious experimental design. Later, when he learned that he was still a freshman or even in the School of Mathematics, he became skeptical.

The more people in the industry are involved, the more they understand the difficulty of developing biomacromolecule drugs, even if the biomacromolecule is a polypeptide substance that exists naturally in organisms.

But if a substance discovered in the 1950s was so easy to manufacture, how could it be left for you to discover?

Wang Jinsong read in historical documents within Merck that in the 1980s, a research and development team within Merck spent two years failing to solve this problem.

Later, I got to know Zheng Li. It was Zheng Li who developed an industrial-scale manufacturing method for endorphins. Ke Chuang Bio started patent licensing negotiations with major international pharmaceutical companies regarding endorphins.

Only then did Wang Jinsong believe that there was such a genius in the world.

Because it is possible to buy a Nature paper, but it is impossible to buy an industrial manufacturing method from others.

Especially after the clinical data of endorphins came out, they were able to almost squeeze out morphine-like drugs without any chance of fighting back.

No one would be generous enough to give up such a huge benefit.

Later, Wang Jinsong joined Kechuang Biotechnology, and not long after he joined, Zheng Li went to Singapore.

However, every time he had a remote video conference, Zheng Li’s views and ideas on small molecule drugs would give him a feeling of enlightenment.

“Dr. Zheng, we plan to use the dual fluorescence cell cycle reporter system to mark the mitotic S-G2-M phase of cells and then display cytokinesis.

In addition, a high-throughput screening system was constructed to screen out 13 small molecules from the chemical small molecule library that can effectively induce cardiomyocytes to enter the cell cycle.

Except for the MCT1 inhibitor, other single small molecules cannot induce cardiomyocyte cytokinesis.”

“You can try to use small molecules in combinations of two or more to verify the efficacy.

Also remember to build a mathematical model to predict the best combination of small molecules for promoting proliferation. I will send you a mathematical model I built earlier, and you can refer to my design ideas. "

Wang Jinsong and his group mainly plan to develop small molecule drugs for cardiovascular diseases.

Later, Wang Jinsong and his colleagues followed Zheng Li's idea and verified through in vitro and in vivo experiments that the small molecule combination 1SM, composed of phenylephrine hydrochloride, baricitinib, dehydrogenated echinopsine, PTEN inhibitor and MCT5 inhibitor, can successfully induce adult mouse and human cardiomyocytes to re-enter the cell cycle and undergo cytokinesis.

In other words, it can promote heart regeneration and treat myocardial infarction.

(The above research ideas come from a paper published by the School of Chemistry and Molecular Biology of Yenching University in a CELL journal in April this year:
"A small-molecule cocktail promotes mammalian cardiomyocyte proliferation and heart regeneration")
They then established a mouse myocardial infarction model and found that 5SM can significantly improve cardiac function and reduce the area of ​​cardiac fibrosis in adult mice after myocardial infarction. Wang Jinsong and his team found that 5SM induced quiescent cardiomyocytes to enter a dedifferentiation state and then a proliferation state.

5SM promotes the conversion of cardiomyocyte metabolism from oxidative phosphorylation to glycolysis by activating lactate signaling and the mTOR pathway, ultimately inducing cardiomyocyte proliferation and division.

Zheng Li's understanding of small molecule drugs is even better than his.

This made Wang Jinsong question his life.

You have to know that he started studying biology as an undergraduate, and it took him a total of seventeen years from undergraduate to postdoctoral studies. He then worked at Merck for another eight years. He has spent more than twenty years in the research and development of small molecule drugs.

But the facts are before him. Zheng Li can also think of what he can think of, and Zheng Li can still think of what he cannot think of.

Whether someone is truly great or not in the field of scientific research can be easily known through communication.

The data in a paper can be falsified, and one can find ways to put someone else’s name on the paper or make it a watered-down paper, but there is no way to take shortcuts in communication.

"Mr. Li, the clinical trial plan for this drug has been reported to Mr. Zheng, and Mr. Zheng has agreed. Now we need your help to review and approve the budget plan."

When Wang Jinsong was reporting to Li Miaomiao, he said that the way one addresses Li Miaomiao can generally tell how close one is to her.

Generally, middle-level and senior executives who have a close relationship with Li Miaomiao will call her "General Miaomiao", while those who have a distant relationship with her will call her "General Li".

Wang Jinsong was actually recruited by Cheng Gang. He did not leave because the project was not completed and the company wanted to retain him.

But in fact his position is rather awkward.

Li Miaomiao replied: "Okay, leave the file there and I will take a look at it later. Also forward me a copy of Zheng Li's reply to you."

All matters, big or small, related to internal R&D at Ke Chuang Bio are decided by Zheng Li, while all other financial, personnel, sales, manufacturing and other work are the responsibility of Li Miaomiao.

Of course, Li Miaomiao will also distribute work to other senior executives. She mainly focuses on personnel and finance.

As long as there are no problems with people and money, the company can maintain a relatively healthy state.

Of course, Zheng Li is in charge here only in the eyes of outsiders. In fact, Zheng Li has handed over most of the work to artificial intelligence.

Only a few tasks that artificial intelligence cannot decide will be judged by Zheng Li personally.

"Okay, Mr. Li, our innovative drug research and development department will have an overall briefing next Monday. Director Wu asked me to invite you to attend. Are you free from 9:30 to 11:00 next Monday morning?"

Li Miaomiao: "Send me your schedule through the internal OA. If I am free tomorrow, I will confirm it before Monday."

Every time Wang Jinsong reported his work to Li Miaomiao, a sentence always flashed through his mind: Choice is more important than hard work.

However, having been in the workplace for so many years, Wang Jinsong knows that he has to accept these things. The world is inherently unfair, and has never been fair. Luck is also a kind of ability.

"There have been a lot more unusual incidents in London recently. We need to intensify our search efforts."

“This is not a question of search intensity at all, but when everyone can learn magic, our management methods need to change.

In addition, the anomaly in London is still at a three-digit level. If this level goes up, the anomaly in London can no longer be concealed. "

"The anomaly in London could not be concealed. Major countries like America, China, Russia, etc. all knew what they should know.

We now need to decide whether or not to issue a temporary control order, otherwise there will be more and more magical incidents, and sooner or later the situation will be out of control.

The number of human reviewers on social media platforms such as FB, Twitter, and Instagram has increased more than tenfold compared to the end of last year, all in an effort to conceal the truth from the public.”

“No, no, no, we are not trying to hide the truth, but to maintain the safety and stability of the city.

If people knew that everyone could learn magic and that spells could only be cast in London, there would be chaos.

People from the entire European Union and even Blue Star will gather in London.

All the people in London will lose interest in work and only want to learn magic."

“I am more optimistic than you. It will only have an impact in the short time after the news is released, but in the long run we will return to a stable state.

Well, maybe there will be some ups and downs and turbulence.”

“There are more and more people in London who can cast spells. If we keep hiding it, there will be a day when we will be unable to conceal it.

We need to make a decision as soon as possible, especially the staff around us. After knowing the existence of magic, many of them have privately contacted the captured spellcasters in various ways, trying to learn magic.

In just two months, more than twenty staff members were internally audited for this reason.”

This is a conversation that took place in England's intelligence agencies.

At this time, three months had passed since Zheng Li set up the magic net in London.

During these three months, more and more people learned magic, and some tried to teach it to their relatives and friends, and many of them succeeded.

English officials found themselves losing control of the situation.

The specific reasons for the suspension of flights in London and the detour of routes have been communicated to major countries through the European Union in London.

They are now struggling with whether to disclose the real reason.

Because the London Magic and Magic Coin systems are completely different, the threshold is too low.

Anyone can learn it, the only difference is the power.

The English government believes that this is a talent, and those who can rely on themselves to obtain magic-related information are considered to be highly talented. Facts have proved that their spellcasting strength is indeed higher.

Most people who learn magic from others have very weak spellcasting abilities, which are almost no different from those of ordinary people.

"Of course, we can announce the truth, but have you thought about the consequences of announcing the truth?

It will not only cause short-term chaos, but chaos is acceptable to the bigwigs above and even in the European Union.

What they couldn't accept was that if the current situation in London was caused by a powerful magical artifact, and the riots caused by our announcement of the cause led to the loss of that magical artifact.

This is a consequence that none of us can afford.”

“The question is, isn’t it possible for magical creations to be lost now?
I think the sooner we reveal the truth and control the situation, the better it will be for us.

At present, the American side has publicly hinted that something is wrong in London."

CNN and FOX, two representative American media, have sent special program teams to London.

The pretext was to make a documentary promoting London.

Everyone present here knows the real purpose.

This chapter contains a lot of professional content. Compared with the previous ones, I have tried my best to compress the content of this part, but sometimes some professional content is needed to make the novel more realistic. Please forgive me.

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(End of this chapter)