Into Unscientific

"Targeted drugs?"

After Xu Yun said this somewhat weird word.

There was a moment of silence in the entire ward, and a needle could be heard in the room, obviously not understanding the meaning of these words.

But fortunately, this is not the first time that Lao Guo heard these weird new gadgets from Xu Yun's mouth, so he quickly came back to his senses:

"Targeted drug? Xiaohan, what is this?"

Xu Yun thought for a moment when he heard the words, but did not give an explanation directly, but turned his head to look at Lin Yu, and said:

"Doctor Lin, the concept of targeted drugs is rather complicated to introduce, so can I trouble you to talk about the current understanding of lung cancer in the medical community?"

Lin Yu nodded immediately:

"no problem."

As a Western medicine expert with overseas study experience, he still has a very detailed grasp of the information on lung cancer, and he quickly talked about it:

"Lung cancer is a disease that has gradually become common in recent years. The number of people suffering from it is less than that of gastric cancer every year, but the growth rate is very fast."

"The reason for its formation is still unknown. Ten years ago, a scholar across the sea proposed the idea that smoking causes lung cancer."

"But a few months before I returned home, a rebuttal called the birthweight paradox emerged, so how lung cancer develops is still a controversial topic today."

Xu Yun nodded slightly.

As a Ph.D candidate in biology at the University of Science and Technology of China, his supervisor is Tian Zhigang, a well-known immunologist in China, so he is no stranger to what Lin Yu said.

It is different from the later generations that Xu Yun traveled through.

In 2023, lung cancer will be the most common and the most deadly cancer among all cancers, known as the king of lung cancer.

There were 820,000 new cases in China last year alone, and 720,000 deaths, let alone the world.

But what few people know is.

More than 100 years ago, lung cancer was actually a very rare cancer.

1912.

Across the sea is a doctor named Emma Watson—yes, the doctor with the same name as Hermione who once mentioned one thing in a medical book:

He searched the literature all over the world, and only found 374 cases of lung cancer.

However, after 1920.

The incidence of lung cancer suddenly began to rise linearly, as if the Shanghai Composite Index had turned upside down.

For this reason, many experts began to pay attention to lung cancer, and found a certain relationship between cigarettes and lung cancer when they studied the cigarette machine across the sea.

Of course.

The reason why scholars can discover this situation is not because of their strong observation and judgment, but because the cigarette market is terrible these years:

Taking last year as an example, the per capita annual smoking across the sea last year was more than 4,000.

That's right.

4000 +.

This is like if you slap yourself more than ten times a day, then the doctor will definitely link the two when checking for kidney deficiency.

However, a "birth weight paradox" emerged across the sea a few years ago, making the relationship between cigarettes and lung cancer blurred a lot.

The rebuttal doctrine goes like this:

If smoking is harmful to health, maternal smoking will lead to low birth weight and infant mortality.

But according to the actual statistics, the scholars across the sea turned out to be just the opposite.

Babies born to smoking mothers have a lower mortality rate than normal babies.

Ever since.

There is another layer of fog between smoking and lung cancer, and no one knows whether the two are related.

This paradox will not be confirmed and explained until 2001, so it is normal for Lin Yu to be unclear at the moment.

Then Lin Yu paused and continued:

"After lung cancer has gradually become a common disease, corresponding treatment options have gradually begun to develop."

"In the 1940s, pneumonectomy was the classic surgical treatment for lung cancer. For example, in early 1941, Dr. Zhang Jizheng of Yanjing Union Medical College Hospital completed the first left pneumonectomy in our country."

"Nowadays, with the development of medical level, our operation has also changed from whole lung to lobectomy, and the scope is relatively much smaller."

"At present, we mainly divide lung cancer into small cell lung cancer and non-small cell lung cancer. Small cell lung cancer is not suitable for surgery, while non-small cell lung cancer is suitable for surgery."

"Of course, this sentence is also relative."

Xu Yun nodded and asked again:

"What about the in-depth study of the pathogenic structure of lung cancer? How far has it developed so far?"

"Disease-causing structure. Oh, you mean the structure of cancer cells?"

Lin Yu blinked when he heard the words, and this time his answer was much more concise:

"Lung cancer cancer cells have mastered the relevant cultivation techniques at home and abroad. After all, the cultivation of cancer cells has been successful fifty years ago, and it is not a big secret now."

"As far as I know, Yanjing has achieved the isolation of solid tumor stem cells using colony formation experiments, and has achieved certain results in the regulation mechanism."

"However, the research on cancer cells is nothing more than that. It seems that there are not many new discoveries even across the sea-at least what I know is the case."

After Xu Yun listened quietly, he looked up at the scene.

At this time, Li Jue still had an [OvO] face.

Lao Guo, Yang Kaiqu, and Zhou Cai all showed a little understanding, and seemed to have kept up with the rhythm.

So he coughed lightly, took over Lin Yu's right to speak, and said:

"Doctor Lin, have you ever shot a target?"

"Target?"

Lin Yu was startled for a moment, and immediately raised his chest:

"Of course I did."

joke.

These people at the scene counted as one, even if it was Li Jue's assistant Zhou Cai and the terminally ill Yang Kaiqu, they had hit targets before.

The popularity of the militia is very high these days, and even the number of civilian guns is quite large.

It is not uncommon for those who have shot before, but it is rare for those who have not.

Then Xu Yun gestured the shapes of several targets in the air with both hands, and said:

"Doctor Lin, since you have shot a target, you must know the process of shooting a target."

"When shooting a target, there will be many targets standing on the range. You can only hit the one that is facing you. If it is crooked, you will not be scored or deducted."

"In the microscopic field, if we regard the tumor as a shooting range, then its interior can obviously be divided into many target areas."

"For example, the bilateral and unilateral RB characteristics proposed by Peter Armitage in 1953, and the Ph chromosome site discovered by the University of Pennsylvania four years ago, etc."

Looking at Xu Yun who talked eloquently.

Lin Yu, who has three overseas doctorate degrees, was suddenly taken aback. Immediately, he realized something and couldn't help but interrupt him:

"Wait, Comrade Han Li, the targeted drug you mentioned."

"Isn't it referring to the 'bullets' that target cancer cells and then precisely destroy them?"

Snapped!

Xu Yun immediately snapped his fingers and said with a smile:

"Doctor Lin, your statement is not completely correct, but it is very close to the concept of targeted drugs."

"However, the concept of targeted drugs in a broad sense is not to destroy cancer cells, but to curb the growth of cancer cells after hitting key nodes."

"Just like a bullet, when a bullet hits a person, it doesn't immediately empty your blood bar. Keke, life, but destroys blood vessels to deactivate your body."

Lin Yu's pupils shrank suddenly.

WTF?

A targeted drug that curbs the growth of cancer cells?

And something like this?

Then he suddenly stood up from his seat, walked quickly to Xu Yun and asked:

"Xiao Han, what is the specific biological mechanism of the targeted drug you mentioned? What about the ingredients? What about the production process?"

Hearing this set of questions in Lin Yu's mouth three times, Xu Yun couldn't help but smile.

It turns out that Lin Yu, a cold-faced boss who looks like a paralyzed face, also has emotional moments

Then he took a deep breath, made an urgent gesture to Lin Yu, and explained:

"Doctor Lin, I just came across the idea of ​​this targeted drug in a book when I was in Europe. The author's name is Ling Ran. So I really don't know much about the specific ingredients and process."

"It's just a biological mechanism. Basically, this drug can act on specific protein molecules, enzymes, and gene fragments through certain reactions."

"After all, cancer cells are produced due to gene mutations, so in theory, there should be some rationality in targeting the mutation site."

"Act on a specific gene segment?"

Lin Yu's pupils shrank again when he heard this, but this time he was not in a hurry to speak out.

Gene.

This is an extremely mysterious and extremely front-end field.

Humans discovered cells very early. As early as the 17th century, Hooker, who fell in love with a calf, discovered cells.

Then in 1836.

Valentine discovered the nucleolus in the nucleus of connective tissue cells, which opened up the study of intracellular structures.

Then came the cell theory of Schleiden and Schwann, Mendel's laws of genetics, Weirshaw's pathology and so on.

Then came the end of the 19th century.

Centrosomes, mitochondria, chromosomes, and Golgi bodies have also been discovered successively.

But the concept of DNA, or gene, was first introduced in 1924.

At the same time, wait until 1944.

Avery and others confirmed that the transformation factor of pneumococcus is DNA, and it was the first time that the gene was determined to be a DNA fragment with genetic effects by experiments.

As for the structure of DNA?

It has only been out for eight years, and it belongs to a brand new field.

So in this day and age.

The word gene is not completely unfamiliar to medical scientists like Lin Yu, but it is extremely mysterious, like an abyss.

But on the other hand.

It is precisely because of the mysterious anomalies in the genetic field that Lin Yu is not sure whether what Xu Yun said is true or not.

after all

In the more general medical field, many drugs have been used in cytotoxic chemotherapy these days.

For example in 1948.

Farber used the antifolate methotrexate to treat acute lymphoblastic leukemia, which opened the prelude to modern cancer chemotherapy.

Since then, with the research and development of anticancer drugs, chemotherapy drugs have also been developed rapidly.

Up to now.

Chemotherapy drugs that have been discovered and used include a large number of categories such as fluorouracil, 6-hydroxypurine, methotrexate, cyclophosphamide, and actinomycin D.

And if Lin Yu remembers correctly.

Internationally, there is a saying about the mechanism of action of these drugs:

The function of these drugs is to interfere with DNA integrity, interfere with DNA replication, act on microtubules in the mitotic spindle, and inhibit mitosis.

Thereby preventing the proliferation, invasion and metastasis of cancer cells until finally killing the cancer tissue.

Indeed.

This mechanism is not consistent with the targeted drug mentioned by Xu Yun, but it is somewhat similar in nature, both of which act on the point in the cell.

So if you think about it from this angle.

Not to mention whether the current technical level can do it, this idea may be true.

Not a big problem?

Of course.

This is just a possibility.

Then Lin Yu adjusted his glasses, regained his original composure, and said to Xu Yun:

"Comrade Han Li, I personally reserve my opinion on the mechanism you mentioned. At least for now, I really can't think of any reason to refute it."

"However. The idea is the idea. For now, we want to implement it in the application. That is, to produce a finished product. It seems that it is not possible at all, right?"

I heard this.

Lao Guo on the side also nodded subconsciously.

Although he is not an expert in biology, he has a very good relationship with Liu Youcheng in the chemical laboratory of the base in private.

When he went to the laboratory for a few days, there happened to be a student who saw some papers about genes in a foreign language journal and asked Liu Youcheng for advice.

At that time, Liu Youcheng's answer was that genes belonged to an undeveloped land, and even the top foreign institutions were still in the situation of half research and half guessing, and the proportion of guessing was even larger.

But facing Lin Yu's question, Xu Yun seemed very calm:

"That's right, Dr. Lin, the production technology of targeted drugs is very difficult and involves many special links."

"But... again, if we want to make a simplified version of targeted drugs, I think it is still feasible."

Xu Yun bit the three words "simplified version" very hard.

well known.

Even in 2023, when Xu Yun travels through, lung cancer is still a terminal disease with a very high mortality rate.

Perhaps some people can live for a long time because of personal physical problems, but at least in the popular field, lung cancer is still somewhat unsolvable.

But on the other hand.

Although lung cancer has developed to the middle stage, there is almost no possibility of radical cure, and the survival probability of most patients is very low.

However, if you want to suppress the disease to a certain extent, it is still possible to add a few years to the patient's life span.

This may be targeted therapy.

Generally speaking.

Even for patients with advanced lung cancer, the use of targeted drugs has the opportunity to live for three to four years or even longer.

The so-called targeted therapy is a treatment method aimed at the cancer-causing sites that have been identified at the cellular molecular level.

The site can be a protein molecule inside the tumor cell, or a gene fragment.

When the targeted drug enters the body, it will specifically bind to the cancer-causing site and cause the specific death of tumor cells without affecting the normal tissues around the tumor.

The origin of targeted drugs can be traced back to 1960, when the biological laboratory of Philadelphia University discovered a chromosomal abnormality associated with many leukemia patients.

Ten years later, when a biomedical scientist named Compli was studying this subject, he discovered that this abnormality occurs when a part of the two chromosomes 9 and 22 translocates.

And this abnormal part was the target of imatinib, the first targeted cancer therapy drug.

Of course.

The source of targeted drugs can be traced back to the current period, but the development of technology is generally after the 1980s or even the 1990s.

Therefore, it is completely wishful thinking to produce a complete targeted drug with the current technology-at least in the short term.

but

Xu Yun thinks it is still feasible to make a simple beggar’s version if you don’t want standard targeted drugs.

after all

He laid a foreshadowing at the beginning.

Think here.

Xu Yun paused again, and continued to explain:

"Targeted drug Targeted drug, we can actually divide this word into two parts, one is targeted, and the other is drug."

"This is somewhat similar to our Zhuxianjian missile. The target is the laser guidance and waverider structure, and the explosive is the warhead and the warhead."

Lao Guo and Lin Yu nodded, the metaphor is very clear.

Then Xu Yun raised a finger, swayed slightly left and right, and said:

"Let's talk about the easier part first, which is the 'dynamite' needed."

"According to the manuscript I saw at the beginning, the most suitable ingredients for targeted drugs should be monoclonal antibodies or small molecule compounds, which are mainly formed through some complex reactions."

"For example, using N-methylindole and dichloropyrimidine as the starting materials, a compound is synthesized through a sylation reaction of a certain substance, and then proceeds to the next step of synthesis."

"But this kind of synthesis is still difficult for us at present. After all, the derivation of ingredients is not something that can be done in a day or two or even a year or two."

"However... I once saw a record in the handbook of Fenglingyueyingzong, saying that hundreds of years ago, someone suffered from 'congestion of the lungs' and was 'almost dying'."

"Later, he accidentally got a folk prescription. He asked someone to bring a wood-boiled decoction from Longyou Road. He decocted it twice a day and finally lived for more than a year."

"So I think if we can find that wood and use it as a prodrug for reference research, there may be a chance to find a suitable targeted drug formulation."

"?!"

Hearing Xu Yun's words.

Old Guo on the side suddenly couldn't sit still, and asked quickly:

"Xiao Han, what is that kind of wood called?"

Xu Yun glanced at him and gave the answer:

"Yew."

yew.

This is a general term for a yew plant, which belongs to an excellent ornamental shrub, also known as yew, also known as yew.

In Xu Yunlai's later generations, it belongs to the national first-class rare protected plants.

But what few people understand is.

The real value of yew is not its ornamental value, but its medicinal value.

Generally speaking.

Most herbal plants can basically produce secondary metabolite derivatives after treatment, that is, extracts.

For example, the extract of aloe vera is very suitable for making facial masks, and the extract of milk thistle is the main ingredient of liver protection tablets, etc.

The same is true of yew, but its extract is

Paclitaxel.

That's right.

Paclitaxel.

This is an anti-tumor active ingredient isolated from the bark of Taxus brevifolia, and it is one of the best drugs for the treatment of metastatic ovarian cancer and breast cancer.

At the same time, it also has significant curative effect on lung cancer and esophageal cancer, and has obvious inhibitory effect on nephritis and parvovirus inflammation.

In general.

About 13.6kg of bark can extract 1g of paclitaxel, and it takes 3-12 yews of more than 100 years to treat a patient with ovarian cancer.

Therefore, the price of this substance has become very high and it has attracted a large number of humans to cut down yews, making the yews that were originally scarce even more scarce and on the verge of extinction.

Of course.

Paclitaxel is a chemotherapeutic drug in nature and is not a conventional targeted substance.

However, some of its structures and characteristics—such as hydrophobic groups, 2'-OH or 7-OH design sites—are very similar to targeted drugs in some respects.

Actually.

The main difference between chemotherapy drugs and targeted drugs is that chemotherapy drugs act non-selectively on actively growing cells, killing cancer cells and also killing normal cells.

Targeted drugs, on the other hand, selectively act on tumor cells.

In addition, the application of chemotherapy drugs is generally determined according to the results of histopathological specimens, while the application of targeted drugs needs to be determined according to the results of genetic monitoring of histopathological specimens.

Some sense Attention is a certain sense.

The difference between chemotherapy drugs and targeted drugs is actually equivalent to an atomic bomb and a neutron bomb.

Atom bombs and neutron bombs are obviously not the same weapon, but they have something in common in some deep aspects.

And once there is paclitaxel as a sample.

Then the task of the rabbits has changed from pure research and development without any reference to the direction of converting chemotherapy drugs into targeted drugs.

True.

Xu Yun can't say how effective this method will be, but at least it is easier than developing a new drug.

For example, the example he gave before is the synthetic route of osimertinib mesylate:

Using N-methylindole and dichloropyrimidine as starting materials, an intermediate product was synthesized by Friedel-Crafts alkylation reaction catalyzed by aluminum trichloride.

Then p-toluenesulfonic acid and the intermediate product were heated to reflux in 2-pentanol to obtain the intermediate product 2.

Condensation with secondary amines in a microwave reactor gave intermediate 3, followed by nitro reduction to give intermediate 4.

Then condense with 3-chloropropionyl chloride to obtain intermediate product 5, and finally dehydrochloride to form mesylate to obtain osimertinib mesylate.

In this step, more than 80% of the substances cannot be produced by the current scientific and technological means, let alone the required microwave reactor and the like.

Therefore, Xu Yun could only find another way, starting directly from the structure.

After all, there are many paclitaxel-based targeted drug papers in later generations, such as 10.1186/S13578-023-01004-6, which Xu Yun was very impressed with, about 90% of the primers and ingredients needed are already known in the chemical community. developed.

The remaining 10% Xu Yun can find opportunities to guide it out, at least it is much simpler and more reasonable than producing 80% of the substances that do not exist today.

Of course.

One of the reasons why Xu Yun remembers this paper is that it contains tamofin in its primers,

This is known as the birth control pill.

But this is also normal.

After all, the early use of tamofen is to hinder the function of estrogen, thereby inhibiting the proliferation of breast cancer cells, which is very suitable for the treatment of breast cancer and adjuvant therapy after breast cancer surgery.

"Is it the yew from Longyou?"

Old Guo heard this and looked at Li Jue subconsciously, Li Jue nodded quickly:

"No problem, didn't we cooperate with the comrades from Longyou once before, and we can just ask them to help find the yew."

Hearing what Li Jue said about cooperation, Xu Yun couldn't help but smile.

What Li Jue was referring to was the fishing trip when he attacked U2, that is, the arrest of the enemy agent who had the pseudonym Chen Wenliang and was surrounded by rabbits acting.

The place where this incident happened was in Jinta County, Longyou. Since Chen Wenliang's identity belonged to a very dense long line, the 221 base and the local forest political commissar could directly communicate.

If you can find yew, just ask the comrades over there to send it over.

Then Lao Guo looked at Xu Yun again and asked:

"Xiao Xu, what about paclitaxel? How do you solve the problem you mentioned?"

"Target"

Seeing this, Xu Yun pondered for a moment, then said to Lao Guo:

"Guo Gong, do you still remember an idea I offered when discussing rice hybrid technology?"

"idea?"

Old Guo was slightly taken aback, and said in surprise:

"what idea?"

Hearing this, Xu Yun picked up the pen on the table, wrote a big R and a small r, and shook it in front of his face:

"At that time, I mentioned an idea of ​​screening high-quality genes, which involved the introduction of the pollen lethal gene R."

"That is to use polyacrylamide gel electrophoresis to determine the size of the fragments present in each base reaction."

"Then the DNA fragments are separated by single-base resolution, and a labeled gel for each base is placed on X-ray film, and some data can be measured."

"This belongs to the category of DNA sequencing. If we further optimize it, we can realize the .PCR technology." (Note: See chapter 581. I have been burying the foreshadowing for a month. Can some people stop writing before I finish writing it? It’s unreasonable to say that it’s unreasonable to engage in targeted drugs. I co-authored the foreshadowing that I didn’t pay attention to it, and then I didn’t pay attention to it, and then I died inexplicably. Originally, everyone was happy when the foreshadowing was received, but now I’m depressed)

That's right.

PCR technology.

As early as when he was communicating about hybrid rice, Xu Yun had already planted the foreshadowing - it's just that he didn't expect to use this thing to make targeted drugs at the beginning, because he still lacked something to make PCR.

But after the rabbits reached a cooperation intention with Germany, Britain and France, this technology has the possibility of appearing in the world in the short term.

This can be regarded as unintentional insertion

And also because of this.

Xu Yunfang dared to throw out the concept of targeted drugs, otherwise he could have chosen a less efficient but more feasible chemotherapy regimen.

And the other side.

Hearing Xu Yun's words "pollen lethal gene", Lao Guo quickly remembered what Xu Yun was referring to.

At that time, Yuan Guoliang and Hou Guangjiong had just arrived at the base with wild rice. While chatting with Yuan Guoliang, Xu Yun mentioned the concept of introducing the pollen lethal gene R into hybrid rice.

At that time, Hou Guangjiong expressed on the spot that there might be technical problems, but Xu Yun proposed a DNA sequencing plan on the spot.

Afterwards, Liu Youcheng took the laboratory members to do a simple test analysis. After the results were obtained, Liu Youcheng only said one sentence to Lao Guo:

"There's a lot to be done about this!"

Think here.

Lao Guo also understood Xu Yun's thoughts:

"Xiao Han, you mean to use DNA sequencing to find the target of targeted drugs?"

Xu Yun nodded:

"That's right."

But after getting his affirmation, Lao Guo's brows still did not loosen, but tightened even more:

"It seems to be feasible, but Xiao Xu, since we are looking for targets, we must observe and compare the cells, right?"

"The cells of ordinary people are easy to say, but the cells of tumors."

Speaking of which.

Old Guo couldn't help but look at Yang Kaiqu who was at the side.

Biological experiments need a control group, which is something he knows as a physicist.

But ordinary human cells are easy to say, and more than 10,000 people in the base can collect them at will.

Even if necessary, he Lao Guo is willing to be the first guinea pig.

But the problem is that it is more difficult for cancer cells, because there is only one lung cancer patient, Yang Kaiqu, in the base.

Whether it is blood drawing or surgical collection, it is very harmful to him, and Yang Kaiqu's current situation simply cannot afford this kind of procedure.

There may be many cancer patients in the capital, but it is obviously not appropriate to use other people's cancer cells for observation, and it is impossible for Yang Kaiqu's character to accept this plan.

However, just as Lao Guo frowned.

Xu Yun's voice sounded beside him:

"Er Guogong, I'm afraid you are thinking wrong, our goal is actually not that complicated."

"After all, what we want to verify is the ability to detect cells, that is, compare two cells with different known points, and then find out the biological abnormalities of the points."

"For example, we can see with the naked eye that the pen is thicker than the ballpoint pen. What the experiment needs to do is to be able to confirm this matter through the measurement results - that is, it must be able to measure that the pen is 1 cm and the ballpoint pen is 0.5 cm. Ability."

"However, this kind of comparison cells does not have to be collected from the human body, as long as there are known obvious differences."

Old Guo was slightly stunned for a few seconds when he heard this, but soon realized what Xu Yun was talking about:

"Xiao Han, what do you mean?"

Xu Yun nodded vigorously, affirming his guess:

"That's right, it's the local donkey."