They’re all reborn, what’s wrong with being a little more almighty?

Chapter 152 Moving forward towards the Nobel Prize!
Although Zhang Weiming knew that nucleoside modification was the core achievement of his project, when the new project started, Zhang Wei did not immediately conduct experiments on nucleoside modification.

The first reason is that the three graduate students who are coming are all second-hand students and have not done many complex experiments. So Zhang Wei could only give them some time to practice their skills first.

Fortunately, those who can enter Tsinghua University for graduate school are all top academics, with extremely strong learning ability, and are quick to master experimental operations. Even complex experiments can be mastered after a little practice. Although not as skilled as a veteran, it will not affect the experimental results.

The second reason is that if you conduct nucleoside modification experiments from the beginning and then produce results, wouldn't that obviously arouse suspicion?

Other scientists have to study for several years and conduct hundreds or thousands of experiments before they can discover something from a certain experiment and finally explore the results.

Fortunately for you, at the beginning of the project, you did an experiment and it produced results. It seems like you already knew that this experiment would produce results, so you went for it.

This kind of thing can't be explained clearly even if the whole body is full of words! Even if you say you are lucky, no one will believe it!

The previous research results on graphene can be said to be good luck. After all, there is only one experimental idea, and that is to stick it with tape. If you stick to the thinnest layer, graphene will always stick out.

But the result of this project is the impact of nucleoside modification on RNA. What impact does nucleoside modification have on RNA? There are several impacts. Which impact is Nobel Prize-worthy? No one knows until the experimental results come out.

Therefore, there are many experimental routes for this experiment. If you don’t do other experiments and just go for the Nobel Prize-level experimental route, this cannot be explained by luck. It is clear that there is something wrong with you!

"That's right. These days, the types of experiments we do are usually not our turn." Ma Jijun said.

Therefore, Zhang Wei can only do some experiments that are destined to be fruitless first to make up the numbers, and it will become more reasonable when the results are produced.

Now that the three graduate students have been trained and the preliminary preparations have been completed, they can finally start making nucleoside modifications.

In the laboratory, before Zhang Wei arrived, the three graduate students looked at the new experimental materials and began to discuss the next experimental plan.

Liu Xuetai shook his head: "He only said to change the idea of ​​​​the experiment, and then asked me to prepare these things. He didn't say anything else. But I thought, no matter what I do, just practice the experimental operation."

……

"Can we complete so many experiments?" Liu Qian asked.

"Zhang Wei said he wanted to change his experimental ideas. What did he specifically say he wanted to do?" Ma Jijun asked.

"The list of materials also includes phosphokinase, adenosine triphosphate, acetyl coenzyme, uridine diphosphate glucose, and glycine-arginine-rich proteins... If it is just a methylation experiment, we should not need so many things!" Liu Xuetai said. .

I went back and took out the experimental records. Didn't you declare the inhibition of RNA recognition by Toll-like receptors before? Why do you do nucleoside modification in the first place? This alone cannot be explained.

Participating in Zhang Wei's project, although there is currently no sign of any results, it is still quite good that the experiment can meet this point. At the very least, it will be a stepping stone for me to accumulate a wave of proficiency in experiments and do projects with other professors in the future.

Starting today, we have changed our thinking, and this project has turned a new page. Next, we will conduct modification experiments specifically on nucleosides, starting with mRNA! "

Even if someone checks the experimental records in the future, Zhang Wei can still say that I did some experiments before but did not get any results, so I decided to change my experimental ideas. Who knew that the new ideas would actually produce results!
During the project process, it is normal to change ideas. Many scientific research results are achieved through repeated failures, sudden inspiration, and then change of ideas, and they are successful.

……

Nucleosides are the building blocks of nucleotides, and nucleotides are the basic structural units of RNA. That is to say, nucleosides can be regarded as one of the more basic components of RNA.

Zhang Wei's voice sounded from behind, and he also came to the laboratory.

Zhang Wei continued: "We are still in the running-in period for the experiment some time ago, and no results have been produced, so don't feel discouraged, let's just treat it as a practice.

"If we were just doing methylation experiments, we wouldn't be able to use so much, so we would have to do phosphorylation, acetylation, glucosylation, and pseudouracilization all at once."

"There are experiments to be done, how can it be too little!" Liu Xuetai said immediately.

"Why, there are so few opportunities for you to do experiments? In other project teams, there are not so many opportunities for experiments!" Zhang Wei said with a smile.

Liu Qian, the only female graduate student, took the list of materials, glanced at it, and said: "There is S-adenosylmethionine. I remember that this thing can be used for methylation experiments. Could it be that it is used for Toll-like receptors?" Methylation?”

There are many types of RNA, such as mRNA, tRNA, rRNA, lncRNA, snRNA, etc. Each type of RNA has different functions. Some are responsible for transcribing DNA information, some are responsible for transporting DNA information, and some are responsible for regulating gene expression.

Among them, mRNA, also called messenger RNA, is responsible for transcribing and transmitting DNA genetic information in the nucleus to the cytoplasm.

Let's take cooking as an example. If DNA is the recipe, ribosomes are the cooks, and RNA is responsible for copying the content of the recipe and passing it on to the cook, then mRNA is equivalent to the content of the menu copied from the recipe.

If the mRNA says scrambled eggs with tomatoes, then the cook will make scrambled eggs with tomatoes. If the menu says hot and sour shredded potatoes, then the cook will make spicy and sour shredded potatoes.

In other words, ribosomes produce the proteins needed by cells based on the information on the mRNA.

After understanding this principle, an idea was born in the scientist's mind. If mRNA can be edited, does it mean that the ribosome's protein production can be controlled?

In other words, although I copied scrambled eggs with tomatoes from the recipe, I wanted hot and sour shredded potatoes, so I replaced the mRNA with hot and sour shredded potatoes and sent it to the cook. Then the cook made hot and sour potatoes. Silk. And if this technology can succeed and allow humans to control what kind of proteins cells produce, it means that humans will conquer most diseases.

For example, in some people with diabetes, the pancreatic islets no longer secrete insulin. At this time, the mRNA can be modified to allow the ribosomes to produce the proteins needed to secrete the pancreatic islets. Then won't the function of the pancreatic islets be restored?
For another example, for patients with heart disease, the mRNA can be modified to generate growth proteins that repair heart tissue, and the heart disease will also be cured.

So starting in the 1990s, humans began to study the technology of synthetically editing mRNA.

But there is one biggest problem that needs to be solved in this research, and that is Toll-like receptors, which are the most basic defense mechanism of cells. The mRNA synthesized by humans is always affected by Toll-like receptors.

In other words, before the synthesized mRNA reaches the target cell, the cell's immune response occurs, and then the immune response destroys the mRNA that does not originally belong here.

To put it simply, a security guard found something wrong with the menu that was delivered, so he tore it up and even beat the person passing the menu to death, so that the menu would not be sent to the kitchen and neither would the cook. Made the wrong dish.

This problem has not yet been completely overcome, restricting the application of mRNA.

It was also because the immune system could not be bypassed that the project had no substantive results. The scientists studying this project were once forced to interrupt their research due to lack of funds.

It was not until later that I cooperated with another scientist and obtained funds from the AIDS treatment project, and then in the name of researching AIDS treatments, the research was able to continue. Later, the Nobel Prize was also awarded to these two people.

By 2005, this research finally made a revolutionary breakthrough.

Scientists have discovered that by using nucleoside modification to change the structure of mRNA, one of the altered mRNAs has the ability to sneak into target cells without triggering immune system defenses.

This is pseudouracil-modified mRNA.

There are four bases in mRNA, namely adenine, guanine, cytosine, and uracil.

Pseudouracilization modification is a modification of uracil, which turns the nucleotides in uracil into pseudouracil nucleotides.

Pseudouracilization-modified mRNA does not trigger the immune system. That is to say, when editing or synthesizing mRNA, only pseudouracilization modification is required to hide it from the immune system, allowing the mRNA to enter the target cells, and ultimately achieve the desired result. Protein required.

Of course, based on the current level of human science and technology, most diseases cannot be overcome using this technology. This technology is mainly used for vaccine research and development.

It is also the mRNA vaccine that we have become familiar with in recent years!

……

There are many types of nucleoside modifications, the most common of which is methylation, which can modify adenine and cytosine in mRNA.

In addition, there are phosphorylation, acetylation, glucosylation, hydroxymethylation, etc., among which pseudouracilization is probably a relatively inconspicuous one.

Because there is something called pseudouracil synthase in the body, which can complete pseudouracil modification. In other words, pseudouracil originally exists in living organisms. This substance that comes with living organisms can easily be ignored.

It would also be unjustifiable if Zhang Wei only conducted pseudouracilization modification experiments. Do you want to make nucleoside modifications, leave out the most common methylation modifications, and do pseudouracil modifications? Is it unreasonable? Is there something wrong with it?

So Zhang Wei simply did other nucleoside modification experiments together, which looked reasonable and could conceal the true intention.

Anyway, there is no need for Zhang Wei to do such troublesome things as experiments. There are three graduate students, and they are eager to practice their experimental skills a few more times!

A wave of nucleoside modification experiments were completed, and the results came out.

Liu Xuetai took the experimental report and began to report the experimental results of various nucleoside modifications.

"The first set of methylation modification experiments, five experimental samples, the immune system works normally!"

For normal people, normal is a good word, but for Zhang Wei, it means failure.

The immune system of the sample is functioning normally, which means that the nucleoside-modified mRNA is still not able to bypass the immune system and enter the target cells.

However, Zhang Wei was not surprised by this result. After all, the only thing that can really bypass the immune system is pseudouracil modification, and the others are just foils.

Liu Xuetai continued to report: "The second set of acetylation modification experiments, five experimental samples, the immune system is functioning normally!
The third group, phosphorylation modification experiment, five experimental samples, the immune system works normally!
The fourth group, glucosylation modification experiment, five experimental samples, the immune system works normally!
The fifth group, pseudouracil modification experiment..."

When it came to the pseudouracil modification, Zhang Wei finally cheered up.

"Five experimental samples, the immune system is functioning normally!" Liu Xuetai said.

Hearing this result, Zhang Wei frowned fiercely.

what's the situation? Does pseudouracilization not bypass the immune system?

The experiment failed?
(End of this chapter)