Chapter 152 Moving forward towards the Nobel Prize!
Although Zhang Wei 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 never 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 can quickly 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 do a nucleoside modification experiment from the beginning and then get results, isn't that obviously arousing 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.
Well 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 effect of nucleoside modification on RNA. What effect does nucleoside modification have on RNA? There are several effects. Which effect is Nobel Prize-level? Before the experimental results come out, ,neither knows.
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!
Looking back and taking out the experimental records, didn't you declare before that it was to inhibit RNA recognition by Toll-like receptors? Why do you do nucleoside modification in the first place? This alone cannot be explained.
So Zhang Wei can only do some experiments that are destined to have no results first to make up for it, 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.
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 knows that the new ideas will 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 then succeed.
......
In the laboratory, Zhang Wei had not yet arrived. The three graduate students looked at the new experimental materials and began to discuss the next experimental plan.
"Zhang Wei said he wanted to change his experimental ideas. What did he specifically say he wanted to do?" Ma Jijun asked.
Liu Xuetai shook his head: "He only said to change the idea of the experiment, and then asked me to prepare these things, and said nothing else. But I thought, no matter what I do, just practice the experimental operation .”
"That's right. These days, the types of experiments we do are usually not our turn." Ma Jijun said.
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? Do you want to methylate Toll-like receptors? ”
“The list of materials also includes phosphokinase, adenosine triphosphate, acetyl coenzyme, uridine diphosphate glucose, glycine-arginine-rich protein... just a For the basicization experiment, you shouldn’t need so many things!” Liu Xuetai said.
“If we are only doing methylation experiments, we naturally won’t use so much, so we have to do phosphorylation, acetylation, glucosylation, and pseudouracilization, all at once.”
Zhang Wei's voice sounded from behind, and he also came to the laboratory.
"Can we complete so many experiments?" Liu Qian asked.
"Why, you still think there are too few opportunities to do experiments? In other project teams, there are not so many opportunities for experiments!" Zhang Wei said with a smile.
"There are experiments to be done, how can it be too little!" Liu Xuetai said immediately.
Participating in Zhang Wei's project, although I can't see any results yet, it is quite good if 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.
Zhang Wei continued: "We are still in the running-in period for the experiments some time ago. No results have been produced, so don't feel discouraged. Let's just practice.
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! ”
……
Nucleosides are the building blocks of nucleotides, and nucleotides are the basic structural units of RNA. In other words, nucleosides can be regarded as the more fundamental components of RNA. One of the components.
There are also 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, and some are responsible for transporting DNA. Information, some are responsible for regulating gene expression.
Among them, mRNA is also called messenger RNA, which 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, the cook will make scrambled eggs with tomatoes. If the menu says spicy and sour potato shreds, the cook will make spicy and sour potato shreds.
In other words, ribosomes generate 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 potato shreds, so I replaced the mRNA with hot and sour potato shreds halfway through and sent it to the cook. Then the cook made What comes out is spicy and sour potato shreds. 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 diabetic patients, 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 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 in the 1990s, humans began to study the technology of synthetically editing mRNA.
But the biggest problem in this research needs to be solved, and that is Toll-like receptors, which are the most basic defense mechanism of cells. The mRNA synthesized by humans is always captured by Toll-like receptors. Influence.
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, there was a security guard who found something wrong with the menu that was delivered, so he tore up the menu and even beat the person who passed it to death so that the menu would not be delivered. In the kitchen, the cook will never make a mistake.
This problem has not been completely overcome so far, 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.
In 2005, this research finally made a revolutionary breakthrough.
Scientists discovered that the structure of mRNA was changed through nucleoside modification, and one of the changed mRNAs actually had the ability to sneak. , can enter target cells without triggering immune system defenses.
This is pseudouracil-modified mRNA.
mRNA contains four bases, 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 in the body called pseudouracil synthase, 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 did the modification experiment of pseudouracilization. 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 seemed 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, this is But 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 group of acetylation modification experiments, five experimental samples, the immune system works normally!
The third group, phosphorylation modification experiments, 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 going on? Does pseudouracilization not bypass the immune system?
The experiment failed?
(End of this chapter)