This year's Nobel Prize in Physiology or Medicine was awarded to the mRNA base modification technology that is crucial to the new coronavirus mRNA vaccine. In fact, since 2021, there have been strong calls for awards to be given to mRNA technology. However, the "accident" was not given in 2021, which is the year most popular among the public. It was also an "accident" that year, which allowed us to quickly see a large number of high-quality analysis articles after the mRNA technology award. This article was written after the mRNA technology did not win the award in 2021, and some of the content has been slightly changed to conform to the changes in the past two years.
It can be seen that scientific breakthroughs such as mRNA vaccines or mRNA technology are not the work of one or two people, nor are they a simple science and technology, but the final achievement of many scientific advances connected together. There are many excellent vaccine technology platforms today, which are the result of countless subtle scientific and technological breakthroughs accumulated over the years. Most of these breakthroughs will never appear in discussions such as the Nobel Prize, but they have made very important substantive contributions to the entire human society.
On September 29, 2020 local time, in Philadelphia, the United States, Hungarian scientist Katalin Karikó (right) and American scientist Drew Weissman (left) took a group photo at the University of Pennsylvania. They won the 2023 Nobel Prize in Physiology or Medicine. Visual China data map
This time, mRNA won the prize. To be precise, the technology of modifying mRNA may win.This technology is an important component of today's mRNA vaccines.However, mRNA vaccines and mRNA technology that uses mRNA to express a certain protein rely on multiple scientific foundations to become a reality. Since the launch of the mRNA COVID-19 vaccine, there have been false news from time to time saying that the mRNA vaccine will change genes, or that the inventor of the mRNA vaccine said that the technology is dangerous. If you review the scientific basis of mRNA vaccines, you will find that these are nonsense.
Theoretical basis of mRNA technology
The basis of mRNA vaccines is the concept of expressing a gene through the artificial introduction of mRNA. This is based on human understanding of the central dogma. The central dogma describes the direction of genetic material. For the human body, genetic information is in DNA. For example, many people are very concerned about the collagen in the skin. The structural information of collagen is all encoded in DNA, and the coding in DNA does not jump directly to protein, but passes through RNA. RNA, the "intermediary", also has several parts. Among them, mRNA carries the genetic information in DNA, and tRNA and rRNA are responsible for manufacturing RNA and proteins. It is equivalent to mRNA transmitting information, and the others are responsible for specific tasks.
Now that we have a central dogma of where genetic material goes, imagine that we can express a protein by introducing DNA or RNA.For example, some medical beauty advertisements talk about injecting collagen. If you consider the central dogma, you can introduce DNA and RNA with collagen genes into cells, and then let the cells use the introduced gene code as a template to produce collagen. Similar to the difference between teaching a man to fish and giving him a fish.
Expression of genes via mRNA is the conceptual basis of mRNA vaccines. The idea is great. Why? Because although DNA is used as a vector to express foreign genes, it has been widely used, such as the production of insulin, and genetically modified crops, one of the pillars of modern agriculture. But in some cases, using mRNA to express genes has advantages over introducing DNA.
For example, using DNA as a carrier to express a gene in the human body is much more complicated. There is often no balance between long-term and short-term expression. Like gene therapy, theoretically it is hoped that once and for all, the gene causing the disease can be directly "fixed" and the problem can be permanently solved once and for all. But it's actually much more complicated. Unlike what some people imagine, people who eat genetically modified food will also become genetically modified. The human body will not directly absorb DNA fragments. It must find a transport vehicle for human cells to accept foreign DNA. Viral vectors are now mainly used. This again involves the safety of the carrier itself. All in all, it is extremely complicated. The final result is that sometimes we want to get rid of it once and for all, but after the introduction of foreign genes, the expression of foreign genes will become less and less over time. But at other times, the carriers transporting DNA can cause some long-term problems, such as running to places they should not go, and going the wrong way on the human genome is very dangerous, and in extreme cases can lead to cell cancer.
In contrast, mRNA works in the cytoplasm. Unlike DNA, which travels to the nucleus, it is located in the outer part of the cell. There is no risk of affecting the human genome, and the "road" for transport into the cell is shorter.Moreover, mRNA itself is unstable, and in some scenarios it avoids the risk of "long nights and many dreams".
In short, firstly, the introduction of using mRNA to express foreign genes has a genetic theoretical basis and is theoretically feasible. Secondly, using mRNA to express genes has advantages in certain situations and there is a demand in reality.
Dilemmas and breakthroughs
It is theoretically possible, and there is a demand in reality, but it may not necessarily be possible to actually do it. The same is true for mRNA technology.When scientists try to use mRNA to introduce genes, the problem they have been unable to solve is that RNA itself is very immunogenic.
This is also in line with the laws of nature: too many viruses have RNA as their genome, and the immune system has long been highly alert to RNA during its long evolution. Although human cells use mRNA to express genes, if it encounters free RNA molecules, the first reaction of the human body is that this guy is a virus and needs to be eliminated immediately. When exogenous mRNA is introduced into animals or humans, what happens is that a strong immune response directly breaks the mRNA molecules into pieces. In the end, not only was the gene not expressed, but the strong immune response also caused serious side effects.
The immunogenicity of strongly stimulating the immune system here refers to stimulating the innate immune system. Nowadays, the immunogenicity of mRNA vaccines is also very good, but they can successfully reach the next step after properly stimulating the innate immune system, which is to stimulate the acquired immune system such as antibodies to form a good immune memory. In the past, the immunogenicity of mRNA did not even touch the door of acquired immunity, which directly caused the overreaction of innate immunity. If we switch to the situation of the new coronavirus vaccine, it is equivalent to having a high fever that does not go away after taking the vaccine. The last bit of antibodies has not been formed and the vaccine has been degraded.
For this reason, the application of mRNA technology has been stagnant for a long time and was considered hopeless by many scientists. This suspicion is not unreasonable, because the problem that mRNA technology wants to solve is how to deceive the human immune system, and its deception is not just petty theft, but basically the level of cheating.
A new coronavirus has made chickens and dogs restless. Humans and even animals have survived after constant battles with many viruses in the history of evolution. In this struggle process, what humans and animals can basically rely on is the immune system.In nature, there is only one possibility for free mRNA molecules, which is a virus.Therefore, the immune system has evolved over millions of years. When it sees an RNA molecule wandering around in the human body, it must immediately identify and eliminate it. Under such circumstances, it is indeed a fantasy to say that we need to deceive the human immune system and release artificial mRNA molecules.
It is also in this context that the emergence of RNA modification technology has become the key to the realization of RNA technology as a whole.This RNA modification technology was developed by Katalin Karikó and Drew Weissman, two scientists who won the Nobel Prize in Physiology in 2023. Since the success of the new coronavirus mRNA vaccine, there have been very high calls for the Nobel Prize to be awarded to them.
Among them, Karikó’s experience was very twists and turns, including being rejected when applying for a fund and almost losing his job. Because these now seem very legendary, they have been exaggerated and reported by many media. However, these reports somewhat overlooked that behind her setbacks actually corresponded to the difficulties of the mRNA technology itself. Take applying for scientific research funds as an example. At that time, some scientists were already trying to use mRNA as a carrier to express genes, and then use this method of expressing genes to deliver drugs. But as mentioned before, the human body does not catch a cold. If you send one, I will cut off one. Fund reviewers will naturally consider whether such projects are wasted efforts.
At the same time, as a scientist, Karikó is not saying that everyone is drunk and I am alone. She is not simply repeating the previous mRNA synthesis and delivery, thinking that this will be successful. She clearly realized that there were problems with the previous method. If the strong immunogenicity of mRNA was not solved, it would be impossible to introduce foreign genes using mRNA. So she and Drew Weissman collaborated on research on mRNA delivery technology and soon turned to how to reduce the immunostimulatory properties of mRNA molecules. In 2005, they discovered that if the U in mRNA, which is uracil, is chemically modified into pseudouracil, the mRNA molecule no longer strongly stimulates immune cells.
This discovery is mRNA modification, a technology used by Moderna and BioNTech’s new coronavirus vaccines. In the past, not everyone believed that mRNA modification was necessary. For example, another German company, CureVac, thought it could be solved by reducing the number of uracils. TranslateBio, acquired by Sanofi, optimized other structures of mRNA (capping). They all believed that these could solve the immunogenicity problem of mRNA. Of course, at least the large-scale and successful use of mRNA vaccines proves that mRNA modification is effective and feasible, and has become the mainstream of mRNA drug delivery.
In addition to solving the immunogenicity problem, the success of mRNA technology also relies on many other scientific breakthroughs.For example, how to effectively deliver mRNA molecules into the human body. Directly importing mRNA molecules into the human body will be very inefficient. If it is not absorbed by human cells, it will not be effective. This involves a breakthrough in liposome packaging technology, which uses lipid molecules to wrap mRNA molecules to form nanometer-level particles in size. Some vaccine conspiracy theories on the Internet use the word nano to make a fuss. In fact, nano is just an order of magnitude.
With mRNA modification and nano-lipid carriers, the development of mRNA vaccines is not smooth sailing. BioNTech and Moderna did not focus on vaccine development before, but used mRNA technology to deliver drugs for other diseases, without making much breakthrough. Even for vaccines, Moderna used to make broad-spectrum influenza vaccines, but the immune response in humans was lower than the results obtained in animal models, and progress slowed down. This breakthrough in the new coronavirus vaccine is also closely related to the characteristics of the new coronavirus itself and the breakthroughs in vaccine design in recent years.
Conclusion
It can be seen that scientific breakthroughs such as mRNA vaccines or mRNA technology are not the work of one or two people, nor are they a simple science and technology, but the final achievement of many scientific advances connected together.
It should also be noted that in addition to mRNA vaccines, new coronavirus adenovirus vaccines and recombinant protein vaccines also have good effectiveness.It reflects that there are many excellent vaccine technology platforms today, which is also the result of countless subtle scientific and technological breakthroughs accumulated over the years. Most of these breakthroughs will never appear in discussions such as the Nobel Prize, but they have made very important substantive contributions to the entire human society.
The author, Zhou Yebin, holds a PhD in genetics from the University of Alabama at Birmingham. He has been engaged in immunology research for a long time and is currently engaged in new drug research and development in a pharmaceutical company. This article was first published on the WeChat public account of "A Biological Dog's Popular Science Garden".