Unstable small molecule
From high school biology textbooks, we can understand that genes are the genetic material of all living organisms. Genes can guide cells to synthesize proteins, and proteins perform various physiological functions, such as hemoglobin transporting oxygen, and digestive enzymes to help break down food proteins into peptides. Or amino acids and so on. However, genes cannot directly guide the synthesis of proteins, and a less stable small molecule is needed to help. This small molecule is mRNA (messenger RNA).
The material basis of genes is deoxyribonucleic acid, or DNA. Biologists have discovered that there is a one-to-one correspondence between genes and proteins, that is, a gene directs the synthesis of an enzyme or protein. In 1953, after American James Watson and British Francis Crick discovered the epoch-making DNA double helix structure, people learned that genes carry genetic information and used this genetic information to guide cells to synthesize proteins. However, biologists soon discovered that genes cannot directly synthesize proteins. They speculated that there may be an unstable small molecule that, like a messenger, transmits the genetic information of genes to the protein synthesis “factory”-ribosomes. , The ribosome synthesizes the corresponding protein according to the genetic blueprint.
So, what is this messenger? Many biologists tried to find it. However, this messenger molecule is very unstable and difficult to separate. In 1961, Sydney Brenner from the University of Cambridge in the United Kingdom collaborated with Francois Jacob from the Pasteur Institute in France and Matthew Messelson from the California Institute of Technology in the United States. The experiment finally captured this fleeting messenger molecule-a single-stranded RNA molecule complementary to DNA. It is called “messenger RNA”, also known as “mRNA”. As the name suggests, messenger RNA is the ribonucleic acid molecule that transmits genetic information.
Life genetic information flow process
For organisms, DNA is the carrier of genetic information, because the double-stranded structure of DNA is very stable; for cells, the main function of DNA is to synthesize proteins. This process is similar to the principle of a tape recorder. Messenger RNA carries DNA. The genetic information is transcribed and transformed into a “postman” of life genetic information. Under the transport of transfer RNA (tRNA), the messenger RNA is transported to the ribosomes in the cell, and then the ribosomal RNA begins to “translate” the messenger RNA. Genetic information assembles the amino acids wandering around in the cell into various proteins, which then perform various physiological functions.
Messenger RNA vaccines that are not favored
Obviously, without the help of messenger RNA, the DNA of the “full belly” can only be stared, unable to guide cells to synthesize proteins, and life will not be able to continue. So, what does messenger RNA have to do with vaccines?
In fact, the working principle of vaccines is to simulate the attack mode of pathogens and carry out “military exercises” against pathogens in humans or animals. Therefore, the earliest vaccines are viruses or bacteria themselves. For example, attenuated vaccines made from weakly toxic viruses, or inactivated vaccines made from viruses that are killed by physical or chemical methods. Take virus vaccines as an example. When these vaccines are injected into the body, they may stimulate the body’s immune response and produce a large number of specific antibodies. These antibodies will be scattered throughout the body to patrol. Once a virus strikes, the antibody will rush to bind to the virus, and the virus will be immobile like it is tied to the hands and feet. Subsequently, with the assistance of some immune cells, the virus is cleared from the body, thereby eliminating the threat of the virus. In addition, the body’s immune system will also produce immune memory against the vaccine. Even if the antibody is insufficient, when the virus strikes, the immune system with immune memory will quickly synthesize a large number of antibodies against the virus.
How messenger RNA vaccines work
Scientists have further researched and found that the reason why these vaccines stimulate the body’s immune system to produce antibodies is that the proteins in the vaccine are actually at work. These proteins are called “antigens”. Attenuated vaccines or inactivated vaccines contain a large number of complex protein antigens, but only some of the antigens can induce the immune system to produce antibodies that can neutralize viruses and other pathogens. Therefore, these traditional vaccines have poor effectiveness. defect. With the rise of genetic engineering technology, researchers have invented antigens with relatively simple components, such as subunit genetic engineering vaccines, which usually contain only one protein or peptide fragment, which is more targeted, safe and effective. During this period, some scientists began to think: Since protein can be used as a vaccine, can the messenger RNA of a certain viral protein be injected into the body, can it also use the cells to synthesize the viral protein, and then exercise the function of a vaccine?
In 1990, a group of scientists from the University of Wisconsin in the United States tried for the first time to inject luciferase messenger RNA from fireflies into the muscles of mice, and soon the expression of luciferase was detected in the mice. Through experiments, they proved for the first time that messenger RNA obtained by in vitro transcription can transmit genetic information in living tissue cells by injection to guide protein synthesis. Two years later, researchers at the Scripps Research Institute in the United States will purify vasopressin messenger RNA or synthetic vasopressin messenger RNA from the hypothalamus of normal rats and inject them into rats that lack vasopressin due to gene mutations. In the hypothalamus, after a few hours, the diabetes insipidus of the genetically mutated rats was relieved and lasted for up to 5 days. This is the first demonstration that the in vitro messenger RNA can guide the synthesis of protein after being injected into the living animal. Protein can also perform normal physiological functions. Both of these research results were published in the internationally renowned academic journal “Science”, allowing people to see the great potential of messenger RNA in disease treatment. Therefore, many researchers hope to use messenger RNA to treat major diseases such as cancer and neurological diseases.
However, the use of messenger RNA as a vaccine has not received enough attention. In 1993, a French research team injected liposome-encapsulated influenza virus nucleoprotein messenger RNA into the muscle of mice to induce the production of anti-influenza cytotoxic T lymphocytes in the body, preliminarily proving the potential of messenger RNA as a vaccine. In 1994, several scientists from the Karolinska Institute in Sweden directly proved for the first time that messenger RNA can be used as a nucleic acid vaccine to induce antibodies in mice. However, messenger RNA has problems such as instability and low transmission efficiency in vivo. Even more deadly, the injection of messenger RNA in the body caused strong adverse reactions in living animals, leading to the death of some experimental animals. Therefore, the prospect of messenger RNA vaccines was not optimistic. At that time, the mainstream of vaccine research and development was still protein and DNA.
New crown messenger RNA vaccine spawned
Katharine Kariko from Hungary is an exception. She has always insisted on carrying out messenger RNA medical research. Although she is often not welcomed by American universities (neither has the desired university position nor applied for sufficient scientific research funding), there is no way out. In 1997, Katalyn Carrico met Drew Weissman, a famous immunology professor who had just arrived at the University of Pennsylvania in the United States. The two met because they were fighting for a photocopier. After in-depth exchanges, Professor Drew Weisman decided to fund the research of Katalyn Carrico. Initially, Katalyn Carrico hoped to use messenger RNA to treat brain diseases and strokes. Since Drew Weissman is an immunologist, the two decided to develop the use of messenger RNA in immunity. As a result, the two began a long-term cooperation in messenger RNA vaccine research, one of the most important research results was announced in 2005.
In this paper published in the journal Immunity, Katalyn Kaliko, Drew Weissman and two other colleagues found that some modified nucleotides in messenger RNA caused adverse immune responses. They found the nucleotides in a messenger RNA that caused the adverse immune response one by one, and then replaced them with artificially synthesized nucleotides. The adverse immune response was significantly weakened. This research has laid an important foundation for the development of subsequent messenger RNA vaccines. Later, Katharine Kariko, Drew Weisman and others improved the messenger RNA vaccine and applied for a patent. At the same time, other researchers have continued to improve the stability of messenger RNA vaccines. For example, a liposome “coat” is used to wrap messenger RNA vaccine so that it will not be decomposed by nuclease before entering the cell.
With the continuous improvement of technology, the hope for the commercialization of messenger RNA vaccines is growing. Compared with traditional vaccines, messenger RNA vaccines have some obvious advantages, such as good safety, low production costs, and short design and development cycles. However, before the outbreak of the new crown pneumonia, the messenger RNA vaccine did not achieve substantial success. Although dozens of mRNA-based vaccines were being developed at that time, and a few of them had entered clinical trials, such as influenza vaccine, Zika virus vaccine and rabies vaccine, none of them had been approved for use in humans.
Just two days after Chinese scientists announced the RNA sequence of the new coronavirus, the American company Modena immediately announced the development of the new coronavirus messenger RNA vaccine mRNA-1273. At the same time, BNT162b2 jointly developed by Pfizer and Biontek in Germany followed closely behind. Both of the above vaccines are against the spike protein of the new coronavirus.
The clinical trial of BNT162b2 started in April 2020 and ended after the Phase III clinical trial in November of that year. After clinical verification by 40,000 volunteers, it is proved that BNT162b2 not only has good safety, but also has a protection rate of more than 91% against the new coronavirus. Beginning in December 2020, countries and regions such as the United Kingdom, the United States, and the European Union have successively approved the listing application of BNT162b2. Pfizer and Biontech announced that they will produce 2.5 billion doses of vaccine in 2021. The clinical trial of mRNA-1273 was also launched in April 2020. The clinical phase III trial recruited 30,000 volunteers, with an effective rate of 94%. At the end of 2020, the United States, Canada, Israel and other countries have successively approved the marketing application of the vaccine.
In less than a year, the above two messenger RNA vaccines have completed the entire process from vaccine design, clinical trials to approval for marketing, which can be called a “miracle in the history of vaccine research and development.” However, this is also a stopgap measure to deal with the global new crown pneumonia epidemic. Follow-up will require further observations on safety, and carry out more clinical trials to expand the adaptation population, and use the messenger RNA vaccine to fight the new crown pneumonia on a larger scale. The role of the epidemic.