Produced by | Tiger Sniff Technology Medical Group
Author | Chen Guangjing
Edit | Miao Zhengqing
Header | AI-generated
In the week after the "Eleventh" holiday, the most exciting thing, in addition to the ups and downs of the market, is the more and more capricious Nobel Prize.
Following the Nobel Prize in Physics on October 8 that fell to "Artificial Neural Networks for Machine Learning", which seems to have nothing to do with physics, on October 9, the popular "Protein Prediction" that originally won the Physiology or Medicine Prize won the Nobel Prize in Chemistry.
With the above two miraculous operations, the Nobel Prize has been out of the circle again, and the people who eat melons have ridiculed that "physics and chemistry are gone", and "the literature award will not be given to ChatGPT......
In the life sciences sector, the situation is not so serious, but it can be called an "accident". The Nobel Prize in Physiology or Medicine fell on the field of microRNA (microRNA, also known as miRNA), which is very unfamiliar to the public, and GLP-1, CAR-T and other "miracle drugs" have fallen off the list, making the excited media, industry professionals and technology enthusiasts all pounce.
You must know that although the field of miRNA is a very important research and was once a big favorite for the Nobel Prize, similar research was awarded 18 years ago (2006), and the Nobel Prize in Physiology or Medicine since 2022 has been awarded to mRNA-related research.
"The Nobel Prize has been awarded to RNA-related research fields for two consecutive years, which is indeed relatively rare." Dr. Zheng Weiyi, chairman of Nanjing Yingnuo Pharmaceutical Technology Co., Ltd., told Tiger Sniff.
Similarly, two awards were awarded to researchers in the field of artificial intelligence in the same year, which was also a precedent.
Behind these unexpected and reasonable laureates, scientific research, especially in the life sciences, is moving to a new stage.
Why miRNAs won the Nobel Prize
The Nobel Prize's "boomerang" has finally hit the miRNA.
Of the 50 trillion cells in the human body, only 2% can be transcribed into coding mRNA (capable of producing proteins), and the remaining 98% can only be transcribed into non-coding RNA (unable to produce proteins). miRNAs are the "hope family" of non-coding RNAs, and about one-third of human genes are regulated by miRNAs, and they are involved in almost all biological functions.
However, it was not until 1993 that miRNA information was first published, and it was not until 2000 that it gradually attracted the attention of the scientific community, and after more than 20 years of development, the attention almost disappeared, and finally won the Nobel Prize. Nowadays, many people are still very unfamiliar with miRNA, and even confuse it with mRNA, the new crown vaccine technology that became popular all over the world during the epidemic.
In fact, miRNA and mRNA do have a relationship. First of all, they come from the same "family" – small nucleic acid molecules (short RNA consisting of 20 to 30 nucleotide molecules in tandem, where mRNA is a generalized small nucleic acid but does not have a regulatory function – Tiger Sniff Note).
"Cells can precisely regulate gene activity, which is essential for the normal activities of living organisms, especially for higher organisms." Virology expert Chang Rongshan told Tiger Sniff.
Multicellular organisms, from the primitive single cell, through gametes, fertilized eggs to adult, each step of the realization requires specific genes in the external environment, time, space to accurately express, this regulation needs to be completed by complex and fine "non-structural genes" expressed ribonucleic acid (RNA) in the genome, in addition to miRNA, there are small interfering ribonucleic acid siRNA and shRNA and so on.
This family of related drugs, known as small nucleic acid drugs, works through RNA interference (RNAi, that is, "silencing" part of the genetic information).
Of course, family members also have their own characteristics, such as: unlike mRNA, miRNA does not code for proteins; siRNAs are double-stranded and miRNAs are single-stranded.
Secondly, mRNA and miRNA are also a good pair.
In the late 1980s, ·Victor Ambos, who was the principal investigator at Harvard University, and Gary · Rufken, who was also the principal investigator at Harvard Medical School at the time, discovered that there was a negative regulatory relationship between the two genes in the body when they studied a 1 mm long worm, Caenorhabditis elegans. After that, in order to find out the mechanism behind it, they did their own research.
It was found that the lin-4 gene produced a very short RNA molecule that, although it did not have the code to produce the protein, could inhibit another gene, lin-14.
More research has shown that this very short RNA, i.e., miRNA, does not inhibit the lin-14 gene from producing mRNA, but binds to some fragments on its mRNA, making it unable to produce the corresponding protein. That's why they won the Nobel Prize.
Schematic diagram of miRNA and its function.
Source: Official website of the Nobel Prize Committee
Interestingly, such a moderating effect is not "one-to-one", but "many-to-many". According to the Nobel Prize Committee, one miRNA can regulate the expression of multiple different genes, and one gene can be regulated by multiple miRNAs, so as to coordinate and fine-tune the gene network. Other studies have shown that a single miRNA can regulate more than 100 genes.
Recent studies on mammalian miRNA-mRNA regulatory networks have found that the balance between miRNA and mRNA networks is essential for health, and once the balance is broken, it may lead to the occurrence of tumors, Alzheimer's disease and other diseases, and is also related to the aging of human organs. Researchers believe that artificially controlling the amount of miRNA to balance it with mRNA is a new way to treat diseases.
There are 1,917 miRNAs encoded by human genes that have been discovered and documented, and behind this is a very large regulatory network.
"Some refractory diseases are more likely to benefit from this type of drug." Zheng Weiyi told Tiger Sniff that many rare genetic diseases involve abnormal expression of specific genes, and miRNA drugs are highly specific by directly regulating these genes or their downstream pathways.
In general, miRNA drugs have shown unique therapeutic advantages in some complex and multifactorial diseases due to their ability to widely regulate multiple genes and pathways, as well as their more precise targeting. This ability to modulate multiple pathways makes miRNAs have great application prospects in areas of diseases that are currently difficult to treat, such as cancer and neurological diseases.
In addition to drugs, researchers are also trying to use miRNAs in disease prevention fields such as early tumor screening; Based on the theory that plant miRNA can enter human cells to participate in the regulation of genes, many Chinese medicine researchers are even trying to use miRNA to unravel the mystery of traditional Chinese medicine regulating human body functions.
As stated on the official website of the Nobel Prize Committee, the groundbreaking discovery of miRNAs is unexpected and reveals a new dimension of gene regulation. Behind it, the life sciences, and indeed the scientific community as a whole, are moving in a more complex direction.
Challenge intractable diseases
In the life sciences sector, in addition to powerful tools such as AI, direction is also very important. miRNAs seem to be a good breakthrough. Its "many-to-many" gene regulatory mechanism, which surprised the Nobel Prize committee, could take disease treatment to new heights.
"This kind of gene regulation of multiple pathways can be called the ultimate means of disease treatment." Zheng Weiyi told Tiger Sniff.
In this sense, the Nobel Prize can be regarded as sounding the rallying cry to the life sciences community in order to completely overcome intractable diseases.
The ability of human beings to fight diseases has rapidly reached one peak after another in the past few decades, and the average life expectancy has doubled, but bottlenecks are also emerging - there are more than 200,000 drugs in the world, but there are still more than 10,000 diseases, accounting for more than 90% of all diseases, and there is no effective treatment. In addition to rare diseases, there are more than 3,000 common diseases.
With the deepening of the aging problem, the increasing incidence of neurological diseases such as Alzheimer's disease and Parkinson's disease, degenerative diseases such as cardiovascular and cerebrovascular diseases, metabolic diseases such as diabetes, rheumatoid arthritis, tumors and other immune-related diseases have become a headache for countries around the world.
Data show that globally, cardiovascular and cerebrovascular diseases alone cause more than 17 million deaths every year; In the United States, diabetes cost more than $100 billion a year as early as 2003.
The pathogenesis of these diseases can no longer be explained by a single target. At the same time, the success rate of traditional new drug research and development has also been reduced to less than 2%. All this points to the need for more efficient solutions for life science research.
At least 20 drugs have been approved for miRNA siRNAs, such as siRNAs and ASO (antisense oligonucleotides, small nucleic acids designed for artificiality). These drugs have achieved zero breakthroughs in the field of many refractory diseases, such as nusinersen sodium, which became famous for "soul bargaining" in the past two years, is an ASO drug, which is the world's first SMA (spinal muscular atrophy, a neuromuscular disease) treatment drug.
In contrast, miRNAs are considered to have more potential due to the advantages of multi-target regulation. As mentioned earlier, miRNAs are not only related to rare diseases associated with single genes, but also to complex and refractory common diseases, and also have the effect of regulating aging, which is expected to prolong the healthy survival of humans.
Source: Official website of the Nobel Prize Committee
There are also more than a dozen miRNA projects in clinical trials around the world, covering cancer, heart disease, dry eye, Huntington's disease, NASH and other diseases. In China, XtalPi, Miran Biopharma, Mirui Group, etc., also have a layout in drugs and disease diagnosis.
However, no miRNA drug has been approved so far, and there have been projects entering phase II clinical trials that have been terminated or suspended.
"miRNAs do not require high sequence matching, and do not need to be completely matched to the target gene like siRNA, which may inhibit multiple target genes at the same time, but the risk of off-target will also increase." Yang Shuo, director of Yuekang Science and Technology Innovation Small Nucleic Acid New Drug Discovery, told Tiger Sniff. This means that there may be more side effects from the drugs in question. In addition, "miRNA modification technology is also a problem, and there is not much research on this area at present. He said.
Although small nucleic acid molecules can do many things inside cells, they are very fragile in their own right. Studies have shown that unmodified small nucleic acid molecules will be degraded by blood nucleases in up to 10 minutes, and they are also attacked by the immune system.
In addition to using the "spaceship" of the delivery system, modifying the small nucleic acid molecules is equivalent to putting on an "invisibility suit" for them. This strategy has been validated in the new crown mRNA vaccine, and United States scientists Catalin · Carrico and Drew · Weissman also won last year's Nobel Prize in Physiology or Medicine for their contributions to mRNA modification.
Yang Shuo believes that the lack of breakthroughs in miRNA research is also related to the lack of current research momentum. "The main reason is that the current inhibition efficiency of siRNA is already very high, and people may not have the motivation to study miRNA."
Although not as well-known as mRNA vaccines, siRNA is also a "popular fried chicken" in the field of small nucleic acid drugs. According to statistics, the total market size of small nucleic acid drugs will be about US$3.8 billion in 2022 and is expected to reach US$8.2 billion this year. Among them, the market size of siRNA has increased by more than 132 times in just six years from 2018 to 2023, and is expected to reach $3 billion in 2024.
However, the development and commercialization prospects of miRNAs are not clear, and it is indeed difficult to be competitive.
Behind the frequent upsets of the Nobel Prize, the low-hanging fruits of the scientific community have been picked, and it is difficult to make new breakthroughs by relying on manpower alone, and a paradigm revolution is about to emerge.
For example, in the field of life sciences, the research and development of antibody drugs is penetrating from monoclonal antibodies for a single target to bispecific, triple, and quadruple antibody drugs for multiple targets, and even shows better therapeutic potential than monoclonal antibodies. However, this has also made the difficulty of drug research and development geometrically increased, giving birth to the rapid development of AI+ pharmaceutical technology.
It can be seen that following Sanofi's announcement of "All-in-AI", AstraZeneca, Eli Lilly, and Johnson & Johnson are actively cooperating with AI companies. AI has also developed from the prediction of protein structure to the prediction of complex structures composed of small molecules such as proteins and nucleic acids, and then the prediction and screening of the structure of compounds such as miRNAs.
This time, the forward-looking Nobel Prize has put the miRNA, which has been "neglected" for many years, back in front of global researchers, entrepreneurs, and investors, and is also sending a "hero post" to the industry - those who can cure diseases and even extend the healthy life of humans by repairing genes will be the pioneers of new drug research and development models, and will also be the real winners who seize future opportunities.
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