Carolinska Institutet of Sweden announced on October 7: United States scientists Victor · Ambrose and Gary · Rubkan have been awarded the 2024 Nobel Prize in Physiology or Medicine for their discovery of miRNA (microribonucleic acid) and its role in post-transcriptional gene regulation.
When the news came, domestic experts in related fields congratulated and called it a milestone event and another major discovery in modern biology. Back in 2006, when the Nobel Prize was awarded to "the discovery of RNA interference – the silencing phenomenon caused by double-stranded RNA", many people felt that Ambrose and Rovkan also deserved the award, but fortunately the honor came belatedly. The discovery of miRNA has played a huge role in human exploration of the nature and universal laws of life phenomena, and has a wide application prospect.
A low-key and dedicated scientist in the eyes of Chinese scholars
Professor Liu Rujuan from the School of Life Sciences of ShanghaiTech University had just returned from Canada to attend an academic conference, and during the conference, she happened to meet Professor Ambrose, the new Nobel Laureate in 2024. "He is a textbook figure in our academic world, and I mention Professor Ambrose in every PowerPoint presentation to my students. In particular, he will be mentioned for his major discoveries made during 1993. ”
In 1993, Ambrose cloned the LIN-4 gene in nematodes using the classical localization cloning method, and found that lLIN-4 did not code for a protein, but produced a small RNA molecule through site-directed mutagenesis. This small RNA molecule can inhibit the expression of LIN-14 by interacting with its target mRNA in a specific region (the 3'UTR region) in a non-fully complementary manner, ultimately leading to a decrease in LIN-14 protein synthesis, a phenomenon known as "translational inhibition".
"The big expert is very easy-going and low-key, I met him when I took the elevator, greeted him, introduced myself as a scholar at ShanghaiTech University in China, and Professor Ambrose also introduced himself." Liu Rujuan recalled that the two also had a discussion on teaching, "This well-known scientist in the academic world carefully guided me, and the next time I showed the PPT to the students, I could change the way of thinking and give the students a topic, how to discover siRNA at the same time." His dedication to science is evident. ”
It can be called another major discovery in the field of modern biology
The full name of miRNA is microRNA, a class of small endogenous non-coding RNAs in eukaryotes. In 1993, two labs led by Ambrose and Ruffkan each found a gene called LIN-4 in nematodes. This gene does not code for a protein, but rather expresses a small RNA with a length of 22 nucleotides, which inhibits the expression of the LIN-14 gene, a nuclear protein, which regulates the development of nematodes. The scientists hypothesized that this inhibition mechanism lies in the ability of LIN-4 to complement the unique repetitive region on the 3'UTR region of LIN-14 mRNA.
However, this discovery was only considered a special case at the time. It wasn't until seven years later, in 2000, that a second discovered miRNA was named LET-7, a 21-nucleotide long, discovered by Rubkan in his study of nematodes. Similar to LIN-4, LET-7 can also regulate nematode development by binding to the 3'UTR region of the mRNA of some target genes. Based on this, the two scientists realized that this is a universal mechanism for regulating gene expression.
In the years since, thousands of miRNAs have been discovered in a variety of species, including almost all groups of plants and animals such as humans, mice, rats, fruit flies, zebrafish, Arabidopsis, rice, etc., opening up a new and vast space for scientific research.
"The two scientists were the first to discover miRNAs and their role in the regulation of gene expression, which is another major discovery after the central principles of modern biology." Liu Rujuan told reporters, "There is no doubt that miRNA will be widely used in the fields of medicine and agriculture, and the prospects are promising." At present, although the FDA has not approved miRNA-related drugs, there are drugs in the clinical trial stage, and miRNA has been widely used, including detection technology, biological diagnosis and other fields, many laboratories will be involved, and miRNA will show greater scientific value in the future. ”
Advance research "seven years of loneliness" will break out again
"The Nobel Prize was awarded to two well-known scientists, and the biggest revelation for me is that what we don't see doesn't mean it doesn't exist. In fact, a lot of RNA research has been done, but everyone didn't expect that the last thing that regulates gene expression is small miRNA. Wu Ligang, a researcher at the Center for Excellence in Molecular and Cellular Innovation of the Chinese Academy of Sciences (formerly the Institute of Biochemistry and Cell Research of the Chinese Academy of Sciences), was interviewed by reporters and said a fate. Wu Ligang was a scholar at Harvard Medical School, and his mentor once worked with Ambrose, "At that time, my supervisor was a professor and Ambrose was an assistant professor, and when his laboratory researched important regulatory factors, he finally found that there was a big gap with his imagination. At first, I thought it would be a kinase or protein regulation, but I didn't think it was just a small miRNA. No second miRNA was found for seven years after that. Ambrose himself left Harvard Medical School in 1994, which shows that the most authoritative and mainstream schools at the time were not necessarily optimistic about this research. ”
It wasn't until seven years later that Professor Rovkanin found LET-7, an miRNA that is not conserved in species such as fruit flies and mice, and many scientists speculate that miRNA has many important functions, so that mankind has ushered in a great stage of miRNA development. Wu Ligang said, "From the experience of the two scientists, sometimes scientific discoveries are too advanced, and they have to endure loneliness for many years, which is why scientists need to persevere." ”
What can miRNAs bring to humans? Embryonic development, apoptosis, tumor growth, ...... miRNAs are involved in a series of physiological and pathological processes, and various genetic, metabolic, infectious and tumor-related miRNAs may become reliable disease biomarkers. At present, miRNAs have shown potential in the diagnosis and treatment of chronic diseases such as cancer, liver disease, neurological disease, infectious disease, coronary heart disease, and metabolic disease. Relevant statistics show that in 2019, the global miRNA market size was $215.4 million, and it is expected to grow from $254.8 million in 2020 to $613.2 million in 2027, with a compound annual growth rate of 13.4%.
It will have great potential prospects in the field of medical agriculture
Today, new miRNAs are still being discovered from time to time. According to statistics, the number of miRNA entries included in the miRBase database has increased from 218 in 2002 to 271 species in 2023, covering tens of thousands of records, and the number of miRNAs encoded by the human genome alone has reached 1,917. The academic community is actively seeking ways to intervene and treat diseases by changing the function of miRNAs and developing new in vivo delivery methods.
Taking cancer as an example, the National Cancer Society of United States has released a study saying that more than 90% of cancer patients have treatment failures related to drug resistance. Therefore, studying the mechanism of drug resistance, finding new anti-tumor targets, and developing new anti-tumor drugs have always been the focus of the world.
Scientists from Shanghai, China, are constantly making progress in related fields. The reporter learned that the team of the Drug Safety Evaluation Center of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, discovered for the first time that miR-145 can directly target MRP1 and enhance the effect of doxorubicin on drug-resistant triple-negative breast cancer, providing new targets, new mechanisms and new treatment methods for anti-tumor drug resistance research. Meng Xiangjun's team from the Ninth People's Hospital affiliated to Shanghai Jiao Tong University School of Medicine revealed that m6A-modified miR-30d is a new target of YTHDC1, and miR-30d can block the occurrence and metastasis of pancreatic ductal adenocarcinoma by inhibiting aerobic glycolysis, and can also independently predict the prognosis of patients. Under the guidance of Fan Jia, an academician of the Chinese Academy of Sciences, and led by Zhou Jian, a professor from Zhongshan Hospital affiliated to Fudan University, a circulating miRNA liver cancer early diagnosis model has been constructed, and the sensitivity is 30% higher than that of the commonly used alpha-fetoprotein (AFP) in clinical practice.
As Ambrose once wrote, in the future, at a more mature stage, biochemical and genetic research will reveal the extraordinary complexity of miRNA regulation mechanisms and biology, leading to more satisfying answers, and ultimately helping humans to understand life more scientifically.
Editor: Wen Xiting
Source: Shangguan News
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