Go deep into the micro and expand the understanding of life sciences

Hair strands, which are about the limit of what is visible to the naked eye, are about 100 microns in diameter, the cells are 1/10 the size of human hair, and the nucleus is only a few microns. However, this small nucleus carries a huge amount of high-value genetic information.

To study the fine structure of cells and improve the understanding of life, we must go deep into the microscopic scale.

"From population ecology to living individuals, organs, tissues, cells, to biological macromolecules, and even the details of atoms in biological macromolecules, life sciences involve multi-scale studies from macro to micro." Gao Pu, a researcher at the Institute of Biophysics of the Chinese Academy of Sciences and head of the research group of the Key Laboratory of Biomacromolecules, said that as an important frontier of contemporary life sciences, biomacromolecules are a typical field of extremely microscopic research.

How do scientists do research at the very micro scale? How can we grasp the trends of microscopic scientific research? The reporter conducted an interview.

With the help of advanced precision observation technology, cells can be "seen" at the molecular scale

Walking into the Key Laboratory of Biological Macromolecules, Ji Wei is guiding students to debug the optoelectronic correlation microscope. Not long ago, the researcher at the Institute of Biophysics of the Chinese Academy of Sciences and the head of the research team of the Key Laboratory of Biological Macromolecules led a team to develop a new observation method based on photoelectric correlation microscopy.

"To study biological macromolecules, you must first 'see' it." Ji Wei told reporters that the assembly structure of biological macromolecules such as nucleic acids and proteins is complex and precise, and the clearer you observe them, the more profound your understanding of the mysteries of life can be.

At the Key Laboratory of Biological Macromolecules, Institute of Biophysics, Chinese Academy of Sciences, Ji Wei is debugging an optoelectronic correlation microscope. Photo by Yu Sinan

In the 17th century, Netherlands scientists used homemade microscopes to observe single-celled organisms for the first time, opening the door to microbiology. In the following 300 years, optical microscopy has been developed, but the resolution is limited by diffraction, and it is difficult to break through after reaching a few hundred nanometers. At the beginning of the 21st century, with the advent of super-resolution fluorescence microscopy and cryo-electron microscopy, scientists were able to observe subcellular structures at the scale of tens of nanometers to tenths of a nanometer, which greatly expanded the cognitive horizon of life science.

With the deepening of the exploration of microstructure, scientists continue to improve observation techniques and challenge the limits of microscopy.

Looking at the cell structure displayed on the computer screen, Ji Wei introduced: In order to "see" the fine structure of the cell, scientists need to observe a specific molecular state. However, cryo-EM beams can only image biological samples of about 200 nanometers, and cells a few microns thick need to be thinned and observed, but this thinning is random and does not ensure that the target molecule remains in the section. In order to achieve targeted thinning of cells, Ji Wei's team has developed a cryofluorescence-guided thinning technology, which is equivalent to installing a "navigation and positioning system" on the cryo-double-beam electron microscope, which can efficiently achieve target-directed thinning.

Focusing on the frontier of biological macromolecule research, the Key Laboratory of Biological Macromolecules mainly focuses on three aspects: precision observation technology of biological macromolecules, precise assembly principle of biological macromolecules, and precise regulation design of biological macromolecules. "For biological macromolecules, these three aspects of research correspond to observing it, understanding it, and using it, respectively, and are logically closely related and mutually reinforcing." Gao Pu said.

Ji Wei mainly researches and develops the precise observation technology of biological macromolecules, and Gao Pu mainly researches the principle of precise assembly of biological macromolecules. "Biological macromolecules and complexes are the executors of all life activities, and when these molecular machines go wrong, they often cause diseases." Gao Pu told reporters that with sophisticated observation technology, scientists can better study the orderly assembly and dynamic regulation of biological macromolecules, and understand this process can help scientists do a good job in the precise regulation design of biological macromolecules, so as to put forward effective coping strategies.

For example, how does the host respond to abnormal nucleic acid signals, and how is this process regulated? With the help of advanced biomacromolecule research methods, Gao Pu and his team have made a series of breakthroughs in this field, improving people's understanding of the mechanism of nucleic acid immune response. Going deeper into the microscopic level, there are still many such important achievements in the Key Laboratory of Biological Macromolecules.

In recent years, the Key Laboratory of Biological Macromolecules has produced a number of cutting-edge research results in three directions. In terms of precision observation technology, it achieves photoelectric correlation imaging by breaking through the spatiotemporal resolution of optical and electron microscopy imaging, leading the development of cutting-edge technologies of super-resolution microscopy and bioelectron microscopy. In terms of the principle of precise assembly, a series of new principles of biological macromolecule assembly regulation in many important life processes such as photosynthesis, infection immunity, and organelle dynamics have been revealed. In terms of precise regulation and control design, a series of important breakthroughs have been made in the design of new vaccines, the research and development of new drugs, and the design and application of nanozymes.

"Biological macromolecule research is an important means to cultivate and develop new quality productivity." Gao Pu told reporters that as the commanding heights of life medicine research, biological macromolecule research is changing the paradigm of drug and vaccine research and development, and the future market scale is huge, and the potential economic value is very high, "Whether it is leading the frontier of science, or providing a technical basis for the development of drugs and innovative vaccines, biological macromolecule research is a key area that we need to pay attention to." ”

The regulatory mechanism of crop trait formation is explained at the molecular level, and the breeding method innovation is brought about

"Lo and behold, this is a picture of a section of the root tip cell of a rice seedling. A closer look at this image shows that there is a problem with the transport of cell wall-forming substances in the cells of the mutants, and a closer study of this phenomenon may lead to the discovery of new genes that regulate the development of rice stalks. In the transmission electron microscope room of the Institute of Crop Science of the Chinese Academy of Agricultural Sciences (hereinafter referred to as the "Institute of Agricultural Sciences"), Cheng Zhijun pointed to the photo and explained to reporters.

Cheng Zhijun is a researcher at the Institute of Crop Sciences of the Academy of Agricultural Sciences, and one of the members of the rice functional genome research innovation team led by Academician Wan Jianmin of the Institute. At the nanoscale, observing the morphology and structure of samples of different materials has become an indispensable technical link for Wan Jianmin's team to carry out functional gene research.

Cheng Zhijun told reporters that rice has more than 50,000 genes, with different functions, and the differences in "tall, short, fat and thin" between rice varieties, disease resistance, drought resistance, quality, taste and other characteristics all stem from the differences between genotypes. In order to screen out excellent rice varieties, the conventional breeding method is to select individual plants with phenotypic separation of offspring on the basis of parental crossbreeding and field performance. In order to ensure that the selected individual plants have excellent traits, it takes many years of multi-point observation and experiment, which takes a long time, and the improvement efficiency of traits whose phenotypes are easily affected by the environment is low. "Breeding is more like an art, and the process is more empirical and lacks specificity."

Functional genomics research provides a new approach to rice breeding. "Functional genomics research focuses on the regulation of gene expression and its response mechanisms to the environment, and studies 'how genes work'." Ren Yulong, a member of Wan Jianmin's team and a researcher at the Institute of Agricultural Sciences, said.

Starting from the micro level, through molecular design, purposefully aggregate key trait genes, optimize the genotype of target varieties, and cultivate varieties in a targeted manner is the road to efficient breeding in the future.

Through functional genomics research methods, researchers can start from understanding genes and select varieties in a targeted manner. For example, if patients with kidney disease cannot eat rice with high absorbable protein content, researchers can find the gene that regulates the protein in rice, and then cultivate rice with low absorbable protein content through mutagenesis and other methods. In the future, researchers can accurately design and breed the varieties they need through molecular design.

Wan Jianmin is one of the first scientists in China to propose and practice molecular design breeding of rice. In China, Wan Jianmin led the team to lay out functional genomics research very early. After years of continuous research, the team has excavated a number of key genes for important agronomic traits in rice, and the research results have strongly promoted the original innovation in the field of rice functional genomics and provided scientific and technological support for the development of the rice industry. Among them, overcoming the problem of "rice hybrid sterility" is one of the representative achievements.

Indica rice is mostly grown in the south, and japonica rice is mostly grown in the north. The genetic difference between the two is large, and the heterosis is obvious. It is estimated that if indica rice and japonica rice subspecies can be bred into super hybrid rice, it is expected to increase the yield by more than 15% compared with the existing hybrid rice. However, indica-japonica hybrids have problems such as low seed setting rate, and this reproductive isolation phenomenon hinders the utilization of heterosis.

What to do? Starting from the molecular level, Wan Jianmin led the team to elucidate the molecular mechanism of "hybrid sterility" between and within the seed of rice, and solved the mystery of rice reproductive isolation. This breakthrough is hailed as a milestone achievement in the field of rice heterosis, which lays a theoretical foundation for the use of indica-japonica heterosis in production.

"The key to ensuring national food security lies in agricultural science and technology innovation." Ren Yulong said that from the perspective of crop functional genomics research, it is helpful to deal with the major problems faced by the mainland's grain production, especially the sustainable development of agriculture and food security in the period of socio-economic structural transformation.

Adapt to the trend of microscopic scientific research, and do more original work on the frontiers of science

"Going deep into the microcosm is an important way to explore the material world, the essence of life and the laws of operation." Chen Zhi, director of the Institute of Science, Technology and Economic and Social Development of the Chinese Academy of Science and Technology Development Strategy, said that because major breakthroughs at the micro level often lead to disruptive technological changes, related research has become the focus of international attention.

What are the trends in biomolecules, functional genomics research, etc.?

The interviewed experts said that the mainland has a relatively deep accumulation of biological macromolecule research, among which the Key Laboratory of Biomacromolecules of the Institute of Biophysics of the Chinese Academy of Sciences is recognized as an important base and academic highland for cutting-edge research at home and abroad. At present, the research of biological macromolecules is advancing to a more microscopic field, and the requirements for precision observation technology will be higher and higher. "We need to develop more precise observation technology, and work with international counterparts to promote the upgrading of biological macromolecule observation from static and in vitro observation to dynamic and in-situ observation." Ji Wei said.

Research is going deeper to the micro level, and multidisciplinary integration is becoming more and more important. "Biological macromolecule research involves talents from different majors such as mathematics, chemistry, physics, biology, etc., to create an atmosphere that encourages cooperation, so that scientific researchers can focus on a number of major scientific problems, give full play to their respective strengths, and learn from each other's strengths to achieve the effect of 1+1>2, and promote the mainland's related research to a new level." Ji Wei said.

Ren Yulong told reporters that with the deepening of research, functional genomics will pay more attention to interdisciplinarity. Knowledge from biology, agronomy, computer science, mathematics and other fields will be integrated with each other to jointly promote the development of functional genomics.

To promote the research of crop functional genomics, germplasm resources are important carriers. The National Crop Germplasm Resource Bank preserves more than 90,000 rice germplasm resources. Ren Yulong said that each update and iteration of rice varieties is inseparable from the exploration and utilization of major genetic resources. In the future, the team will strive to explore the key genes for the formation of important agronomic traits in rice, elucidate their functions, build a molecular regulatory network for the formation of high-yield and high-quality traits, and effectively transform resource advantages into innovation advantages and industrial advantages.

Going deeper into the microscopic means that most of the research is original work at the frontier of science. The interviewed experts generally suggested that to adapt to the trend of microscopic scientific research and grasp the initiative of scientific and technological innovation and development in the future, we should further strengthen the stable support for excellent teams, so that scientific researchers can do basic research with peace of mind.

"Scientific research instruments need to be continuously upgraded and improved in iterations, and everyone must be twisted into a rope. After running-in, the team must remain stable in order to continue to produce results. Ji Wei told reporters, "We should give more trust and a longer support cycle to scientific researchers, and encourage them to do major research in ten years." ”

Cheng Zhijun believes that if basic research is done well, the foundation of molecular breeding will be more solid, which often requires a long period of accumulation. At present, the funding cycle for agricultural research is still relatively short, and there is not enough room for basic research, "I hope to give long-term stable support to a group of excellent teams and encourage them to explore valuable research." ”

Source: People's Daily

Reporter Yu Sinan