Rewrite the textbook! Chinese scholars subvert the two major laws of bacterial reproduction and explain the laws of natural creation.

This paper is reprinted from "deeptech science and technology", and the original title is "the latest research released by Shenzhen Advanced Institute of Chinese Academy of Sciences: revising the two major rules of bacterial reproduction, or will your textbook be rewritten?" Francois Jacob once said, "the dream of every cell is to become two cells.".this dream is the basis for all kinds of life forms to exist and continue in the long river of time.bacteria are one of the main groups of organisms. It is of great scientific significance to understand the basic laws of bacterial cell growth and cell cycle control, and to clarify the molecular regulatory mechanism behind cell cycle related events, which is a basic problem to be solved urgently in microbial physiology.on May 18, the journal Nature microbiology published the research results of Liu Chenli, researcher Laboratory of Shenzhen Institute of advanced technology, Chinese Academy of Sciences and Shenzhen Institute of synthetic biology innovation - "general quantitative relations linking cell growth and the cell cycle" Cell cycle in Escherichia coli, which breaks through two major laws in this field - "SMK growth rule" and "constant initial quality hypothesis", reveals the new law of bacterial cell growth and cell cycle control.(source: nature Microbiology) research team, based on stable and reliable experimental system and experimental methods, focused on "how does bacterial cell realize its dream and become two cells" We have carried out systematic and comprehensive research on this important basic scientific problem, and obtained a new "individual growth and division equation", which provides a quantitative basis for predicting cell growth cycle relationship.in other words, "SMK growth rule" and "constant initial mass hypothesis" written in textbooks for many years may be subverted."microorganisms are everywhere" "microorganisms are everywhere, and microorganisms are everywhere in nature.they are important symbionts of plants and pathogens causing human diseases.they play an important role in the geochemical cycle. At the same time, microorganisms are used in mining, pharmaceutical and food fields.in scientific research, the principles of genetics and biochemistry, including the popular gene editing technology, are all derived from microbial research. Liu Chenli, the corresponding author of the paper, said in an exclusive interview with deeptech.but it was not until 1674, when Antonie van Leeuwenhoek invented the microscope, that human beings could observe microorganisms for the first time.after hundreds of years of exploration, since the 1950s, thanks to the innovation of relevant experimental methods and concepts, people began to explore and understand bacterial cell growth and cell cycle from a quantitative perspective.Liu Chenli believes that understanding the operating law of bacterial growth and reproduction can help us make better use of microorganisms, better resist diseases and apply them in agriculture, food and pharmaceutical industry.in addition, exploring the basic principles of bacterial cell growth and reproduction can provide quantitative theoretical guidance for scientific research and guide the next research and development. Br / "if we can explain the law of God through the study of God, then we can compare it with the law of God."to subvert the two laws and explain the law of creation of the hand of God" nature ", the stable operation of cell cycle needs to coordinate the most basic three events cell growth, DNA replication and cell division.in 1958, based on the quantitative study on the growth rate and cell size of Salmonella in different media, schaechter et al. Proposed "schaechter maal ó e-kjeldgaard growth rule" (SMK growth rule), which was the first time to quantitatively link the population average cell size with the growth rate, and pointed out that there was an approximate exponential relationship between the two.in 1968, Donachie proposed the "constant initial mass hypothesis" and explained the SMK growth rule quantitatively in mathematics. in the following half century, people thought under the paradigm framework described by the "constant initial mass" hypothesis model, and tried to verify the above hypothesis model and find the molecular mechanism behind it through experiments, but it was still unsuccessful. "there is a premise that the above two rules can verify each other. They require that the interval from the beginning of DNA replication to the corresponding cell division (i.e., the C + D cycle) should be kept constant; however, when the doubling time is more than one hour, this premise does not hold. that is to say, in this case, "SMK growth rule" and "constant initial mass hypothesis" should not hold. "said Liu. "in the past, the detection range was limited, mainly focused on bacterial cells under high growth rate conditions, and relatively few studies under low growth rate conditions. "in order to explore the coordination mechanism between bacterial cell growth and cell cycle, the research team selected E. coli cells as a model organism to carry out their research. in order to cover a wider range of growth rates, the research team has selected more than 30 different media to carry out this study; it is the most widely used medium and the widest coverage of growth rate among similar studies reported so far. Liu Chen Li believes that stable experimental system and accurate and reliable quantitative methods are important prerequisites for the smooth development of experimental scientific research. the researchers found that after inoculating E.coli cells cultured overnight in fresh medium, the total population biomass (OD600) began to increase exponentially after a period of time, but during this period of exponential growth of OD600, the average cell size of the population was increased (), the average number of single cell replication starting points () was not stable, but correlated with the specific sampling time point (Fig. 1, left, light gray area). therefore, the research team has carried out in-depth exploration on the cultivation methods of bacterial cells and established corresponding experimental methods to ensure that the relevant parameters of bacterial cell cycle involved in the study are the values measured under the condition of steady state growth. the so-called steady growth refers to that the total biomass (e.g. OD600) and cell number increase exponentially at the same growth rate (i.e. λ M = λ C); in this state, many bacterial cell physiological parameters, including cell cycle related parameters, remain stable, independent of sampling time. Figure 1 the importance and verification of steady growth state (source: the above paper) on the basis of ensuring the steady growth state and combining with quantitative experimental methods, the research team systematically and comprehensively measured the growth rate of E.coli cells in different media and the corresponding cell cycle related parameters. based on the quantitative data obtained, the research team first verified the "SMK growth rule" and the "constant initial mass hypothesis", which have dominated the research on bacterial cell cycle for more than half a century. the results showed that although there was a positive correlation between the population average cell size and growth rate, the quantitative relationship between the two could not be described by a straight line on the semi logarithmic coordinate axis (left of Fig. 2); "initial mass" () had obvious growth rate dependence, whether it was "SMK growth rule" or "constant initial quality hypothesis" Both of them can not explain the experimental results very well, which means that the two basic "rules" which have dominated the research of bacterial cell cycle for more than half a century are not accurate. Figure 2 SMK growth rule and constant initial mass hypothesis are not tenable (source: the above paper). Then, based on the quantitative analysis of bacterial cell cycle related parameters, the research team found that the quantitative relationship between population average single cell replication starting point number () and growth rate (λ) can be described by a straight line on the semi logarithmic coordinate axis (Fig. 3) The research results in this part liberate people from the thinking mode of dividing the growth rate into "high growth rate" and "low growth rate" and independently studying the corresponding bacterial cell cycle regulation mechanism; and explore the unified bacterial cell cycle regulation mechanism that may exist under different growth rate conditions. more importantly, this study reveals a new "individual growth and division equation" (Figure 3, bottom left), which is suitable for different growth rate conditions, that is, cell size () is directly proportional to the product of growth rate (λ) and C + D cycle (constant independent of growth rate) "Mathematical formulas mean quantitative relationships. Biological phenomena that can be described by formulas are predictable biological phenomena, while biological experiments are usually qualitative rather than quantitative. Therefore, predictability is very important, which can provide guidance for the application of microorganisms, such as Production and fermentation process of industrial microorganism. "Liu Chen emphasized. (source: Shenzhen Advanced Institute) at the same time, under the constraint of "individual growth and division equation", the research team proposed that bacterial cell division should consider both cell biomass accumulation and chromosome related events, and predicted the possible molecular regulatory mechanism. "the process of DNA replication is a linear growth process, and in the process of value-added, the change of cell mass is exponential growth. We speculate that the above two biological processes with different rates jointly affect the formation and accumulation of" division permit ". When the accumulation of" division permit "reaches the threshold, the cell will divide. "based on the above model, the research team successfully reproduced the experimental phenomena observed in a series of population or single cell level experiments, including" individual growth and division equation "," incremental phenomenon of cell division "and" cell size distribution within a population ", etc. based on quantitative proteomic analysis, the team found that the concentration of key proteins including FtsZ, ftsK and ZipA remained constant at different growth rates, further supporting the above conjecture. Liu Chenli said that on the one hand, the focus of future work is to understand the dynamic process of the formation of "cleavage permit" and its relationship with DNA replication events; on the other hand, for Shenzhen Advanced Institute, the original intention of research is "substitution" based on synthetic biology. "after understanding the principles, we will use substitutable substances to create a division permit to achieve the purpose of artificially controlling bacterial cell proliferation. "Liu Chen Li believes that there are two aspects that are particularly important for the successful discovery of the" individual growth split equation ": first, the laws are hidden behind the real experimental data, and the experimental process needs to optimize the measurement means to ensure the accuracy of the measurement results; second, enough time to observe and sort out the data and find the clues hidden behind the data. in general, based on stable and reliable experimental systems and experimental methods, the research team focused on the important basic scientific question "how does a bacterial cell realize its dream of becoming two cells?"