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2024

Diet Regulation Biocomputer: Opening a New Chapter of Endogenous Gene Logic Operation

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In order to survive, organisms constantly carry out complex "calculations" in response to environmental changes. This information processing is at the heart of living systems. Imagine that thousands of genes in the body are like flexible switches, adjusting their state and expression at any time, and all of this depends on accurate biological computing. However, at present, the biological computers constructed in mammals mainly operate on exogenous genes, and the logical operation ability of endogenous genes naturally existing in the body is relatively weak, especially in the face of complex high-order operations. In addition, the computing power of these systems in animals has not been fully verified.

On October 7, 2024, the team of Ye Haifeng and Guan Ningzi of East China Normal University in their earlier resveratrol (PNAS,2021) and protocatechuic acid (Science Translational Medicine, 2019) on the basis of the study of regulating gene expression, a new type of biological computer REPA was successfully developed._CRISPR. This calculator includes REPA_CRISPERand REPA_CRISPRATwo versions are used to suppress and activate transcription of endogenous genes, respectively. The results of this study have been published online inCellSub-journal 《Cell Systems", the paper is entitled:"A digital CRISPR/dCas9-based gene remodeling biocomputer programmed by dietary compounds in mammals". This innovative research combines CRISPR gene editing technology with logical operations to achieve precise regulation of endogenous genes. More revolutionary, the research team used red wine ingredient resveratrol and green tea metabolite protocatechuic acid as input signals, breaking the traditional limitation of antibiotics as signal input. This breakthrough has opened up a new path in the field of biological computing and laid the foundation for the future development of more accurate, safe and non-invasive gene regulation methods.

Building the REPA _CRISPRThe process is like an interesting game of "building blocks": first, the research team collects biological components that can respond to resveratrol and protocatechuic acid, and assembles basic logic operation gates, such as AND gates, OR gates and NOT gates, like building blocks, to complete the construction of the "first floor. Then, on this basis, more complex splicing is carried out to build high-order logic gates, such as exclusive or gates and half-adder, to build a "second floor". Finally, install functional transcription factors that can regulate endogenous genes on the "second floor", and "turn on the switch" by activating the corresponding genes, or "turn off the switch" by inhibiting the genes, so as to accurately control the state and expression of the genes. Complete the top-level construction of this "building block building. This process not only demonstrated scientific creativity, but also opened new doors to the field of gene regulation.

REPA _CRISPRNot only can you perform basic logic operations, such as AND gates, OR gates, and NOT gates, but you can also handle more complex operations, such as exclusive OR gates and half-adder. It's like a computer solving a math problem, and our cells can respond to these logical operations. Even more exciting, the team found that the amount of transcriptional expression of genes can be regulated by the concentration of input signals. To do this, they built mathematical models of the various logical operations to predict the relationship between the input signal concentration and the amount of gene transcription expression. This means that scientists can more precisely regulate gene expression within cells and achieve the desired level of gene expression by pre-setting the concentration range of the input signal. In a diet-induced obesity mouse model, the research team successfully demonstrated thymic stromal lymphopoietin in mouse liver cells ( Tslp) gene logic operation regulation, significantly reduced the weight of obese mice. This result allows us to imagine that in the future, it may be possible to adjust the two food components in the daily diet to perform biological calculation, so as to achieve a safe, painless and healthy weight management method.

This innovative CRISPR calculator not only enriches the synthetic biology toolbox, but also opens up new possibilities for the precise manipulation of endogenous genes in the future. The corresponding authors of the paper are Associate Researcher Guan Ningzi and Researcher Ye Haifeng of the School of Life Sciences of East China Normal University, and Associate Researcher Yin Jianli and PhD student Wan Hang are the co-first authors. Thanks to the team of Lou Chunbo of the Shenzhen Advanced Institute of the Chinese Academy of Sciences for assisting in the construction of the mathematical model. The research work was supported by the National Natural Science Foundation of China and Shanghai Science and Technology Commission.

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