2. Academic Validation
  3. Multi-layered computational gene networks by engineered tristate logics

Multi-layered computational gene networks by engineered tristate logics

  • Cell. 2024 Jul 23:S0092-8674(24)00716-5. doi: 10.1016/j.cell.2024.07.001.
Jiawei Shao 1,  Xinyuan Qiu 2,  Lihang Zhang 3,  Shichao Li 4,  Shuai Xue 5,  Yaqing Si 6,  Yilin Li 4,  Jian Jiang 6,  Yuhang Wu 6,  Qiqi Xiong 6,  Yukai Wang 7,  Qidi Chen 8,  Ting Gao 9,  Lingyun Zhu 10,  Hui Wang 11,  Mingqi Xie 12
Affiliations

Affiliations

  • 1 Department of Pharmacy, Center for Regenerative and Aging Medicine, the Fourth Affiliated Hospital of School of Medicine and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, Zhejiang 322000, China; Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Medicine and School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310024, China; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang 310024, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, Zhejiang 310024, China. Electronic address: jiaweishao@zju.edu.cn.
  • 2 Department of Biology and Chemistry, College of Science, National University of Defense Technology, Changsha, Hunan 410073, China; College of Computer Science and Technology, National University of Defense Technology, Changsha, Hunan 410073, China.
  • 3 Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Medicine and School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310024, China; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang 310024, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, Zhejiang 310024, China; Research Center for Life Sciences Computing, Zhejiang Laboratory, Hangzhou, Zhejiang 311100, China.
  • 4 Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Medicine and School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310024, China; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang 310024, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, Zhejiang 310024, China; College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.
  • 5 Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang 310024, China.
  • 6 Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Medicine and School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310024, China; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang 310024, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, Zhejiang 310024, China; School of Life Sciences, Fudan University, Shanghai 200433, China.
  • 7 Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang 310024, China; School of Engineering, Westlake University, Hangzhou, Zhejiang 310030, China; School of Life Sciences, Fudan University, Shanghai 200433, China.
  • 8 Department of Pharmacy, Center for Regenerative and Aging Medicine, the Fourth Affiliated Hospital of School of Medicine and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, Zhejiang 322000, China.
  • 9 Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Medicine and School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310024, China; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang 310024, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, Zhejiang 310024, China.
  • 10 Department of Biology and Chemistry, College of Science, National University of Defense Technology, Changsha, Hunan 410073, China. Electronic address: lingyunzhu@nudt.edu.cn.
  • 11 Research Center for Life Sciences Computing, Zhejiang Laboratory, Hangzhou, Zhejiang 311100, China. Electronic address: hui.wang@zhejianglab.com.
  • 12 Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Medicine and School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310024, China; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang 310024, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, Zhejiang 310024, China; School of Engineering, Westlake University, Hangzhou, Zhejiang 310030, China. Electronic address: xiemingqi@westlake.edu.cn.
PMID: 39089254 DOI: 10.1016/j.cell.2024.07.001
Abstract

So far, biocomputation strictly follows traditional design principles of digital electronics, which could reach their limits when assembling gene circuits of higher complexity. Here, by creating genetic variants of tristate buffers instead of using conventional logic gates as basic signal processing units, we introduce a tristate-based logic synthesis (TriLoS) framework for resource-efficient design of multi-layered gene networks capable of performing complex Boolean calculus within single-cell populations. This sets the stage for simple, modular, and low-interference mapping of various arithmetic logics of interest and an effectively enlarged engineering space within single cells. We not only construct computational gene networks running full adder and full subtractor operations at a cellular level but also describe a treatment paradigm building on programmable cell-based therapeutics, allowing for adjustable and disease-specific drug secretion logics in vivo. This work could foster the evolution of modern biocomputers to progress toward unexplored applications in precision medicine.

Keywords

cell-based implants; computational gene network; designer cells; diabetes mellitus; full adder; full subtractor; mammalian synthetic biology; tristate logic.

Figures
Products