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Network Biology, 2027, 17(2): 538-585
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Article

General design principles for combining functional modules into complete cells: From compatibility to emergence

WenJun Zhang
School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China; International Academy of Ecology and Environmental Sciences, Hong Kong

Received 27 August 2026;Accepted 6 September 2026;Published online 15 September 2026;Published 1 June 2027
IAEES

Abstract
Bottom-up synthetic biology has achieved substantial progress over the past decade, enabling the reconstitution of gene expression, metabolic cascades, and signal transduction as independent functional modules within giant unilamellar vesicles. However, combining these modules into integrated complete cells continues to face fundamental difficulties. Resource competition, signal crosstalk, chemical incompatibility, and loss of function after combination occur frequently. This study proposes a three-layer design principle framework organized around constraint, coupling, and emergence. Module independence is limited by the thermodynamic constraints of a shared resource pool, and the operation of any module inevitably alters the host free energy landscape and metabolic state. The feasible region of module coupling is defined jointly by the capacity of information transfer channels and noise tolerance. The function of a complete cell is not a simple superposition of module functions but emerges as new system-level dynamical behaviors when inter-module coupling strength crosses a critical threshold. This study formalizes these principles into an operational module compatibility matrix and a coupling strength criterion, and proposes experimental validation strategies. This framework offers a unified theoretical perspective for rational design from modules to complete cells, transforming scattered engineering experience into testable design principles.

Keywords synthetic cells;synthetic biology;modular design;non-equilibrium thermodynamics;self-organization;emergence;general design principles.


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