Abstract
Remarkable progress in bioengineering over the past two decades has enabled the formulation of fundamental design principles for a variety of medical and non-medical applications. These advancements have laid the foundation for building multicellular engineered living systems (M-CELS) from biological parts, forming functional modules integrated into living machines. These cognizant design principles for living systems encompass novel genetic circuit manipulation, self-assembly, cell–cell/matrix communication, and artificial tissues/organs enabled through systems biology, bioinformatics, computational biology, genetic engineering, and microfluidics. Here, we introduce design principles and a blueprint for forward production of robust and standardized M-CELS, which may undergo variable reiterations through the classic design-build-test-debug cycle. This Review provides practical and theoretical frameworks to forward-design, control, and optimize novel M-CELS. Potential applications include biopharmaceuticals, bioreactor factories, biofuels, environmental bioremediation, cellular computing, biohybrid digital technology, and experimental investigations into mechanisms of multicellular organisms normally hidden inside the “black box” of living cells.
Highlights
It is possible to create novel multicellular living machines never seen before
These cognizant design principles for living systems encompass novel genetic circuit manipulation, self-assembly, cell–cell/matrix communication, and artificial tissues/organs enabled through systems biology, bioinformatics, computational biology, genetic engineering, and microfluidics
An interesting example of an integrated biological system is provided by the model organism Drosophila whose larvae exhibit peristaltic crawling motion coordinated by central pattern generating (CPG) neural circuits
Summary
It is possible to create novel multicellular living machines never seen before. The past few decades have witnessed the convergence of the fields of synthetic biology, bioengineering, stem cell biology, computational biology, and molecular genetics, coupled with increased training of interdisciplinary scientists across two or more of these domains (Fig. 1).[1–46] This convergence has been accompanied by advances in the design and implementation of technologies such as organoids, microfluidics, biological robots (biobots), nanofabrication, and genetic engineering. Designing living systems from the ground up requires developing a better understanding of biological building blocks and constructing a set of design principles that define how the blocks fit together and can be manipulated These design principles enable M-CELS to bring a new perspective to how we think about biology. Our high-level definition of M-CELS is that these are engineered multicellular systems that have emergent behaviors with desired natural or non-natural form and/or function This Review provides bioengineers with a set of primary design principles to guide the future design and manufacture of M-CELS. There are intrinsic and dynamic properties of multicellular systems, which must guide these principles a priori These include spatial and gradient properties that play important roles in developmental biology and create the desired form and function.
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