Automation in synthetic biology using biological foundries

Abstract

Synthetic biology applies engineering principles for the deliberate design, engineering, and de novo creation of artificial biological systems with certain functions. Due to the complexity of living systems and lack of rational design principles, iterative trial-and-error experiments are often necessary, but the dependence on human researchers limits the throughput, efficiency, and consistency of such endeavor. To overcome these limitations, biofoundries are developed as an integrated infrastructure for accelerating the "design-build-test-learn" cycles in synthetic biology research and biotechnology applications. Computer-aided design and robotic automation are applied in the physical manufacturing and prototyping of engineered DNA and genetically reprogrammed organisms. Currently, many biofoundries are being created around the world, and a Global Biofoundry Alliance has been established to promote coordination and collaboration. This paper aims to summarize the recent advances in synthetic biology automation and introduce design and construction of current and future biofoundries. We start with key technologies that promote automation in synthetic biology, including computer-aided design, highthroughput instrumentation, robotic integration, automation-compatible workflows for DNA assembly and chassis engineering, and analytical approaches. For bio-design automation, we introduce existing software tools such as j5 from Agile Biofoundry, iBioCAD from Illinois Biological Foundry for Advanced Biomanufacturing (iBioFAB), and CUBA from Edinburgh Genome Foundry (EGF). Moreover, software and hardware for creating automated build and test workflows are summarized, followed by recent advances in DNA synthesis, DNA assembly, nucleic acid extraction and analysis, chassis manipulation, and high-throughput testing. Notable examples are discussed, including automated DNA assembly using the Golden-Gate method, multiplex automated yeast genome engineering, and artificial intelligence (AI)- guided optimization of biosynthetic pathways. Then, representative biofoundries and their software systems, robotic platforms, and available workflows are discussed. Biofoundries are categorized by various formats of integration, including full integration (e.g., iBioFAB and EGF), modular integration (e.g., London Biofoundry, Singapore Biofoundry, and Concordia Genome Foundry), and manual integration. Commercial biofoundries are also compared and contrasted with their academic counterparts, using the ones at Gingko Bioworks Inc. as an example. Furthermore, the design of Shenzhen Biofoundry is discussed in detail, whereby a centralized cloud lab is envisioned to serve the domestic and international synthetic biology communities. Shenzhen Biofoundry will consist of a build platform for engineered DNA, phage, bacteria and yeast, a test platform for optics, chromatography and mass spectrometry, and fermentation scale-up, and a design/learn/cloud platform to coordinate and integrate the whole facility. We conclude with the future challenges and promises of biofoundries and synthetic biology automation. We propose key research directions, including new automation technologies, data-driven and intelligent design, and automation-compatible workflows in synthetic biology. Systems approach and interdisciplinary collaboration are necessary for biofoundries development, which requires synergistic integration of synthetic biology, analytical chemistry, robotics, instrumentation, informatics, and smart manufacturing. Just like foundries initiated the magnificent prosperity of the semiconductor industry, biofoundries will unleash the potential of synthetic biology to revolutionize our society.