Living cells display remarkable behaviors, such as adapting to new environments, transitioning between distinct cell states, and self-organizing into multicellular tissues. These complex capabilities are programmed into the cell through molecular “circuits” – consisting of interacting genes and proteins – which process signals, execute computations, and store memory of past events. Our laboratory combines two complementary bioengineering approaches to uncover the design principles of these cellular circuits and how they evolve to enable cells to innovate new functions. First, we use synthetic biology to design molecular “parts,” using them to build genetic circuits that drive desired cellular functionality. This bottom-up approach helps us to identify which circuits are sufficient to program cellular function and tune critical biochemical parameters, as well as test different circuit designs to understand why a circuit has been evolutionarily selected to perform a specific function. Second, we invent laboratory technologies, such as the eVOLVER platform, that provide unprecedented ways of evolving biological systems and tracking adaptation to environmental changes. Together these approaches are bringing us closer toward a quantitative understanding of how functions and phenotypes emerge from underlying cellular networks, and establishing powerful tools to engineer designer molecules and organisms for applications, including new cell-based devices for cell immunotherapy, antibiotic resistance, and neurodegeneration.

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Environmental Fluctuations Reshape an Unexpected Diversity-Disturbance Relationship in a Microbial Community
Christopher P. Mancuso, Hyunseok Lee, Clare I. Abreu, Jeff Gore and Ahmad S. Khalil
bioRxiv, doi: 10.1101/2020.07.28.225987

Automated Continuous Evolution of Proteins In Vivo
Ziwei Zhong*, Brandon G. Wong*, Arjun Ravikumar, Garri A. Arzumanyan, Ahmad S. Khalil and Chang C. Liu
ACS Synthetic Biology, 9: 1270-1276 (2020)

Barcoded Microbial System for High-Resolution Object Provenance
Jason Qian*, Zhi-xiang Lu*, Christopher P. Mancuso*, Han-Ying Jhuang*, Rocío del Carmen Barajas-Ornelas*, Sarah A. Boswell*, Fernando H. Ramírez-Guadiana, Victoria Jones, Akhila Sonti, Kole Sedlack, Lior Artzi, Giyoung Jung, Mohammad Arammash, Mary E. Pettit, Michael Melfi, Lorena Lyon, Siân V. Owen, Michael Baym, Ahmad S. Khalil, Pamela A. Silver, David Z. Rudner and Michael Springer
Science, 368: 1135-1140 (2020)

Protein Assembly Systems in Natural and Synthetic Biology
Giulio Chiesa*, Szilvia Kiriakov and Ahmad S. Khalil
BMC Biology, 28: 35 (2020)

Designing Automated, High-Throughput Continuous Cell Growth Experiments Using eVOLVER
Zachary J. Heins, Christopher P. Mancuso, Szilvia Kiriakov, Brandon G. Wong, Caleb J. Bashor and Ahmad S. Khalil
Journal of Visualized Experiments, 147: e59652 (2019)

Complex Signal Processing in Synthetic Gene Circuits Using Cooperative Regulatory Assemblies
Caleb J. Bashor*, Nikit Patel*, Sandeep Choubey, Ali Beyzavi, Jane Kondev, James J. Collins and Ahmad S. Khalil
Science, 364: 593-597 (2019)

Functional Genomics of the Rapidly Replicating Bacterium Vibrio natriegens by CRISPRi
Henry H. Lee, Nili Ostrov, Brandon G. Wong, Michaela A. Gold, Ahmad S. Khalil and George M. Church
Nature Microbiology, 4: 1105-1113 (2019)

Engineering Epigenetic Regulation Using Synthetic Read-Write Modules
Minhee Park, Nikit Patel, Albert J. Keung and Ahmad S. Khalil
Cell, 176: 227-238 (2019)

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