Zoom Meeting (Information posted at the end of the announcement)
Engineering of Synthetic Biology Tools for De Novo Assembly of Human Cells
Organs for transplantation have continuously been in short supply and, given COVID-19’s adverse impact on solid organs, the shortage will likely become exacerbated. Tissue engineers have developed innovative methods to generate model tissues de novo. Top-down approaches, such as microfluidics and 3D bioprinting, provide spatial control by patterning, but face challenges in reproducing physiologically accurate cell types and interactions. Bottom-up methods, such as organoids, induce cells to differentiate into aggregates resembling in vivo counterparts, yet the complexity is limited by nutrient diffusion and the morphology cannot be controlled. We aimed to bridge the strengths of both approaches through a sequential gene expression system that programmatically aggregate and differentiate cells. We characterized 28 recombinases to determine efficiency and compatibility for mammalian recombinase genetic circuits (RGC). We then designed an RGC that expresses 12 genes sequentially, providing a framework for simulating the gene expression cascades. To elucidate the kinetics of recombinases in mammalian cells, we formulated a mathematical model and validated it with experimental data. We found that recombinases have variable expression levels, catalytic rates, and binding affinities, which impacts RGC design. Separately, we designed a platform for engineering membrane proteins for inducing cell-cell interactions, called helixCAM. We demonstrated that helixCAMs induce cell assemblies in E. coli, yeast, and human cells, and further utilize a library-on-library approach to engineer new helixCAMs. These genetic tools establish groundwork towards tissue engineering strategies for patterning while enabling endogenous differentiation and interactions to form, ultimately serving as a template for large-scale tissue and organs de novo.
Thesis Supervisor:
George Church, PhD
Robert Winthrop Professor of Genetics, HMS
Thesis Committee Chair:
Sangeeta Bhatia, MD, PhD
John J. and Dorothy Wilson Professor of Health Sciences and Technology and of Electrical Engineering and Computer Science, MIT
Thesis Reader:
James Chou, PhD
Professor of Biological Chemistry and Molecular Pharmacology, HMS
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Zoom information
Topic: George Chao: MEMP PhD Thesis Defense
Time: Thursday, September 10, 2020 2:30 PM Eastern Time (US and Canada)
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