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Multicellular Circuit Design in Mammalian Cells

Citation

Zhu, Ronghui (2023) Multicellular Circuit Design in Mammalian Cells. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/p0fn-qa56. https://resolver.caltech.edu/CaltechTHESIS:07252022-061122576

Abstract

Multicellular circuits control the development of multicellular organisms, through programming processes such as cell proliferation, cell differentiation, cell movement, and cell signaling. A fundamental goal of biology is to understand the design principles of these multicellular circuits, and use these principles to design synthetic multicellular systems for therapeutic purposes. Top-down approaches, for example analyzing embryos bearing genetic mutations, have identified key genes in many multicellular circuits, but are challenging to study these circuits in an isolated context and in a quantitative and systematic manner. An alternative, complementary approach is to engineer or reconstitute multicellular circuits from bottom-up, which allows us to overcome the limitations of top-down approach and gain quantitative insights into multicellular circuit design. In this thesis, we use this bottom-up approach to explore the design principles of two multicellular circuits. In the first project, we took inspiration from two prevalent features from natural multistable circuits, namely competitive protein-protein interactions and positive autoregulation, to design a synthetic multistable circuit architecture called MultiFate. Both in the model and in the experiment, MultiFate circuits generate multiple cellular states, each stable for weeks, allow control over state-switching and state stability, and can be easily expanded to generate more states. In the second project, we use a gradient reconstitution system to systematically analyze a gradient modulation circuit consisting of BMP4 and its modulators, Chordin, Twsg and BMP-1. We found that the circuit can give rise to diverse gradient modulation capabilities. In particular, the full circuit is sufficient for active ligand shuttling and generation of non-monotonic displaced gradient. These multicellular circuits could provide a foundation for engineering synthetic multicellular systems in mammalian cells.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:Developmental biology; Systems biology; Synthetic biology
Degree Grantor:California Institute of Technology
Division:Biology and Biological Engineering
Major Option:Biology
Thesis Availability:Restricted to Caltech community only
Research Advisor(s):
  • Elowitz, Michael B.
Thesis Committee:
  • Hay, Bruce A. (chair)
  • Bjorkman, Pamela J.
  • Murray, Richard M.
  • Thomson, Matthew
  • Elowitz, Michael B.
Defense Date:14 June 2022
Non-Caltech Author Email:zhuronghui2011 (AT) gmail.com
Record Number:CaltechTHESIS:07252022-061122576
Persistent URL:https://resolver.caltech.edu/CaltechTHESIS:07252022-061122576
DOI:10.7907/p0fn-qa56
Related URLs:
URLURL TypeDescription
https://doi.org/10.1126/science.abg9765DOIA published version of chapter 2 of the thesis
ORCID:
AuthorORCID
Zhu, Ronghui0000-0001-8171-482X
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:14986
Collection:CaltechTHESIS
Deposited By: Ronghui Zhu
Deposited On:29 Jul 2022 18:37
Last Modified:29 Jul 2022 18:37

Thesis Files

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