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Engineering Logical Inflammation Sensing and Secreting Circuit for Gut Modulation


Merk, Liana Noor (2021) Engineering Logical Inflammation Sensing and Secreting Circuit for Gut Modulation. Senior thesis (Major), California Institute of Technology. doi:10.7907/wr7s-6436.


The mammalian gut contains trillions of microbes that interact with host cells and monitor changes in the environment. Opportunistic pathogens exploit environmental conditions to stimulate their growth and virulence, leading to a resurgence of chronic disorders such as inflammatory bowel disease (IBD). Current therapies are effective in less than 30% of patients due to the lack of adherence to prescription schedules and overall, off-target effects. Microbial therapeutics can be engineered to colonize the gut, providing in situ surveillance and conditional disease modulation. However, many current engineered microbes can only respond to single gut environmental factors, limiting their effectiveness. In this work, we implement a previously characterized split activator AND logic gate in the probiotic E. coli strain Nissle 1917. Our system can respond to two input signals: the inflammatory biomarker tetrathionate and a second input signal, IPTG or aTC. We report 4-6 fold induction with minimal leak when both signals are present. We model the dynamics of the AND gate using chemical reaction networks, and by tuning parameters in silico, we identified perturbations that affect our circuit’s selectivity. We then engineer our optimized AND gate to secrete an anti-inflammatory therapeutic cytokine, IL-22, using the hemolysin secretion pathway. We anticipate that our results will prove useful for designing living therapeutics for spatial targeting and signal processing in complex environments.

Item Type:Thesis (Senior thesis (Major))
Subject Keywords:microbiome engineering, synthetic biology, inflammation, circuit modeling
Degree Grantor:California Institute of Technology
Division:Engineering and Applied Science
Major Option:Bioengineering
Awards:George W. and Bernice E. Green Memorial Prize, 2021.
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Murray, Richard M.
Thesis Committee:
  • None, None
Defense Date:4 June 2021
Non-Caltech Author Email:liana.merk (AT)
Record Number:CaltechTHESIS:06042021-234419803
Persistent URL:
Merk, Liana Noor0000-0001-9711-954X
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:14245
Deposited By: Liana Merk
Deposited On:09 Jun 2021 20:47
Last Modified:03 Nov 2021 19:04

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