About This Project
We are studying the co-evolution of synthetic genetic circuits and their carrier host strains. The parasitic resource demand of the circuit impacts the fitness of the carrier cell. In turn, the evolutionary pressure on the carrier cells impact the genetic stability of the circuit. We are building a laboratory evolution platform with the capabilities for robust long-term culture maintenance and automated fossil record collection to study the evolution of this coupled system over time.
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What is the context of this research?
Engineered genetic circuits consist of a collection of genes that are artificially introduced to reprogram a cell for performing a desired task. As these circuits impose a resource demand on their carrier cells for their function and maintenance, mutations and circuit loss that relieve the demand are selected during evolution, resulting in unstable performance. The lack of genetic stability of engineered genetic circuits as a result of their resource demand on the host cell is a major obstacle towards their applications, as reviewed here. To identify the design elements that are critical for determining genetic stability, we are building a laboratory evolution assay to study the evolution of circuits in cells carrying various designs of engineered circuits.
What is the significance of this project?
The project will deliver a low-cost automated platform for laboratory evolution of microbial systems. This platform will enable a wide range of researchers from the fields of engineering biology and microbiology to quantitatively study the evolution of engineered/natural microbial systems. We aim to illustrate its potential in bioengineering applications through the analysis of evolution of engineered genetic circuits. The analysis of phenotypic and genotypic landscapes of circuit evolution will offer insights into the key variables deteremining their genetic stability. The study of evolution of engineered biosystems will also guide safe strategies for their biocontainment to avoid risks from uncontrolled evolution in the application context.
What are the goals of the project?
The goal of this project is to design a laboratory evolution assay which will enable bioengineers to reliably test the genetic stability of their engineered biosystems. To achieve this, we will pursue the following objectives: 1 - Design a microbial bioreactor for automated long-term maintenance of cultures of bacteria containing genetic circuits. 2 - Develop an automated fossil record collection system for high-resolution analysis of phenotypic and genotypic trajectories of circuit evolution. 3 - Publish manuscript describing the integrated platform and biological testing data for its performance benchmarking. Upload design files and parts list to Hackster site for easy open sharing.
We have prototyped a bioreactor system for maintaining and studying a growing microbial culture over extended periods, for studying the evolution of its genome and genetic circuits within it. We would like to expand the system to include on-demand media preparation and automated sterilisation capability. These two modules are critical for long-term stable performance against contamination issues. We need pumps and valves for these modules.
Additionally, we plan to engineer a fossil-record collection module for automatically collecting and storing samples for sequencing analysis. To build this, we need to purchase stepper motors and linear translation stages for positioning the dispensed sample.
Finally, we need some funding to carry out the necessary sequencing analysis of the evolved circuits and the host genome.
We have already invested >15k into this project, from the Biomaker challenge award and a small Mathworks grant. We need the additional fund for further advancement.
The project milestones consist of engineering goals (developing the automated laboratory evolution platform) and biological analysis goals (studying the evolution of the circuit-host system). The individual milestones are described below.
Aug 14, 2023
Aug 15, 2023
Complete the reactor prototype (hardware and software)
Sep 15, 2023
Complete the fossil record collection system (hardware)
Oct 15, 2023
Complete the fossil record collection system (software)
Dec 15, 2023
Set up the on-demand media preparation system
Meet the Team
Our team members are part of the Laboratory of Synthetic and Systems Biology in the Engineering Department at Cambridge University. James Morgan is an MEng student, who is interested in applying his engineering knowledge and skills in tackling challenges in bioengineering. Jack Bradley is an incoming PhD student interested in the role of resource burden in limiting the performance of synthetic bioproduction systems. Dr. Somenath Bakshi will supervise the project.
Somenath Bakshi is an Assistant Professor in the Department of Engineering at the University of Cambridge. He did his PhD in University of Wisconsin Madison under Professor James Weisshaar – developing super-resolution imaging technologies to study central cellular processes in microbes. After finishing his PhD, he moved to Harvard University for his postdoc with Professor Johan Paulsson in the Department of Systems Biology. During his postdoc Somenath developed high-throughput timelapse imaging technologies to study stress-response in bacteria. In 2019, he moved to Cambridge, and established the Laboratory of Systems and Synthetic Microbiology. His work focuses on the analysis of the genetic and metabolic factors underlying the emergence of antibiotic resistance, and engineering diagnostic and therapeutic genetic circuits to combat the spread of antibiotic resistance. He is also the head of the recently established Smart Microscopy Laboratory, which is a cross-school platform for bringing together engineers, computer scientists, and biologists to develop targeted imaging solutions for specific biological problems.
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