Gene Circuits Move onto “The Grid”

Published in Chemistry
Gene Circuits Move onto “The Grid”

Synthetic biology sits at the interface between biology and engineering, and through the rational assembly of biomolecular systems seeks create new function.  The field is transitioning from a primarily tool-building phase into a phase that is increasingly pointed toward practical applications.  This trend is bringing the field toward even greater interdisciplinarity as synthetic biologists incorporate engineered materials and hardware to enable the practical implementation of their tools.  Our project, published in Nature Chemistry today, reflects this trend with a report that brings synthetic biology together with electrochemistry.  This first attempt to directly couple these systems comes from a collaboration of efforts in cell-free synthetic biology from my group, electrochemistry from the Kelley lab and sensor design from the Green lab.  

Before getting into the details of this work, it is probably useful to step back and provide some context for readers who may be less familiar with the field of synthetic biology and cell-free applications.  In recent years, there has been an emergence of cell-free synthetic biology, which when reactions are freeze-dried, can allow genetically encoded tools to be deployed outside of laboratory in a biosafe format.  Powered by the cell-free enzymes of transcription and translation, the addition of DNA encoding a gene-circuit-based sensor transforms these biochemical systems into portable tools for point-of-need detection.

In moving these systems into practical applications, like any diagnostic technology, we faced the challenge of how to test for the range of possible diseases that can arise from a set of observed symptoms.  The conventional approach would be to use a separate test for each pathogen, with each test representing an additional unit of cost.  Such gene-circuit-based sensors have relied on optical reporter proteins (e.g. colorimetric, fluorescent) which have limited capacity for discrete signaling due to the crosstalk between wavelengths.  It is through this lens that we decided to tackle the challenge of multiplexing and in doing so we built an electrochemical interface that has the potential for as many as ten distinct gene circuit outputs in a single reaction.  We demonstrate the technology in a series of validation experiments, including the parallel detection of antibiotic resistance genes for colistin, a last line antibiotic.  

What is not evident from the technical details of the paper are the struggles faced in bringing this technology into practice.  And for this I applaud all members of the team who made this project a reality, especially the co-first authors Peivand, Sarah and Jenise whose efforts were critical in establishing the core technology.  Some examples include the Herculean task, led by Peivand, of methodically screening over 60 enzymes to identify the final set of potent reporters.  Sarah and Jenise, similarly faced great challenges in developing the electrodes best suited for the job, and I’m sure the team easily reached their 10,000 daily steps running up and down the stairs between our respective labs!  None of these challenges were met in isolation and the collaborative spirit shone throughout the project.   

Beyond our present study, we are excited by how this work may move the field toward more sophisticated synthetic biology applications and greater interaction with electronics and software.  Moving synthetic biology out of the cell has already greatly reduced the complexity of creating engineered gene circuits and we see the direct interface with electronics as a further step toward simple, rational design.  Here, biohybrid systems have the potential of off-loading the tasks of logic calculation and memory, which are complex and time-consuming functions to encode genetically, to electronics.  While not without limitations, we see the merger of synthetic biology’s capacity for molecular recognition with electrochemistry as a formative step toward biohybrid systems that can be programmed using both nucleic acid sequences and a keyboard.

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