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Components Designed to Improve Genetic Circuits

Matthew Bennett

Matthew Bennett (Rice University)

12 January 2018. Researchers in Houston, Texas created a set of components like those in electronics that help make synthetic gene circuits more accurate and predictable. A team from Rice University and University of Houston describe their discoveries in the 4 January issue of the journal Nature Communications.

The researchers led by Rice biophysicist Matthew Bennett are seeking tools for improving the performance of genetic circuits in synthetic biology, to produce biological systems that operate with more precision and reliability than their natural counterparts. An example are probiotics, gut microbes essential for human health and of growing interest to synthetic biologists for new diagnostics or disease therapies. “Such engineered probiotics,” says Bennett in a university statement, “would be able to produce drugs or other complex molecules within the human body to fight diseases ranging from cancer to inflammatory bowel disease.”

Engineering probiotics is a continuing project of Bennett’s lab. In October 2016, Science & Enterprise reported on a grant awarded by NIH to Bennett for developing synthetic intestinal microbe circuits that respond to food to release therapeutic proteins.

Accomplishing these goals require genetic systems that can sense conditions in their environment, then respond predictably and with precision, which in most cases are not possible with genes in their natural state. Bennett and colleagues designed a set of components that send genetic signals, but work like logic gates in semiconductors, switching ON and OFF states as needed. The components focus on the promoter region of DNA, the part of the genetic code that defines where the code begins to translate into enzymes known as RNA polymerase, and where related proteins bind to the genetic code to start that transcription process.

Using Escherichia coli or E. coli bacteria as a test case, the Rice-Houston researchers built circuits in the promoter region of their bacterial DNA. A type of E. coli bacteria can cause food poisoning, but other benign forms of the microbe are often used in biology labs as model organisms. The circuits operate with Boolean functions and represent the range of biochemical interactions for binding and release of RNA polymerase to begin transcription. Mathematicians from University of Houston, led by  Krešimir Josic, calculated specific properties needed for the circuits, later collected into a library of components for testing in E. coli.

One of the key properties designed into the synthetic gene circuits is control of leakiness, a problem in some natural genes, where even in an OFF state, the promoter still allows some transcription to take place. Stopping leaks from the synthetic genes allows for more precise control over transcription of genetic codes, which enables the circuits to be assembled into more complex genetic forms.

The authors conclude their technology offers a simple and cost-effective method of engineering promoter genes that allow users to fine-tune synthetic biological and chemical circuits inside living cells. Josic’s lab makes available the R statistical code for engineering promoter-genetic circuits through GitHub.

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