In synthetic biology, there is currently a great deal of work being done with light. Thus for example bio-engineers are designing genetic networks that they can use light to control. These biological circuits consist of components – mostly various genes and proteins – that are logically linked to one another, and are incorporated into living cells. They can be switched on and off with light, because, for example, a light-sensitive molecule activates the imported gene. The “output” is ultimately a particular protein. Thus researchers working with ETH Zurich’s Professor Martin Fussenegger of the Department of Biosystems Science and Engineering (D-BSSE) have unveiled a light-sensitive gene network of this kind that can be activated by blue light and produces a hormone that regulates insulin (see ETH Life of 24.06.2011).

One difficulty with such circuits is that the production of the desired protein is not constant over time. With computer control, the three groups from the D-BSSE, the Department of Information Technology and Electrical Engineering (D-ITET), and the University of California, San Francisco, have managed to regulate a light-sensitive gene network in such a way that it “works” robustly for hours, and achieves a stable yield. This work, led by the three principal investigators John Lygeros (D-ITET), Mustafa Khammash (D-BSSE) and Hana El-Samad (University of California), was recently presented in “Nature Biotechnology”.

Control promotes protein production

The gene network that has been incorporated into yeast cells can be switched on with a red light and off with a darker red. Once it has been activated, it produces a particular protein. The production of this protein does, however, decrease over time if no further light pulse is used to activate the corresponding gene. It is here that the computer control system which the electrical engineers have developed intervenes. The software registers the gene activity and compares the actual state of protein production in the cell with the target value specified in the program. If the actual value differs from the desired pre-set level, the computer calculates the necessary response in order to reattain this level, for example which light signal must be given in order to boost protein production. This enables the “output”, in other words the desired protein, to settle at a constant level.

“With our control system, we have been able not only to increase synthesis of the protein in the cells, but also to stabilise it”, says co-author John Lygeros, Professor at ETH Zurich’s Automatic Control Laboratory. He believes it allows the biological system to work more robustly, and, ultimately, better.

Great potential for applications

The experiments were tough for the students, recalls the professor. His students had to conduct them in the middle of the night, as the manipulated cells could not be exposed to light under any circumstances. The cells were sealed in a mini dark room, in which the light pulses were emitted.

John Lygeros foresees great potential for applications of this technology. In the future, the approach could be used for achieving better control of biological processes. Thus, for example, genetically modified bacteria could be used for the production of antibiotics or bio-fuels; with external control, these could be made to achieve greater yields.