Publication! Recreating signals in the cell

Last week, ir. Rik van Roekel and Tom de Greef published in the renowned journal Nature Chemistry, one of the most important journals in their field of expertise, in collaboration with their colleagues of the Radboud University of Nijmegen. In the article, they write about their findings regarding recreating oscillations in the cell (Rational design of functional and tunable oscillating enzymatic networks, Nature Chemistry7, 160-165 (2015)).

Oscillations as signal
In the body and bodily cells, a continuous process of communication takes place with a great variety of signals. Our knowledge about these signals and processes in the cell is still limited, however the results of this research shed some new light; the researchers have managed to recreate oscillations outside of the cell.

Biochemical oscillations occur as a consequence of an auto-catalytic process: on the one hand, the molecule multiplies itself, increasing the concentration of the molecule. At the same time, the molecule breaks itself down, the so-called inhibition, resulting in a reduction of the concentration. This inhibition is a process the molecule cannot do by itself, a reroute is necessary with help of different molecules. If this positive feedback (multiplying) and negative feedback (inhibition) are precisely in tune, an oscillation (wave pattern) takes shape in the concentration of the molecule.

From theory to functional system
In this research, the enzyme trypsin was used; this enzyme is easily available and therefore a good starting point for building an oscillating biomolecular circuit outside of the cell.

Computer models
To achieve an oscillation of the trypsin concentration, many factors have to be tuned meticulously. This is too complex for manual calculations and therefore computer models were an important part of the research. By making a computer model of the entire system involving all the enzymes, concentrations and settings, the process could be analyzed. As a result of this analysis, the conditions needed for an oscillation pattern were found: the concentration of trypsin increases and decreases in a stable wave pattern that is maintained by the system.

Laboratory set-up
Subsequently, this system with trypsin is rebuild in a laboratory set-up with the help of microfluidics; with this technique, very small volumes (micro scale) of liquids are mixed, moved, separated or otherwise processed. Ultimately, the oscillation pattern was successfully reproduced in the laboratory set-up.

What will the future bring?
This research is still in full swing. Firstly, the researchers are looking at expanding the system with other or more settings or enzymes. Secondly, there are plans to develop a comparable model for other enzymes (instead of trypsin), which are for example important in the cell or in the extracellular matrix. Naturally, this research reaches beyond this single process and work is also done on the analysis of different kinds of signals and circuits of signals, for example a constant signal that is active during a certain period of time.

Possible applications
What the far future will bring is still unsure. However, this field of research has a lot of potential. The more we learn about the cell, the signals and enzymes, the more we can understand complex diseases. There are multiple ideas on how the results of this research can be used in society in the future, like influencing the release of medicine. Currently, medicine is released in a constant flow, but there is research that shows that cells respond differently and possibly better to an oscillating flow. Tom de Greef Tom de Greef is specialized in synthetic biology. He is assistant professor in the research group Computational Biology of prof.dr. Peter Hilbers of the department of Biomedical Engineering. He works in close collaboration with the research groups Chemical Biology and Biomedical Chemistry and with the Institute for Complex Molecular Systems (ICMS).

Synthetic biology
Research in the field of synthetic biology focusses on the construction of cells and biological materials using a bottom-up method. With this method, instead of zooming in from the human body towards the cells and molecules, research starts at a molecular level and works upwards towards systems and cells. The purpose is to gain more knowledge about the cell and get more insight into processes in the cell.

Research Center for Functional Molecular Systems
The research is part of the Research Center for Functional Molecular Systems (FMS), a partnership of the chemistry research groups of Eindhoven University of Technology (TU/e), Radboud University Nijmegen and the University of Groningen. Since 2013, they work together in this cooperation on the field of chemical self-assembly, focusing on the construction of functional lifelike molecular systems. The center is founded within the gravitation program with a grant of 26 million euros of the Ministry of Education, Culture and Science.