A possible new way of optimising resources in synthetic cells

Whether it’s to decipher the rules of life or to design technologies inspired by how cells work, scientists working on synthetic cell research are trying to reconstitute the main characteristics of life and, ultimately, to build a model, a synthetic cell, from scratch. Building a model of a cell, in which all the parts are perfectly understood and compatible with each other, is so complex and difficult that scientists try to use only a limited number of components.

Roy Bar-Ziv’s team in Israel may have a new method to propose to help with this ambitious project. With colleagues in Germany and the United States, they have demonstrated and characterised a mechanism that regulates genes and could help, in the context of synthetic cells, to optimise resources and functions.

Genetic circuits unexpectedly created outside closed compartments

The DNA molecules of living cells contain genes, each carrying information encoded to make specific proteins and enable cells to function properly. In closed compartments, such as in living cells or artificial vesicles, the production of a protein can trigger a cascade of reactions, interacting with other genes, and activating or repressing their expression. This loop of reaction is a genetic circuit and plays a role in regulating gene expression.

In a previous experiment, Roy Bar-Ziv‘s team had been surprised to observe the formation of genetic circuits in semi-open compartments where the proteins produced were highly dilute and therefore not expected to bind to other genes and regulate their expression. They hypothesised that a process of “co-expressional localisation” had facilitated the creation of genetic circuits on these single DNA molecules. The same team at the Weizmann Institute of Science in Israel has now observed and demonstrated this hypothesis. 

Genetic circuits are formed by nascent proteins before they are carried away

Roy Bar-Ziv and Ferdinand Greiss

In a recent study published in Nature Communications, in collaboration with researchers in Germany and the United States, first author Ferdinand Greiss used his expertise in fluorescence microscopy to develop a method for observing the production of proteins from a single molecule of DNA outside a compartment.

Using this method, they were able to identify what they call the “co-expressional localisation” mechanism: they observed that the nascent protein, still attached to the DNA molecule via the gene expression machinery decoding the gene, had time to interact and bind to another site on the same DNA molecule before being carried away. They then used this mechanism to design, under cell-free conditions, DNA nanodevices encoding proteins that would regulate other genes from the same DNA molecule.

Could this mechanism be applied to the design of synthetic cells? Doing more with less

“When a DNA molecule only produces five to ten proteins per hour, you have to find ways to be efficient with those proteins,” said Ferdinand. “The colocalisation mechanism increases the effective concentration of proteins in the vicinity of the DNA molecule, leading to greater efficiency in the design of genetic circuits and gene regulation.”

Ferdinand and his colleagues believe that this co-expressional localisation mechanism could help make the most of the limited resources introduced in synthetic cells and optimise the functions that develop within them.

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