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New opportunities for on-demand activation of synthetic cells

The team of Alexander Zelikin from Aarhus University in Denmark aims to engineer synthetic cells with responsive and adaptive behaviour. They have recently designed artificial vesicles that can sense an extracellular stimulus and respond by activating the process of transcription, which is essential for life. They have also highlighted the importance of cellularity by showing that the different processes could not have occurred without the presence of a separating membrane. Their work opens up new work opportunities in the field of controllable, on-demand activated synthetic cells, bringing us a step closer to practical applications.

The study was published in Advanced Materials in February 2024.

Schematic illustration of the transmembrane activation of transcription by alkaline phosphatase, mediated by the thiogen. Advanced Materials, 2024, Volume: 36, DOI: (10.1002/adma.202309385)

Controlling the response of synthetic vesicles to external events

The responsive behaviour of living cells relies on transmembrane signalling, followed by downstream signalling inside the cell. Transplanting natural signalling pathways from living cells into their synthetic counterparts has so far had only limited success. It is for this reason that the engineering of responsive behaviour in synthetic cells represents a major challenge.

The Zelikin lab is seeking to meet the challenge of engineering and controlling responsive behaviour in synthetic cells. To this end, this team has previously developed transmembrane signalling systems using synthetic organic molecules and has succeeded in activating enzymatic activity on demand, enabling them to engineer downstream signalling.

In their new study, in which they used giant unilamellar vesicles as models of synthetic cells, the team accomplished transmembrane activation of the synthesis of ATP, a molecule that provides energy to cells and supports many cellular processes; and transcription, an essential process for living cells to produce components they need, in this case, RNA.

“The key design consideration for this study was the use of chemical zymogens. These are enzymes, catalysts, that we designed to be activated on demand. We developed an approach to reversibly deactivate the enzymes and thus block the process of transcription. Then we engineered a transmembrane event, connecting an extracellular trigger to the production of the enzyme activator, which penetrated through the lipid bilayer of the membrane and activated the production of ATP and RNA within the GUVs,” said Alexander Zelikin.

The importance of compartmentalisation

This study also highlights the importance of cellularity. “The extracellular trigger we used, namely alkaline phosphatase, is a poison for transcription itself. Mixed in the same volume, it inhibited the production of RNA. But separated by the cell membrane, it became the activator of the whole reaction. So everything works because it’s been done in a compartmentalised environment. We stress this because we know that life has progressed on the planet by becoming increasingly compartmentalised.”

References

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