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Designing synthetic condensates that can control cell behaviour

In a recent paper published in Nature Chemical Biology, researchers from Duke University have developed a novel engineering approach to create “synthetic condensates” that can control cellular biochemical processes. In the study, researchers demonstrate that their synthetic condensates can control major cellular processes such as targeted plasmid sequestration and regulation in bacteria, transcription of DNA and RNA in E.coli, and the modulation of protein circuits in mammalian cells.

Engineering intracellular machines

Biomolecular condensates are intracellular structures that play a critical role in regulating cellular behaviour. They are membrane-less organelles are formed by liquid-liquid phase separation, giving them the ability to selectively enrich or exclude biomolecules, RNA and proteins into well-defined yet dynamic structures. This enables active control over cellular processes – the mechanisms behind phase separation weren’t uncovered until 2009, so scientists are only just beginning to understand how these structures work.

Synthetic condensates made with native “intrinsically disordered proteins” (IDPs) fused to functional domains have been used to control cellular behaviours such as proliferation and metabolic flow, as well as reassign codons of selected mRNAs. IDPs are proteins which lack a fixed three-dimensional structure, often due to a lack of interaction with other proteins or RNA. Until now, the ability to manipulate these systems has been limited, as native IDPs can cross-react with other components in the cell. Previous studies have investigated the sequence heuristics, or rules/patterns, that drive the phase transition of IDPs. By applying these heuristics, the team at Duke University designed synthetic IDPs fused with functional domains to engineer the formation of condensates with specific physical properties, through which they can control different cellular processes.

Controlling a cell’s behaviour

In the study, researchers engineered different types of synthetic condensates to control different biomolecular processes (Figure 1). This included building condensates that can control DNA sequestration thus regulating gene flow in bacteria. These condensates could therefore inhibit a process called bacterial conjugation, a major mechanism of horizontal gene transfer – one of the primary methods pathogens use to spread antibiotic resistance genes. They also built condensates that clustered key components that make up transcriptional machinery together with plasmids in E.coli, boosting transcription of specific genes. They then applied this approach to modulate protein circuits in mammalian cells.Regulating the activity of specific genes and proteins in this way could be a potentially revolutionary new way of treating a variety of diseases.

Figure 1 ¦ The design of synthetic condensates and the cellular functions that they can control, as demonstrated by the study.

A new approach

This research is significant because it offers a new way of controlling cellular activity. Previous research has relied heavily on “lock and key” mechanisms, and using proteins, genetic strands or other biomolecules that are just the right shape and size to interact with a specific target.

But cells regulate their activity in a more nuanced way than what is possible with a simple “lock and key” mechanism. Moreover, the dense packing of biomolecular machinery in cells forms a vast and complex network, making it difficult to target specific proteins or molecules, and hard to anticipate all the consequences or compensatory mechanisms that come about by going after a specific target molecule.

By using biomolecular condensates, researchers can create small compartments within cells that either separate or trap certain proteins and molecules, either hindering or promoting their activity. Although the research is still in its early stages, the potential to program cellular behaviour in this way offers exciting possibilities for the future. As Ashutosh Chilkoti, an author of the study noted, “This paper shows that we, as biomedical engineers, can design new molecular parts from the ground up, convince the cell to make them, and assemble these parts inside the cell to make a new machine. These synthetic condensates can then be turned on inside the cell to control how the cell functions. This paper is part of an emerging field that will allow us to reprogram life in new and exciting ways.”

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biotechnology / Synthetic Biology