Bacterial Approach Brings Life-Like Synthetic Cells a Step Closer to Reality

Researchers in the United Kingdom have made an important advance in the development of synthetic cells that more accurately mimic the structure and function of living cells.

Establishing true-to-life functionality in synthetic cells—also known as protocells—is an endeavor pursued globally and spanning multiple fields like synthetic biology, bioengineering, and origin-of-life research. After previous attempts to model protocells using microcapsules fell short, the University of Bristol team turned to bacteria to build complex synthetic cells using a living material assembly process. The results were published recently in the journal Nature.

“Achieving high organizational and functional complexity in synthetic cells is difficult especially under close-to-equilibrium conditions,” says Professor Stephen Mann from the University of Bristol’s School of Chemistry and the Max Planck Bristol Centre for Minimal Biology. “Hopefully, our current bacteriogenic approach will help to increase the complexity of current protocell models, facilitate the integration of myriad biological components and enable the development of energized cytomimetic systems.”

In the first step, Mann and colleagues exposed empty, viscous micro-droplets to two types of bacteria. One population spontaneously was captured within the droplets while the other was trapped at the droplet surface.  Then, both types of bacteria were destroyed so that the released cellular components remained trapped inside or on the surface of the droplets to produce membrane-coated bacteriogenic protocells containing thousands of biological molecules, parts and machinery. 

The researchers discovered that the resulting protocells were able to produce energy-rich molecules (ATP) via glycolysis and synthesize RNA and proteins by in vitro gene expression, indicating that the inherited bacterial components remained active in the synthetic cells.

Further testing the capacity of this technique, the team employed a series of chemical steps to remodel the bacteriogenic protocells structurally and morphologically. The released bacterial DNA was condensed into a single nucleus-like structure, and the droplet interior infiltrated with a cytoskeletal-like network of protein filaments and membrane-bounded water vacuoles.

As a step towards the construction of a synthetic/living cell entity, the researchers implanted living bacteria into the protocells to generate self-sustainable ATP production and long-term energization for glycolysis, gene expression and cytoskeletal assembly. Curiously, the protoliving constructs adopted an amoeba-like external morphology due to on-site bacterial metabolism and growth to produce a cellular bionic system with integrated life-like properties.

“Our living-material assembly approach provides an opportunity for the bottom-up construction of symbiotic living/synthetic cell constructs. For example, using engineered bacteria it should be possible to fabricate complex modules for development in diagnostic and therapeutic areas of synthetic biology as well as in biomanufacturing and biotechnology in general,” says first author Dr Can Xu, Research Associate at the University of Bristol.