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Bionic chemistry: developing tailor-made functional units for bacterial cells

Dr. Stefan Schiller from the Center for Biological Systems Analysis (ZBSA) at the University of Freiburg combines synthetic biology and synthetic chemistry concepts in order to equip bacterial cells with organelle-like compartments. He has countless biotechnological applications in mind. In 2014, Schiller received the research prize “Next Generation of Biotechnological Methods – Biotechnology 2020+”. The prize is awarded every two years and provides around 3.4 million euros in funding for a period of five years.

New cellular compartment: (I) schematic representation, (II) TEM image showing the formation of compartments within E. coli visualised by fluorescence staining (top image). © Dr. Stefan Schiller, University of Freiburg

No one has yet come up with a standard definition for the discipline of synthetic biology, which is a combination of many research approaches in chemistry, engineering and the life sciences. Synthetic biology is still mainly basic research aimed at designing biological systems with new properties and functions that can be used to create beneficial applications.

The chemist Dr. Stefan Schiller from the Center for Biological Systems Analysis (ZBSA) at the University of Freiburg explores and designs nanobiotechnological systems to develop new processes in cells for application in biotechnology, medicine, chemistry and the material sciences. His goal is to expand the functional spectrum of cells to enable them to carry out new reactions. The idea is to use a synthetic biology approach to enable bacteria, which in contrast to eukaryotic cells lack intracellular departments, to form membrane-enclosed departments.

Synthetic organelles for E. coli

Schiller has always been fascinated by complex systems and the development of new, defined structures from their building blocks. He calls his field of research ‘bionic chemistry’, which essentially means adopting molecular concepts from nature. “At this level, cells are particularly beautiful because you can grasp their molecular composition and discern the many hierarchical levels of their structures,” he says. “We take molecules and functions from natural biological systems and redesign them using methods from synthetic chemistry and synthetic biology to develop new compartments with new properties and functions,” says Schiller. Schiller therefore focuses on ways that enable the de novo synthesis and self-assembly of organelle-like compartments in bacteria in vivo, i.e. reaction chambers in which active substances, chemicals and biomaterials can be produced. “We are seeking to create modular units that can be assembled in various combinations for use in a broad range of biotechnological methods,” says the scientist.

His plan is also to equip enzymes with new functions so that they work more efficiently under new conditions. The materials he will use include biohybrid nanomaterials consisting of biological, chemical-organic and inorganic molecules. The hybrid character of the proteins which Schiller has designed gives the vesicle-like organelles new physical properties. Moreover, Schiller’s designer proteins are amphiphilic and spontaneously form artificial membrane-based organelles.

This idea of modifying bacteria for the environmentally friendly and energy-efficient production of substances led to Schiller and his team being awarded the BMBF research prize “Next Generation of Biotechnological Methods – Biotechnology 2020+”. Schiller will use the prize money to finance six staff members to help him advance the project over the next five years.

Elastin-like proteins and hybrid catalysts

E. coli as living factory: the bacterial cell produces a protein (red) which was genetically engineered to contain a new component. This synthetic protein leads to the formation of a new compartment. © Dr. Stefan Schiller, University of Freiburg

This innovative project involves both natural and synthetic components and processes: the DNA of the bacterial cell is modified to code for proteins with the desired properties; synthetic and hybrid components are then constructed outside the cell and subsequently introduced into it. Schiller’s work focuses on biological protein building blocks. The membrane of cellular organelles is normally composed of phospholipid building blocks, which have the disadvantage of being secondary gene products and as such not directly encoded in the genes. They cannot therefore be upregulated directly to produce new or extra compartments. “We then came up with the idea of developing proteins that had the required design and functionality,” says Schiller. 

The researchers ideas are based on elastin, an elastomeric protein that is also comprised in vesicular cell structures. The researchers used elastin-like proteins (ELP), i.e. artificial genetically encodable proteins, for their research. The modifications provided the new ELP with suitable amphiphilic properties (i.e. a suitable hydrophilic versus hydrophobic ratio) that enabled it to form vesicular structures without any other cellular constituent. “This molecular constituent has a very simple basic geometric structure and easily and spontaneously forms vesicular structures in vivo,” says Schiller who has previously demonstrated that ELPs form such structures in vitro in cooperation with his colleagues Dr. Matthias Huber and Dr. Andreas Schreiber. 

The concept can also be used to form fusion proteins equipped with a specific component that gives them a specific function. Creativity knows no bounds. Schiller and his colleagues have shown that there are other ways of giving the new cellular organelles new functions. For example, catalytic metal-based units can be brought into cells that would otherwise not synthesise them. This essentially means that the cells perform chemical processes they would not naturally perform. 

Bacteria as living molecular factories

Schiller and his team of researchers are currently testing whether de novo organelles can be used as reaction chambers for interesting biotechnological applications. Many researchers are considering functionalising these compartments to enable bacterial cells to produce molecules which, under normal circumstances, would lead to cell death. The substances could thus be incorporated actively or passively into the organelles, which would then assume the function of vacuoles. Substances could either remain in place when no longer needed or be removed if they turned out to be of interest for a particular process.

In addition, it is also possible to equip the inner and outer surfaces of the vesicle-like vacuoles with enzymes that can convert a substrate into products. Potential limitations regarding transport of the raw materials into the organelles and the function of the enzymes on the compartment surfaces still need to be examined.

However, it is probably safe to assume that there are not only more but also more complex applications than those that are currently possible with genetic methods. Everything is feasible, from the production of complicated active ingredients for biopharmaceutical drugs to sustainable raw materials for energy carriers and biomaterials. “We are open to every possibility,” says Schiller, “whether it’s the living cell system fermenting something really special or the entire cell being added to a reaction mixture. We are happy with whatever works.”

Further information:

Dr. Stefan Schiller

FRIAS (Freiburg Institute for Advanced Studies)
University of Freiburg
Albertstr. 19
79104 Freiburg
Tel.: +49 (0)761 / 203 97405
E-mail: stefan.schiller(at)frias.uni-freiburg.de

ZBSA (Center for Biological Systems Analysis)
University of Freiburg
Habsburgerstr. 49
79104 Freiburg
Tel.: +49 (0)761 / 203 97194


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