Synthetic Biology: Engineered Bacteria

The E. coli bacterium produces a protein to which a sugar is attached using an engineered glycosylation machinery. Outside the cell, enzymes trim off the monosaccharide. Other chemically synthesized sugars are then attached. (Diagram: F. Schwarz / ETH Zurich)

When the intestinal bacterium E. coli and the diarrheal pathogen Campylobacter work together, it does not have to result in serious illness. Rather, when biologists and chemists team to use the product of this bacterial collaboration, it opens up a whole new technology with potential pharmaceutical applications. Now, the PhD student Flavio Schwarz from Professor Markus Aebi's group at the Institute of Microbiology of ETH-Zurich and researchers from the University of Maryland have developed a new method for producing glycoproteins.

New tool

E. coli is a well-known biological workhorse that can be used to produce recombinant proteins. The problem is that E. coli is missing many of the functions required to modify proteins with sugar molecules. Markus Aebi's team, however, recently discovered that Campylobacter can do something that only eukaryotes like human cells can: attach sugar molecules to proteins following synthesis to produce glycoproteins.

The researchers recently reported this ground-breaking work in the journal Nature Chemical Biology. In this engineered glycosylation system, some of the genes from the Campylobacter glycosylation machinery are introduced into E. coli, thereby enabling the E. coli to produce glycoproteins. In a second step, unnecessary parts of the sugars are removed outside the bacterial cells and replaced with chemically synthesized sugar molecules of different size and structure, to produce sugar structures resembling human glycans.

Glycoproteins define blood group

This means that different glycoproteins can now efficiently be produced, thus helping researchers to analyze the structure and function of individual glycoproteins in a more precise manner. If you want to study host-pathogen interactions, for instance, you need pure samples of a particular glycoprotein, whereas natural systems can only offer researchers a highly complex blend of such substances.

Glycoproteins play a crucial role in biology. They are found more frequently on the surface of cells than "normal" proteins and they participate in numerous cellular processes, such as cell to cell communication. They are present throughout the human body, also in mucus, and the different glycosylation of blood proteins contribute to define the blood group antigen.

Blossoming concept

The new technology also has great potential for the development of new cancer treatments. These therapeutic glycoproteins can be produced specifically-tailored to remain in the bloodstream longer while targeting cancerous cells.

"For now, we have simply managed to prove that our concept works. It remains to be seen what potential practical applications it might have," says Flavio Schwarz from the Life Science Zurich Graduate School. The new process was actually a "by-product" of his dissertation -- further proof that basic research can also produce application-oriented results. It just needs resourceful people like Flavio Schwarz who recognize this.