From semi-synthetic to fully biological

Designing novel pathways for the production of pharmaceuticals and biochemicals using advanced engineered micro-organisms: that is the major challenge for the next years of BE-Basic’s Flagship 2 programme which covers nitrogen-based specialities. “This is high risk research, but if we succeed it will also have a high impact.”

“We are working on nitrogen-based compounds, for example proteins and pharmaceuticals. These are mostly specialities, some of which are only produced in small amounts but which have high added value, the opposite of the carbon-based compounds of Flagship 1 that are mostly bulk commodities,“ says Prof. Arnold Driessen of the University of Groningen and Director of the Groningen Biomolecular Sciences and Biotechnology Institute. “What we have in common is that we work in close collaboration with Dutch industry. Our scientists do part of their work at the companies and part at the university.” The consortium focuses on three major themes. The first of these concerns improving the protocols for the purification of proteins by studying practical cases from industry. “Developing an effective purification method is a time-consuming process. We are going to speed that process up by miniaturisation and the automation of test protocols. This enables us to screen a wide variety of conditions which delivers reliable predictions for optimal conditions for the purification process at a larger production scale,” Driessen explains. “This enabling technology means the industry can bring its products to the market faster.”


Reprogramming pathways

There is a need for antibiotics that are not already naturally made by microorganisms. The second research theme focuses on the production of these kinds of antibiotics with the aid of microorganisms. “We are looking at antibiotics for which a semi-synthetic route already exists. A part of the production process is biological via fermentation, another part is done chemically. What we want to reach is a fully biosynthetic process,” says Driessen. Making these compounds demands extensive reprogramming of the microorganism. The problem is that the enzymes needed to take over the chemical steps do not yet exist. “Therefore we have to reprogram the antibiotic production pathways completely by designing new enzymes that catalyse the conversion steps we require. This is a major challenge”, says Driessen. “It is high risk research, but if we succeed it will also have a high impact. We are confident that it will be possible at the end.” The organisms that he and his colleagues are working on are closely related to the organisms that are used in an industrial setting. “You get what you ask for,” according to Driessen. “When you focus on a certain model organism you eventually get a working process in that particular organism. You can compare this to the development of drugs against cancer. Being able to fight cancer in a mouse using a certain drug does not mean that you can treat cancer in humans. There is still a large step to make. This is why we are working close to the real production micro-organism, to make the transition easy at the valorisation step.”

Unnatural compounds

The third theme is still in a pilot phase and concerns the biological production of chemical compounds for biomaterial from renewable sources. At present these compounds are made of fossil fuels. “In our specific case we are working on an unnatural compound. The biological processes for synthesising these compounds are not known, so we have to start almost from scratch. This requires a huge amount of work compared with some of the carbon-based compounds, such as bio-ethanol, for which the biological production pathways exist in nature.” Another challenge is that material applications require bulk amounts of the intended chemical which therefore has to be produced in large quantities. This means a very efficient process is needed to overcome the low margins on profit in bulk commodities. “We are still in the enzyme design and enzyme discovery process and are now working on a proof of principle. But if we succeed, we will open a drawer full of possibilities for similar components that can be produced this way.”


January 2010