Diverse genetic error modes constrain large-scale bio-based production

Only a few bioprocesses are functional in the large fermentation volumes that industry requires. A team of Danish researchers may have found the key

The transition towards sustainable biobased chemical production is important for green growth, but productivity and yield of engineered cells frequently decrease in large industry-scale fermentation. This barrier to commercialization of more bioprocesses is largely ascribed to the physical inefficacies of large cubic-meter steel tanks.

“One central issue is that bioproduction in large-scale fermenters is limited by toxicities and stresses that allow evolution to reduce or eliminate production of chemicals by engineered cells. This makes it expensive and challenging to commercialize biobased production systems in particular when large amounts of chemicals are needed” says Morten Sommer, Professor and Scientific Director of the Bacterial Synthetic Biology section at the Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark.

The key to overcoming this, say scientists from the Novo Nordisk Foundation Center for Biosustainability, is to rewire production cells to grow only when they contain high product concentration, thus circumventing evolution. Cells will then be able to produce the biochemicals within an industrial time scale.

“When we rewire the production microorganism to slow down growth in case it loses production, we efficiently prevent it from performing evolution on the genes leading to production. This allows us to maintain productive cells even when the cells divide to fill up large fermentation tanks,” says Peter Rugbjerg, Postdoc at the Novo Nordisk Foundation Center for Biosustainability.

Evolution is beneficial for the cell. However, what is good for the cell may not be good for a biobased process in a fermentation tank. In a fermentation tank evolution can eliminate production – especially during large scale fermentations.

The underlying idea of the new study is to circumvent the evolution occurring in production cells by using a so-called molecular biosensor that senses the product, mevalonate, inside the production cells. The biosensor has the ability to shut down growth if the production concentration declines below a certain point.

This concept is demonstrated by the scientists and can help in driving the development towards a more sustainable society. At this point, microorganisms do not naturally produce high amounts of valuable chemicals, which demands the use of many R&D resources. An expensive process that delays the launch of new biobased processes.

“Engineered, high-level bioproduction of chemicals is not attractive for the cell that tends to grow slower and explore ways to evolve and stop production. This makes it difficult to bridge the gap between research conducted in lab shake flasks and industrial need for large cubic-meter quantities,” emphasizes Peter Rugbjerg.

If the findings from the study are broadened out to more production cases, a major obstacle for investing in biobased production is removed. The group at the Novo Nordisk Foundation Center for Biosustainability currently collaborates with biotech companies to investigate and solve the impact of the evolution in current fermentation tanks.

“The biotech industry clearly indicate that they see a great potential in solving this problem. This study can be a step towards more efficient and affordable large-scale biomanufacturing to the benefit of society”, says Morten Sommer.


… you may read the full article first appeared in open-source journal Nature Communications


Nature, 2018-02-20.


nature (Journal)
Technical University of Denmark – DTU


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