Novo Nordisk Publishes New Study on Bioproduction of Chemicals

On Feb. 19, 2018, the Novo Nordisk Foundation Center for Biosustainability announced a new study done by its scientists and published in the Proceedings of the National Academy of Sciences (PNAS) that suggests that cells can be engineered to overcome the evolutionary pressure of limited bioprocesses and can be made to stably produce high levels of valuable chemicals.

The bioproduction of chemicals using engineered microorganisms is routine, but there are only a few bioprocesses that are functional in the large fermentation volumes that the industry requires. The lack of successful scale-up over the long-term remains a major challenge for engineers who seek to replace oil-derived production with biobased production of chemicals, according to Novo Nordisk.

"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," said Morten Sommer, professor and scientific director of the Bacterial Synthetic Biology section at the Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, in a company press release.

Scientists conducting the study noted that the key to overcoming the evolutionary limitations in bioprocessing is to rewire production cells to only grow when product concentration is high. This would circumvent the cell evolution, enabling them to produce the biochemicals within an industrial time scale, according to the study.

"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," said Peter Rugbjerg, postdoc at the Novo Nordisk Foundation Center for Biosustainability, in the press release.

Addresses costly evolution

Although evolution is beneficial for the cell, 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, according to Novo Nordisk.

The new study demonstrates the circumvention of the evolution occurring in production cells with the use of a molecular biosensor that senses the product, mevalonate, inside the production cells. This biosensor has the ability to shut down growth if production concentration declines below a certain point.

This concept can help in driving the development of a more sustainable cellular society.  Currently, microorganisms do not naturally produce high amounts of valuable chemicals, and this demands the use of significant R&D resources, which can delay the launch of new biobased processes.

"Engineered, high-level production of sustainable 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," Rugbjerg noted in the press release.

A viable alternative

If the findings from the study are applied to more cases of bioproduction, this may remove a major obstacle for investing in biobased production.  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," said Sommer in the press release.

The Novo Nordisk Foundation Center for Biosustainability has been working on developing and perfecting foundational engineering approaches for bio-manufacturing since 2011.

Source: Novo Nordisk Foundation Center for Biosustainability