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Industrial Systems Biology of Yeast and A. oryzae

Final Report Summary - INSYSBIO (Industrial Systems Biology of Yeast and A. oryzae)

There is an urgent need for replacing fossil-based production of chemicals with more sustainable production processes, and biobased production represents an attractive alternative. However, advancement in the field is hindered by the slow and expensive development of cell factories that can produce chemicals in a cost-competitive fashion. Besides their future use for production of chemicals, cell factories also represent ways of producing advanced pharmaceuticals, and also in this area there is a need for reducing the development time by using platform cell factories. This project has significantly contributed to solve these problems as it has advanced metabolic engineering of fungal cell factories through development of several new technologies and through generation of several novel fungal strains with improved performance for production of chemicals and proteins.

The project has primarily involved engineering of yeast. Thus, yeast strains have been developed that can efficiently produce 3-hydroxypropionic acid, which can be used for production of acrylates used in super-absorbing materials applied in diapers etc. A number of other chemicals have also been produced in yeast, e.g. 1-butanol, isoprenoids, and fatty acid derived products, and the project has hereby demonstrated that it is possible to engineer yeast metabolism to produce a wide range of chemicals. Yeast is also used for the production of a range of different pharmaceutical proteins, and in this project yeast has been engineered for improved protein production. Also novel screening methods have been applied for identification of yeast strains with improved protein secretion capacity. These strains represent excellent platform cell factories for production of a range of recombinant proteins. In another line of the project adaptive laboratory evolution was used for identification of novel biological mechanisms that confer improved growth on galactose, improved tolerance to high temperatures and low pH. Combining genome-sequencing with advanced systems biology analysis it was possible to identify specific mutations that confer desirable phenotypes. In order to evaluate whether knowledge on yeast metabolic engineering could be transferred to filamentous fungi, the project also involved metabolic engineering of Aspergillus oryzae for production of malic acid, which is used in the food industry and can be chemically converted to 1,4 butanediol, a key chemical building block. The engineering resulted in a very efficient strain for production of this valuable chemical.

In parallel with the engineering and development of novel cell factories the project resulted in advancement of several key technologies for metabolic engineering. Thus, genome-scale metabolic modeling was significantly advanced through incorporation of a description of the protein secretion pathway. Also a novel screening method based on micro-fluidics screening was developed for screening for yeast strains with improved protein secretion. Finally, several novel systems biology computational techniques were developed, which allows for rapid phenotypic analysis of strains that have been engineered or evolved.

Many of the results from the project have been disseminated to industry or to a small spin-out biotech company, and hence the project have had a significant impact on society.

In conclusion the project has been very successful resulting in a large number of high-impact research papers, training of more than 15 researchers (PhD students and post docs), several patent applications, and dissemination of results for further exploitation to the benefit of the European biotech industry.