ABSTRACT

In the biotech industry there has been a constant strive for improving the eciency of the cell factories used for the production of fuels and chemicals, which is well illustrated by the more than 10,000 fold improvements obtained in the productivity of penicillin by the lamentous fungus Penicillium chrysogenum over the last 60 years. With the introduction of genetic engineering by Cohen, Boyer and coworkers in 1973 there was opened for a new approach to optimization of existing biotech processes and development of completely new ones. Shortly aer the introduction of genetic engineering followed several successful applications of microorganisms for the production of human proteins, e.g., the production of growth hormone and human insulin by Escherichia coli and Saccharomyces cerevisiae, respectively. With the further development in genetic engineering techniques the possibility to apply this for optimization of classical fermentation processes soon became obvious. However, it was soon realized that it was technologically dicult to engineer metabolic pathways, and even though there are several examples of engineering microorganisms for production of chemicals, e.g., production of indigo by E. coli, few of these examples developed into industrially viable processes. It is a rst in recent years that the use of directed pathway engineering has taken of in industry, and today the eld of industrial biotechnology is a rapidly growing eld. In the increasing shi toward a bio-based economy, there is a demand for being able to quickly and reliably develop ecient cell factories that can produce desirable products. Metabolic engineering is the enabling science in the eld of industrial biotechnology, as it focuses on developing new cell factories or improving existing cell factories (Bailey, 1991). ere are several denitions, but most of these are consistent with: the use of genetic engineering to perform directed genetic modications of cell factories with the objective to improve their properties for industrial application. In this denition the word improve is to be interpreted in its broadest sense, i.e., it also encompasses the insertion of completely new pathways with the objective to produce a heterologous product in a given host cell factory. Metabolic engineering distinguishes itself from applied genetic engineering by the use of advanced analytical tools for identication of appropriate targets for genetic modications and oen mathematical models are used to perform in silico design of optimized cell factories. In fact the reason for the relatively slow migration of genetic engineering into the eld of industrial biotechnology is primarily due to the requirement for advanced analytical techniques that allows for mapping of activities in dierent parts of the metabolism and detailed phenotypic characterization. With the developments in genomics, primarily driven by the large investments in the medical sciences, several advanced new techniques have been developed for phenotypic analysis, and with these techniques it has become possible better guiding the introduction of directed genetic modications. Metabolic engineering is therefore oen seen as a cyclic process (Nielsen, 2001), where the cell factory is analyzed and based on this an appropriate target is identied (the design phase). is target is then experimentally implemented and the resulting stain is analyzed again.