A paradigm shift in protein production

Many sectors, ranging from food to pharmaceutical production, require proteins in high quality and quantity. But how can they be produced as efficiently and sustainably as possible? A CD Laboratory has the answer.

What is at issue?

Proteins are extremely important ‘building blocks’ for the biopharmaceutical industry, the food industry and as technical enzymes; they should be available in the highest possible quality and in large quantities. A tried-and-tested method for producing proteins is the use of yeast cultures, as these secrete proteins.

The problem with this is that yeasts are single-celled fungi and, as such, like all other microorganisms, they strive to grow – that is, to produce biomass. In the context of yeast-based protein production, however, biomass is an undesirable by-product: the more biomass that is produced, the more energy must be expended on aeration and cooling, which results in additional costs and environmental impact. If yeast only secretes proteins whilst it is growing, it seems almost impossible to make this process more efficient.

The research question: Proteins vs. biomass

When the CD Laboratory for Growth-decoupled protein production in yeast was launched in 2017, the fact that yeast only secretes proteins whilst it is growing was taken for granted. However, Head of Laboratory Brigitte Gasser and her team turned this challenge on its head in an ingenious way: what if it were possible for yeast to secrete proteins even at near-zero growth – in other words, if the proteins could be transported out of the yeast cells without simultaneously producing ever-increasing amounts of biomass?

The ambitious, central focus of the research was therefore to understand microbial (yeast) cells at zero growth, analyse them system-wide and, in doing so, derive strategies to decouple growth from protein secretion: given the current state of research, success here would lead to a true paradigm shift whilst simultaneously enabling more efficient, sustainable and cost-effective protein production.

Cooperation at the CD Laboratory

In the biopharmaceutical sector, commercial partner Lonza AG operates as a CDMO (Contract Development and Manufacturing Organisation); in other words, it does not manufacture its own products in the traditional sense, but collaborates with other firms, enabling them – through its expertise and equipment – to carry out biotechnological production themselves, such as protein production using yeast.

The excellent collaboration between the CD Laboratory and the commercial partner allowed Prof. Gasser and her team to address Lonza AG’s industrial challenges (such as the potential reduction of biomass generated during protein production) with considerable scientific freedom: it was only through this that the innovative approach of decoupling cell growth from protein production emerged, from which the commercial partner in turn benefited.

Results: A true paradigm shift

The starting point was the tried-and-tested ‘Retentostat’ cultivation technique, which allows (yeast) cells to be placed in a nutrient-limited yet still metabolically active state: on this basis, the researchers were able to carry out extensive analyses of the yeast cells’ states. In this way, they came to understand how the secretion of proteins by these cells is linked to their growth, and how this link can be broken. One of the outcomes of this research is the now award-winning method of bringing the yeast species ‘Pichia pastoris’ into a state in which it secretes proteins even when growth is virtually zero.

For the research, the main findings therefore represent significant scientific insights into the coupling of the cellular processes of growth and protein secretion: on this basis, technologies were developed in the CD Laboratory which, in turn, can be utilised by Lonza AG and its external customers to achieve the decoupling of both processes. Consequently, the research findings have not only provided Lonza AG with a competitive advantage in the highly competitive international market for protein production, but have also enabled the sustainable production of proteins in large quantities and of high quality with significantly reduced resource consumption – a benefit to society as a whole.