Animal Cell Technology & Engineering
Compared to other pharmaceuticals, therapeutic proteins saw an incredible growth rate over the last years. The scientific community and also industry still experience a great enthusiasm and an atmosphere of “gold rush” and innovation. Nevertheless, the development of both cell lines and processes is still mostly based on empirical trial and error methods. The mechanistic details of how a cell is able to handle high production rates of a foreign protein have not received the same attention and optimization within industry.
Therapeutic proteins are mostly produced in Chinese hamster ovary cells, as these CHO cells are able to synthesize proteins similar to those in humans.
Fortunately, the genomes of several Chinese hamster ovary cell lines and the species of origin, the Chinese Hamster itself, were published with major contributions by an acib research cooperation. acib’s focus is to use this genome information to perform a step change in the ability to produce therapeutic proteins at large scale, low cost and high speed. Scientific excellence should overcome the main problem – that mammalian cells like CHO are extremely complex, with many layers of regulation and control present. With systems biology approaches and –omics analytic tools, acib wants to understand all levels of molecular regulation.
acib’s goal is to achieve in-silico modeling of cellular processes and metabolism at a level of detail that would allow prediction of cellular behaviour. Together with the key players of the scientific community acib wants to establish detailed databases and bioinformatics tools for the interpretation and use of –omics results.
Based on such knowledge in animal cell technology & engineering it will be possible to understand the state of the cell at an unprecedented level, thus enabling industry to predict process results with increased reliability. Our long term goal is to achieve reduced production costs of valuable therapeutic compounds that are then affordable for most health systems.
Systems biology for mammalian production cells is the focus acib, aiming to achieve the paradigm shift from empiricism to controlling the molecular basis of productivity and product quality in mammalian cells. The establishment of bioinformatics tools, statistical analyses and mathematical models will enable the identification of relevant parameters and the prediction of cell behavior during bioprocesses, which, amongst other benefits, will lead to reduced costs for monitoring and control. As CHO production cell lines vary largely both in their genotype and phenotype, the identification of patterns of gene expression, protein activities and metabolite fluxes that correlate to process relevant properties of production cell lines, is a major goal of acib which will deliver both new engineering strategies and process monitoring protocols that focus on the state of the cells.
In view of the genome size of mammalian cell lines which is up to three orders of magnitude larger than that of bacteria or yeast, several challenges need to be overcome and will be addressed at acib. Improved protocols for assembly of large genomes or validated methods of model reduction for the exponentially larger metabolic models based on the high number of coding genes will be developed within acib projects. Similarly, the analysis of –omics results is more complex and interactive and thus requires new algorithms, specifically those that predict the impact of one layer of regulation on the next (eg. impact of microRNA expression on mRNA and protein concentrations). Both infrastructure and software will be provided to develop, host and maintain databases for use by researchers, the pharmaceutical industry and regulatory authorities. Finally results not covered by intellectual property rights will be made publicly accessible (www.CHOgenome.org) with a downloadable stand-alone version provided to industrial partners.