A new public resource for optimizing a common biofactory
Biotherapeutic proteins including antibody therapies are often produced in Chinese hamster ovary (CHO) cells. A Cell Systems paper has novel insights about these cells and a new model for improving their productivity. The senior author is Nathan Lewis, who codirects systems research on CHO cells for the Novo Nordisk Foundation Center for Biosustainability at the Technical University of Denmark (DTU Biosustain). The center works on sustainable production in E. coli, yeast, and CHO cells. The CHO program, Lewis says, aims for “a whole-cell view of protein production including genomics, protein folding, post-translational modification, and secretion.”
A genome-scale metabolic model
Lewis is an assistant professor at University of California San Diego, but says DTU Biosustain functions as a single unit. “We’re in constant communication,” he says, “exchanging data, analyses, and people.” His graduate student, Hooman Hefzi, did some of his research at DTU. He is first author on the Cell Systems article describing a genome-scale metabolic model of CHO cells.
Starting with their sequence of the Chinese hamster genome, the researchers used computational methods to map 1766 genes to metabolic reactions in biochemical pathways. The resulting model predicts how molecules such glucose flow through the pathways. It points out bottlenecks, where genetic engineering or growth conditions might improve protein production. The model questioned some long-held assumptions about CHO cells.
What increases production?
While validating the model, Hefzi et al. found that not all CHO cell lines require an amino acid that was previously thought to be an essential supplement. In addition, the model suggests that common efforts to boost protein production, using temperature and drug treatments, are inefficient. Genetic engineering, the scientists report, has more potential to redirect resources toward generating recombinant proteins.
Now, Lewis says, “we’re using the model to predict the best ways to improve bioprocesses.” For example, protein synthesis is hampered by lactic acid production. The researchers are studying how to minimize this side product.
The model was an international effort. After realizing that several laboratories were working on genome-scale metabolic models for CHO cells, the DTU Biosustain group coordinated efforts including by the groups of Dong Yup Lee (Singapore), Nicole Borth (Austria), Lars Nielsen (Australia), Ziomara Gerdtzen (Chile), Mikael Rørdam Andersen (Denmark), and Bernhard Palsson and Michael Betenbaugh (US). They created a single, publicly available model (http://bigg.ucsd.edu and http://chogenome.org/).
“We did it as a community effort,” Lewis says, “to make a better, stronger model. It’s a public resource because the goal of DTU Biosustain is to do science that benefits everybody.”
1. Hefzi H, Ang KS, Hanscho M, Bordbar A, Ruckerbauer D, Lakshmanan M, Orellana CA, Baycin-Hizal D, Huang Y, Ley D, Martinez VS, Kyriakopoulos S, Jiménez NE, Zielinski DC, Quek LE, Wulff T, Arnsdorf J, Li S, Lee JS, Paglia G, Loira N, Spahn PN, Pedersen LE, Gutierrez JM, King ZA, Lund AM, Nagarajan H, Thomas A, Abdel-Haleem AM, Zanghellini J, Kildegaard HF, Voldborg BG, Gerdtzen ZP, Betenbaugh MJ, Palsson BO, Andersen MR, Nielsen LK, Borth N, Lee DY, Lewis NE. A Consensus Genome-scale Reconstruction of Chinese Hamster Ovary Cell Metabolism. Cell Syst 2016. 3(5):434-443.e8.