The emerging role of systems biology for engineering protein production in CHO cells

Abstract

To meet the ever-growing demand for effective, safe, and affordable protein therapeutics, decades of intense efforts have aimed to maximize the quantity and quality of recombinant proteins produced in CHO cells. Bioprocessing innovations and cell engineering efforts have improved product titer; however, uncharacterized cellular processes and gene regulatory mechanisms still hinder cell growth, specific productivity, and protein quality. Herein, we summarize recent advances in systems biology and data-driven approaches aiming to unravel how molecular pathways, cellular processes, and extrinsic factors (e.g. media supplementation) influence recombinant protein production. In particular, as the available omics data for CHO cells continue to grow, predictive models and screens will be increasingly used to unravel the biological drivers of protein production, which can be used with emerging genome editing technologies to rationally engineer cells to further control the quantity, quality and affordability of many biologic drugs.

Fig 1. Three waves of different technologies have enabled continued improvement of recombinant protein production in CHO cells

(a) Recombinant protein production has steadily improved over the past few decades thanks to innovations in bioprocessing, targeted genetic manipulation of cells, and systems biology approaches. Together, novel technologies, approaches and discoveries in each field have been of great importance. (b) A comprehensive survey of the CHO bioprocessing literature [60] highlights the historical development of the field in CHO cell research. The first wave-bioprocess development has been driving most of the earlier studies, while the targeted genetic manipulation, omics studies, and modeling efforts have become increasingly important after the mid-2000s with the increased prevalence of genomic resources, genome editing technologies, and development of novel computational models and algorithms.

Fig. 2. Published specific productivity, cell density and total product titer has improved steadily over the years

The trend for three major productivity metrics reported by literature from 2000- 2010 [60]. As a result of development in bioprocessing and feeding strategies, the volumetric yield has been greatly improved. The introduction of cell engineering to CHO has further improved the per-cell productivity since the mid-2000s.