The emerging CHO systems biology era: harnessing the 'omics revolution for biotechnology.

Chinese hamster ovary (CHO) cells are the primary factories for biopharmaceuticals because of their capacity to correctly fold and post-translationally modify recombinant proteins compatible with humans. New opportunities are arising to enhance these cell factories, especially since the CHO-K1 cell line was recently sequenced. Now, the CHO systems biology era is underway. Critical 'omics data sets, including proteomics, transcriptomics, metabolomics, fluxomics, and glycomics, are emerging, allowing the elucidation of the molecular basis of CHO cell physiology. The incorporation of these data sets into mathematical models that describe CHO phenotypes will provide crucial biotechnology insights. As 'omics technologies and computational systems biology mature, genome-scale approaches will lead to major innovations in cell line development and metabolic engineering, thereby improving protein production and bioprocessing.

[1]  A. Wouwer,et al.  A detailed metabolic flux analysis of an underdetermined network of CHO cells. , 2010, Journal of biotechnology.

[2]  T. Jakobi,et al.  Unraveling the Chinese hamster ovary cell line transcriptome by next-generation sequencing. , 2011, Journal of biotechnology.

[3]  G. Lee,et al.  Protein reference mapping of dihydrofolate reductase‐deficient CHO DG44 cell lines using 2‐dimensional electrophoresis , 2010, Proteomics.

[4]  C. Clemens,et al.  Into the unknown: expression profiling without genome sequence information in CHO by next generation sequencing , 2010, Nucleic acids research.

[5]  Royston Goodacre,et al.  Evaluation of extraction processes for intracellular metabolite profiling of mammalian cells: matching extraction approaches to cell type and metabolite targets , 2010, Metabolomics.

[6]  Katie F Wlaschin,et al.  Recombinant protein therapeutics from CHO cells : 20 years and counting , 2007 .

[7]  Yelena Lyubarskaya,et al.  Metabolomics profiling of cell culture media leading to the identification of riboflavin photosensitized degradation of tryptophan causing slow growth in cell culture. , 2011, Analytical chemistry.

[8]  L. Quek,et al.  A Multi-Omics Analysis of Recombinant Protein Production in Hek293 Cells , 2012, PloS one.

[9]  Peter G. Slade,et al.  Identifying the CHO secretome using mucin-type O-linked glycosylation and click-chemistry. , 2012, Journal of proteome research.

[10]  H. Ohtake,et al.  Construction of BAC‐based physical map and analysis of chromosome rearrangement in chinese hamster ovary cell lines , 2012, Biotechnology and bioengineering.

[11]  Kelvin H. Lee,et al.  Genomic sequencing and analysis of a Chinese hamster ovary cell line using Illumina sequencing technology , 2011, BMC Genomics.

[12]  Dong-Yup Lee,et al.  Metabolomics-based identification of apoptosis-inducing metabolites in recombinant fed-batch CHO culture media. , 2011, Journal of biotechnology.

[13]  W. Hancock,et al.  Analysis of dynamic changes in the proteome of a Bcl‐XL overexpressing Chinese hamster ovary cell culture during exponential and stationary phases , 2012, Biotechnology progress.

[14]  B. Pfeifer,et al.  Metabolic flux analysis and pharmaceutical production. , 2010, Metabolic engineering.

[15]  Renate Kunert,et al.  Next-generation sequencing of the Chinese hamster ovary microRNA transcriptome: Identification, annotation and profiling of microRNAs as targets for cellular engineering , 2011, Journal of biotechnology.

[16]  B. Palsson,et al.  Constraining the metabolic genotype–phenotype relationship using a phylogeny of in silico methods , 2012, Nature Reviews Microbiology.

[17]  Susumu Goto,et al.  KEGG for integration and interpretation of large-scale molecular data sets , 2011, Nucleic Acids Res..

[18]  C. Clarke,et al.  Engineering CHO cell growth and recombinant protein productivity by overexpression of miR-7. , 2011, Journal of biotechnology.

[19]  C. Clarke,et al.  Utilization and evaluation of CHO‐specific sequence databases for mass spectrometry based proteomics , 2012, Biotechnology and bioengineering.

[20]  Niraj Kumar,et al.  Initial identification of low temperature and culture stage induction of miRNA expression in suspension CHO-K1 cells. , 2007, Journal of biotechnology.

[21]  Thomas R. Kiehl,et al.  Transcriptomic responses to sodium chloride‐induced osmotic stress: A study of industrial fed‐batch CHO cell cultures , 2010, Biotechnology progress.

[22]  Scott B. Crown,et al.  Rational design of 13C-labeling experiments for metabolic flux analysis in mammalian cells , 2012, BMC Systems Biology.

[23]  P. Stanley,et al.  Glycomics Profiling of Chinese Hamster Ovary Cell Glycosylation Mutants Reveals N-Glycans of a Novel Size and Complexity* , 2009, The Journal of Biological Chemistry.

[24]  Nathan E Lewis,et al.  Analysis of omics data with genome-scale models of metabolism. , 2013, Molecular bioSystems.

[25]  Minsoo Kim,et al.  A mechanistic understanding of production instability in CHO cell lines expressing recombinant monoclonal antibodies , 2011, Biotechnology and bioengineering.

[26]  Niki S. C. Wong,et al.  Combined in silico modeling and metabolomics analysis to characterize fed‐batch CHO cell culture , 2012, Biotechnology and bioengineering.

[27]  M. Gerstein,et al.  RNA-Seq: a revolutionary tool for transcriptomics , 2009, Nature Reviews Genetics.

[28]  Kelvin H. Lee,et al.  Chinese hamster genome database: an online resource for the CHO community at www.CHOgenome.org. , 2012, Biotechnology and bioengineering.

[29]  R. Goodacre,et al.  Metabolite profiling of recombinant CHO cells: designing tailored feeding regimes that enhance recombinant antibody production. , 2011, Biotechnology and bioengineering.

[30]  Nitya M. Jacob,et al.  Reaching the depth of the Chinese hamster ovary cell transcriptome. , 2010, Biotechnology and bioengineering.

[31]  Wei-Shou Hu,et al.  Quality assessment of cross-species hybridization of CHO transcriptome on a mouse DNA oligo microarray. , 2008, Biotechnology and bioengineering.

[32]  Profiling conserved microRNA expression in recombinant CHO cell lines using Illumina sequencing. , 2012, Biotechnology and bioengineering.

[33]  M. Dunn,et al.  A proteomic study of cMyc improvement of CHO culture , 2010, BMC biotechnology.

[34]  Aliaksandr Druz,et al.  A novel microRNA mmu‐miR‐466h affects apoptosis regulation in mammalian cells , 2011, Biotechnology and bioengineering.

[35]  R. Goodacre,et al.  Metabolite extraction from suspension-cultured mammalian cells for global metabolite profiling , 2011, Nature Protocols.

[36]  W. Hancock,et al.  Proteomic profiling of a high-producing Chinese hamster ovary cell culture. , 2009, Analytical chemistry.

[37]  M. Antoniewicz,et al.  Metabolic flux analysis of CHO cells at growth and non-growth phases using isotopic tracers and mass spectrometry. , 2011, Metabolic engineering.

[38]  Katie F Wlaschin,et al.  EST sequencing for gene discovery in Chinese hamster ovary cells. , 2005, Biotechnology and bioengineering.

[39]  C. Clarke,et al.  CGCDB: a web-based resource for the investigation of gene coexpression in CHO cell culture. , 2012, Biotechnology and bioengineering.

[40]  Nicholas E. Timmins,et al.  Metabolite profiling of CHO cells with different growth characteristics , 2012, Biotechnology and bioengineering.

[41]  Wei-Shou Hu,et al.  Comparative transcriptome analysis to unveil genes affecting recombinant protein productivity in mammalian cells , 2009, Biotechnology and bioengineering.

[42]  Nitya M. Jacob,et al.  Conserved microRNAs in Chinese hamster ovary cell lines. , 2011, Biotechnology and bioengineering.

[43]  Dong-Yup Lee,et al.  LC‐MS‐based metabolic characterization of high monoclonal antibody‐producing Chinese hamster ovary cells , 2012, Biotechnology and bioengineering.

[44]  Wei-Shou Hu,et al.  Transcriptome and proteome analysis of Chinese hamster ovary cells under low temperature and butyrate treatment. , 2010, Journal of biotechnology.

[45]  Mark Leonard,et al.  Microarray and proteomics expression profiling identifies several candidates, including the valosin‐containing protein (VCP), involved in regulating high cellular growth rate in production CHO cell lines , 2010, Biotechnology and bioengineering.

[46]  Katie F Wlaschin,et al.  A scaffold for the Chinese hamster genome , 2007, Biotechnology and bioengineering.

[47]  Gary Walsh,et al.  Biopharmaceutical benchmarks 2010 , 2010, Nature Biotechnology.

[48]  L. Quek,et al.  Flux balance analysis of CHO cells before and after a metabolic switch from lactate production to consumption. , 2013, Biotechnology and bioengineering.

[49]  H. Katinger,et al.  MicroRNAs as targets for engineering of CHO cell factories. , 2008, Trends in biotechnology.

[50]  R. Philp,et al.  Transcriptome and proteome profiling to understanding the biology of high productivity CHO cells , 2006, Molecular biotechnology.

[51]  Wei-Shou Hu,et al.  Transcriptome data analysis for cell culture processes. , 2012, Advances in biochemical engineering/biotechnology.

[52]  N. Barron,et al.  Development and characterization of a Chinese hamster ovary cell-specific oligonucleotide microarray , 2011, Biotechnology Letters.

[53]  Kelvin H. Lee,et al.  The genomic sequence of the Chinese hamster ovary (CHO)-K1 cell line , 2011, Nature Biotechnology.

[54]  Dong-Yup Lee,et al.  Metabolomics-driven approach for the improvement of Chinese hamster ovary cell growth: overexpression of malate dehydrogenase II. , 2010, Journal of biotechnology.

[55]  Yuan Tian,et al.  Proteomic analysis of Chinese hamster ovary cells. , 2012, Journal of proteome research.