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Engineering CELLS,
   Engineering RESPONSES

“-OMICS” TECHNOLOGIES

Multi-Level Information for Improved Protein Production

A complete insight into the biological behaviour of a complex system entails pursuing a comprehensive approach, which consists of monitoring global changes at the genome, transcriptome, proteome and metabolome levels. The "-omics" platform includes technical capabilities for acquiring data at these multiple levels, which are subsequently utilised in various applications to improve our understanding of microbial and mammalian cellular systems.

Proteomics

The Proteomics laboratory hosts a repertoire of instrumentation for protein identification, quantitative protein expression profiling and mapping of post translational modifications. 2D Gel electrophoresis is used to separate protein mixtures. Replicate gel maps are compared and differentiating proteins are isolated, digested and identified by mass spectrometry (MS). Metabolic labelling of proteins with stable isotopes and peptide isobaric tagging is used to quantitatively compare the expression levels of proteins by MS. Tandem MS is performed to obtain peptide sequence information to identify proteins and to quantify labelled peptides.

Metabolomics

Metabolomics refers to the global study of small organic molecules with a molecular weight of less than 1000 Da. At BTI, metabolomics is used to study metabolic behaviour related to cell growth, apoptosis and protein productivity. Initial exploration of the metabolome is carried out using ultra performance liquid chromatography-mass spectrometry (UPLC-MS).

The resulting raw MS data is pre-processed and analysed with MetaSuite, an in-house developed software. Targeted profiling of shortlisted metabolites of interest is subsequently carried out via the multiple reaction monitoring (MRM) approach. The resulting information contributes towards improvements in cell culture processes, through guiding the development of optimal culture media and the identification of new targets for cell line engineering.

Microarray

The Microarray Group studies the genetic circuitry underlying cellular metabolism, growth death and protein glycosylation during high cell density production processes and protein-free media adaptation. The research programmes in BTI revolve around identifying targets for genetic engineering of production cell lines leading to enhanced cell viability and productivity.

Bioinformatics

The Bioinformatics Group's strength lies in complex "-omics" data management, analysis and integration. The group has developed various software platforms, including programs for analysis of genomic and transcriptomic Next Generation Sequencing experiments, LC-MS data pre-processing, as well as glycan profile visualization.

Predictive computational models of biological processes can be constructed from various networks to find proteins, genes and metabolites which are highly correlated with various physiological states such as cell growth, apoptosis and antibody production. This integrated approach allows the group to pursue rational design in protein engineering through methods such as codon optimization and molecular modeling.

People

Dr. Ho Ying Swan

PhD in Chemical Engineering (2007), Imperial College, UK

Research Focus/Interests
  • Metabolomics/metabolite profiling of mammalian cell lines to further understanding of intracellular metabolic processes and their impact on recombinant protein production and quality
  • Application of metabolite profiling to identify candidate disease markers and to study aberrant metabolism under disease conditions

Dr. Bi Xuezhi

PhD in Genetics (2000), Wuhan University, China

Research Focus/Interests
  • Mass spectrometry based quantitative and qualitative proteomics
  • Drug target identification and protein post translational modification (PTMs) as well as protein-protein interacting analysis
  • Proteomic profiling of upstream and downstream processes of recombinant protein production in mammalian cells
  • Biopharmaceutical multiple critical quality attributes (CQAs) analysis by mass spectrometry

Dr. Andy Tan

PhD in Immunology (2008), National University of Singapore Graduate School for Integrative Sciences and Engineering, Singapore

Research Focus/Interests
  • Genomic Role of immune cells in immune and autoimmune responses
  • Engineering immune cells for immunotherapy against cancer
  • Engineering of CHO and human cells for efficient bioproduction of biologics based on genomics, transcriptomics and epigenetics studies

Dr. Alison Lee

PhD in Bioinformatics (2009), NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore

Research Focus/Interests
  • Transcriptomics and epigenomics of cell factories of biotechnological interest such as Chinese Hamster Ovary (CHO) cell lines and microbial cells to identify crucial regulatory networks influencing product quality and yield
  • Genomics-based approaches to understand cell phenotypes

Dr. Tan Hwee Tong

PhD in Biochemistry (2008), National University of Singapore, Singapore

Research Focus/Interests
  • Bioprocess characterization with proteomics technology
  • Proteomics discovery of novel biomarkers and therapeutic targets
  • Applications of proteomics in the development of biologics

Dr. Hong Jongkwang

PhD in Biological Sciences (2014), Korea Advanced Institute of Science and Technology, Korea

Research Focus/Interests
  • Omics data analysis / in silico modeling in CHO cells
  • Next generation cell line development and engineering
  • Culture medium and culture process design by systems approaches

Dr. Kok Yee Jiun

PhD in Biochemistry (2016), National University of Singapore, Singapore

Research Focus/Interests
  • Qualitative and quantitative proteomics profiling of mammalian production cell lines
  • Mass spectrometry-based characterization of recombinant therapeutic proteins
  • Identification and characterization of disease-associated biomarkers

Dr. Lillian Liu Chia-Yi

PhD in Cellular Molecular Biology and Physiology (2012), Georgia State University, USA

Research Focus/Interests
  • Comprehensive whole proteome profiling in Chinese Hamster Ovary (CHO) cells by LC-MS
  • Identification of protein post-translational modifications such as glycosylation and phosphorylation
  • Characterization of biological roles of protein modifications in mammalian cells

Dr. Meiyappan Lakshmanan

PhD in Chemical & Biomolecular Engineering (2014), National University of Singapore, Singapore

Research Focus/Interests
  • Cellular metabolism & regulation
  • Omics data analysis
  • Constraint-based modeling
  • In silico strain design

Dr. Yip Lian Yee

PhD in Pharmacy (2015), National University of Singapore, Singapore

Research Focus/Interests
  • Clinical metabolomics of human diseases for biomarker discovery and development
  • Metabolomics-driven cell phenotyping
  • Investigation of host-gut microbiota modulation of therapeutic outcomes using systems biology approach

Dr. Ng Cheng Yang

PhD in Medicinal Chemistry (2017), National University of Singapore, Singapore

Research Focus/Interests
  • Drug target identification and validation
  • Chemical proteomics
  • Bioprocess profiling via mass spectrometry

Dr. Sim Kae Hwan

PhD in Biochemistry (2016), Nanyang Technological University, Singapore

Research Focus/Interests
  • Qualitative and quantitative proteomics profiling of Chinese Hamster Ovary (CHO) cells by SWATH-MS
  • Identification and characterization of potential biomarkers and post-translational modifications in human diseases
  • OneOmics data analysis

Dr. Yang Dongxiao

PhD in Analytical Chemistry (2017), National University of Singapore, Singapore

Research Focus/Interests
  • Metabolomics analysis of mammalian cell lines used for recombinant protein production with spectrometry-based techniques
  • Optimization of metabolomics analysis methods using LC-MS

Year 2018

    Tan Heng Liang, Charlene Yong, Tan Bao Zhu, Fong Wey Jia, Jayanthi Padmanabhan, Angela Chin, Vanessa Ding, Ally Lau, Zheng Lu, Bi Xuezhi, Yang Yuansheng, Andre Choo (2018) Conservation of oncofetal antigens on human embryonic stem cells enables discovery of monoclonal antibodies against cancer. Scientific Reports 8: 11608

    Na Gao, Ming Xia, Jingcheng Dai, Dianzhen Yu, Weixing An, Shuyang Li, Shuangyuan Liu, Penghui He, Liping Zhang, Zhenbin Wu, Xuezhi Bi, Shouwen Chen, Daniel H. Haft and Dongru Qiu (2018) Both widespread PEP-CTERM proteins and exopolysaccharides are required for floc formation of Zoogloea resiniphila and other activated sludge bacteria. Environmental Microbiology 20(5): 1677-1692

    Xuezhi Bi, Lijuan Ye, Ally Lau, Yee Jiun Kok, Lu Zheng, Daniel Ng, Kelly Tan, Dave Ow, Edwin Ananta, Christina Vafiadi and Jeroen Muller (2018) Proteomic Profiling of Barley Spent Grains Guides Enzymatic Solubilization of the Remaining Proteins. Applied Microbiology and Biotechnology 102(9): 4159-4170

    Andy Hee-Meng Tan, Arleen Sanny, Sze-Wai Ng, Ying-Swan Ho, Nurhidayah Basri, Alison Ping Lee & Kong-Peng Lam (2018) Excessive interferon-a signaling in autoimmunity alters glycosphingolipid processing in B cells. Journal of Autoimmunity 89: 53-62

    Sarantos Kyriakopoulos, Kok Siong Ang, Meiyappan Lakshmanan, Zhuangrong Huang, Seongkyu Yoon, Rudiyanto Gunawan and Dong-Yup Lee (2018) Kinetic modelling of mammalian cell culture bioprocessing: the quest to advance biomanufacturing. Biotechnology Journal 13(3): e1700229

    Pranjul Mishra, Na-Rae Lee, Meiyappan Lakshmanan, Minsuk Kim, Byung-Gee Kim and Dong-Yup Lee (2018) Genome-scale model-driven strain design for dicarboxylic acid production in Yarrowia lipolytica. BMC Systems Biology 12(Suppl 2): 12

    David Hutchinson, Judith Müller, Joseph E McCarthy, Yurii K Gun’ko, Navin Kumar Verma, Xuezhi Bi, Luisana Di Cristo, Laura Kickham, Dania Movia, Adriele Prina-Mello & Yuri Volkov (2018) Cadmium nanoparticles citrullinate cytokeratins within lung epithelial cells: cadmium as a potential cause of citrullination in chronic obstructive pulmonary disease. International Journal of Chronic Obstructive Pulmonary Disease 13: 441–449

Year 2017

    TingDong Yan, Wen Fong Ooi, Aditi Qamra, Alice Cheung, DongLiang Ma, Gopinath Meenakshi Sundaram, Chang Xu, Manjie Xing, LaiFong Poon, Jing Wang, Yan Ping Loh, Jess Hui Jie Ho, Joscelyn Jun Quan Ng, Muhammad Khairul Ramlee, Luay Aswad, Steve G. Rozen, Sujoy Ghosh, Frederic A. Bard, Prabha Sampath, Vinay Tergaonkar, James O.J. Davies, Jim R. Hughes, Eyleen Goh, Xuezhi Bi, Melissa Jane Fullwood, Patrick Tan & Shang Li (2017) HoxC5 and miR-615-3p target newly evolved genomic regions to repress hTERT and inhibit tumorigenesis. Nature Communication 9(1): 100

    Zhuangrong Huang, Dong-Yup Lee and Seongkyu Yoon (2017) Quantitative intracellular flux modeling and applications in biotherapeutic development and production using CHO cell cultures. Biotechnology and Bioengineering 114 (12): 2717-2728

    Eun Sung Jung, Hye Min Park, Seung Min Hyun, Jong Cheol Shon, Meiyappan Lakshmanan, Minsoo Noh, Hock Chuan Yeo, Kwang‑Hyeon Liu, Dong‑Yup Lee, Jae Sung Hwang and Choong Hwan Lee (2017) Integrative metabolomic analysis reveals diet supplementation with green tea alleviates UVB-damaged mouse skin correlated with ascorbate metabolism and urea cycle. Metabolomics 13(7): 82

    Lokanand Koduru, Yujin Kim, Jeongsu Bang, Meiyappan Lakshmanan, Nam Soo Han & Dong-Yup Lee (2017) Genome-scale modeling and transcriptome analysis of Leuconostoc mesenteroides unravel the redox governed metabolic states in obligate heterofermentative lactic acid bacteria. Scientific Reports 7(1): 15721

    Jian'er Lin, Shu Hui Neo, Steven C. L. Ho, Jessna H. M. Yeo, Tianhua Wang, Wei Zhang, Xuezhi Bi, Sheng-Hao Chao and Yuansheng Yang (2017) Impact of Signal Peptides on Furin-2A Mediated Monoclonal Antibody Secretion in CHO Cells. Biotechnology Journal 12: 9

    Faraaz Noor Khan Yusufi, Meiyappan Lakshmanan, Ying Swan Ho, Bernard Liat Wen Loo, Pramila Ariyaratne, Yuansheng Yang, Say Kong Ng, Tessa Rui Min Tan, Hock Chuan Yeo, Hsueh Lee Lim, Sze Wai Ng, Ai Ping Hiu, Chung Ping Chow, Corrine Wan, Chen Shuwen, Gavin Teo, Gao Song, Ju Xin Chin, Xiaoan Ruan, Ken Wing Kin Sung, Wei-Shou Hu, Miranda Gek Sim Yap, Muriel Bardor, Niranjan Nagarajan and Dong-Yup Lee (2017) Mammalian systems biotechnology reveals global cellular adaptations in a recombinant CHO cell line. Cell Systems 4(5): 530-542.e6

    Dawn Sow Zong Leong, Janice Gek Ling Tan, Christine Lin Chin, Shi Ya Mak, Ying Swan Ho and Say Kong Ng (2017) Evaluation and use of disaccharides as energy source in protein-free mammalian cell cultures. Scientific Reports Scientific Reports 7: 45216

    Han Bin Pek, Pei Yu Lim, Chengcheng Liu, Dong-Yup Lee, Xuezhi Bi, Fong Tian Wong, Dave Siak-Wei Ow (2017) Cytoplasmic expression of a thermostable invertase from Thermotoga maritima in Lactococcus lactis. Biotechnology Letters (Published Online)

    Ying Swan Ho, Lian Yee Yip, Nurhidayah Basri, Vivian Su Hui Chong, Chin Chye Teo, Eddy Tan, Kah Ling Lim, Gek San Tan, Xulei Yang, Si Yong Yeo, Mariko Si Yue Koh, Anantham Devenand, Angela Takano, Daniel Shao Weng Tan and Tony Kiat Hon Lim (2017) Lipidomic Profiling of Lung Pleural Effusion Identifies Unique Metabotype for EFGR-Mutants in Non-Small Cell Lung Cancer. Scientific Reports 6: 35110

    Yun Sun Lee, Hyun-Seung Park, Dong-Kyu Lee, Murukarthick Jayakodi, Nam-Hoon Kim, Sang-Choon Lee, Atreyee Kundu, Dong-Yup Lee, Young Chang Kim, Jun Gyo In, Sung Won Kwon and Tae-Jin Yang (2017) Comparative analysis of the transcriptomes and primary metabolite profiles of adventitious roots of five Panax ginseng cultivars. Journal of Ginseng Research 41(1): 60-68

    Maximilian Klement, Jiyun Zheng, Chengcheng Liu, Victor Vai-Tak Wong, Andre Boon-Hwa Choo, Dong-Yup Lee, and Dave Siak-Wei Ow (2017) Antibody engineering of a cytotoxic monoclonal antibody 84 against human embryonic stem cells: Investigating the effects of multivalency on cytotoxicity. Journal of Biotechnology 243: 29–37

Year 2016

    Meiyappan Lakshmanan, C. Y. Maurice Cheung, Bijayalaxmi Mohanty and Dong-Yup Lee (2016) Modeling rice metabolism: from elucidating environmental effects on cellular phenotype to guiding crop improvement. Frontiers in Plant Science 7: 1795

    Hooman Hefz, Kok Siong Ang, Michael Hanscho, Aarash Bordbar, David Ruckerbauer, Meiyappan Lakshmanan, Camila A. Orellana, Deniz Baycin-Hizal, Yingxiang Huang, Daniel Ley, Veronica S. Martinez, Sarantos Kyriakopoulos, Natalia E. Jime´nez, Daniel C. Zielinski, Lake-Ee Quek, Tune Wulff, Johnny Arnsdorf, Shangzhong Li, Jae Seong Lee, Giuseppe Paglia, Nicolas Loira, Philipp N. Spahn, Lasse E. Pedersen, Jahir M. Gutierrez, Zachary A. King, Anne Mathilde Lund, Harish Nagarajan, Alex Thomas, Alyaa M. Abdel-Haleem, Juergen Zanghellini, Helene F. Kildegaard, Bjørn G. Voldborg, Ziomara P. Gerdtzen, Michael J. Betenbaugh, Bernhard O. Palsson, Mikael R. Andersen, Lars K. Nielsen, Nicole Borth, Dong-Yup Lee, and Nathan E. Lewis (2016) A consensus genome-scale reconstruction of CHO cell metabolism for improved biotherapeutic protein production. Cell Systems 3(5): 434-443

    Minsuk Kim, Gwanggyu Sun, Dong-Yup Lee and Byung-Gee Kim (2016) BeReTa: a systematic method for identifying target transcriptional regulators to enhance microbial production of chemicals. Bioinformatics (Published Online)

    Andrea Camattari, Amelia Goh, Lian Yee Yip, Gaowen Liu, Ivan Liachko, Maitreya J. Dunham and Giulia Rancati (2016) Characterization of a panARS-based episomal vector in the methylotrophic yeast Pichia pastoris for recombinant protein production and synthetic biology applications. Microbial Cell Factories 15(1): 139

    Nan Yu, Jin-Su Kang, Chung-Chuan Chang, Tai-Yong Lee and Dong-Yup Lee (2016) Robust economic optimization and environmental policy analysis for microgrid planning: An application to Taichung Industrial Park, Taiwan. Energy 113: 671-682

    Hock Chuan Yeo, Sherwin Ting, Romulo Martin Brena, Geoffrey Koh, Allen Chen, Siew Qi Toh, Yu Ming Lim, Steve Kah Weng Oh and Dong-Yup Lee (2016) Genome-Wide Transcriptome and Binding Sites Analyses Identify Early FOX Expressions for Enhancing Cardiomyogenesis Efficiency of hESC Cultures. Scientific Reports 6: 31068

    Hweixian Leong Penny, Je Lin Sieow, Giulia Adriani, Wei Hseun Yeap, Peter See Chi Ee, Boris San Luis, Bernett Lee, Terence Lee, Shi Ya Mak, Ying Swan Ho, Kong Peng Lam, Choon Kiat Ong, Ruby Y. J. Huang, Florent Ginhoux, Olaf Rotzschke, Roger D. Kamm, and Siew Cheng Wong (2016) Warburg metabolism in tumor-conditioned macrophages promotes metastasis in human pancreatic ductal adenocarcinoma. Oncoimmunology 5(8): e1191731

    Bijayalaxmi Mohanty, Meiyappan Lakshmanan, Sun-Hyung Lim, Jae Kwang Kim, Sun-Hwa Ha, and Dong-Yup Lee (2016) Light-specific transcriptional regulation of the accumulation of carotenoids and phenolic compounds in rice leaves. Plant Signalling & Behavior 11(6): e1184808

    Neil Swainston, Kieran Smallbone, Hooman Hefzi, Paul D. Dobson, Judy Brewer, Michael Hanscho, Daniel C. Zielinski, Kok Siong Ang, Natalie J. Gardiner, Jahir M. Gutierrez, Sarantos Kyriakopoulos, Meiyappan Lakshmanan, Shangzhong Li, Joanne K. Liu, Veronica S. Martınez, Camila A. Orellana, Lake-Ee Quek, Alex Thomas, Juergen Zanghellini, Nicole Borth, Dong-Yup Lee, Lars K. Nielsen, Douglas B. Kell, Nathan E. Lewis and Pedro Mendes (2016) Recon 2.2: from reconstruction to model of human metabolism. Metabolomics 12(7): 109

    Kok Siong Ang, Sarantos Kyriakopoulos, Wei Li and Dong-Yup Lee (2016) Multi-omics data driven analysis establishes reference codon biases for synthetic gene design in microbial and mammalian cells. Methods 102: 26-35

    Pranjul Mishra, Gyu-Yeon Park, Meiyappan Lakshmanan, Hee-Seok Lee, Hongweon Lee, Matthew Wook Chang, Chi Bun Ching, Jungoh Ahn, Dong-Yup Lee (2016) Genome-scale metabolic modeling and in silico analysis of lipid accumulating yeast Candida tropicalis for dicarboxylic acid production. Biotechnology and Bioengineering (Published Online)

    Tomoya Fukawa, Benjamin Chua Yan-Jiang, Jason Chua Min-Wen, Elwin Tan Jun-Hao, Dan Huang, Chao-Nan Qian, Pauline Ong, Zhimei Li, Shuwen Chen, Shi Ya Mak, Wan Jun Lim, Hiro-omi Kanayama, Rosmin Elsa Mohan, Ruiqi Rachel Wang, Jiunn Herng Lai, Clarinda Chua, Hock Soo Ong, Ker-Kan Tan, Ying Swan Ho, Iain Beehuat Tan, Bin Tean Teh & Ng Shyh-Chang (2016) Excessive fatty acid oxidation induces muscle atrophy in cancer cachexia. Nature Medicine 22(6): 666-671

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