Engineering quality into protein drugs with systems glycobiology
Time: Wed 2019-11-13 15.00 - 16.00
Lecturer: Assoc. Prof. Nathan E Lewis, University of California, San Diego
Location: Albanova FB54 floor 5, Roslagstullsbacken 21, SE 10691
Protein glycosylation is fundamentally important to most biological processes and it is often important to regulate it in biopharmaceutical development. Thus, substantial efforts have been taken to engineer glycosylation of a variety of biologics. However, the diversity and complexity of glycosylation make it difficult to control the glycan structures and unravel how engineering efforts impact the host cells.
To enable rational glycoengineering and elucidate how such strategies impact the host cell, we have comprehensively studied the impact of glycoengineering on more than 180 CHO cell clones, wherein each has single or multiple glycosyltransferase genes knocked out. First, the clones were all glycoprofiled, and we developed a novel computational platform to rapidly study the changes in glycosylation across all mutants. Second, we quantified the impact of different glycosyltransferase knockouts on the bioprocessing phenotypes of the CHO cells (e.g., cell size, growth, viability, and metabolism). Third, we conducted a large-scale RNA-Seq study of the clones to study the molecular basis of the phenotypic changes.
Through these efforts, we identified dominant glycosyltransferses in CHO cells, and studied instances wherein the cells differentially expressed isozymes in response to a knockout. Furthermore, we identified groups of glycosyltransferases whose deletion had a more severe impact on cell glycoprofiles and phenotype. We also found specific molecular pathways were perturbed when different glycosyltransferase families were perturbed. Through this effort we are gaining a more comprehensive view of the impact of glycoengineering on biopharmaceuticals and the host cells producing the recombinant protein drugs. Finally, accounting for these cellular impacts on glycosylation, we developed a systems biology modeling framework to enable the rational engineering of glycosylation to be able to control this critical quality attribute on diverse recombinant protein drugs.
About Assoc. Prof. Nathan E Lewis
Dr. Lewis is an Associate Professor of Pediatrics and Bioengineering at the University of California, San Diego. He received his BS in biochemistry at Brigham Young University, and his PhD at UC San Diego, where he focused on proteomics and developing novel approaches for analyzing biological big data using genome-scale systems biology modeling techniques. Dr. Lewis completed his postdoctoral training at the Wyss Institute at Harvard Medical School, where he worked on genome editing and the use of systems biology for the interpretation of genetic screens. Dr. Lewis' lab integrates all of his previous work by focusing heavily on the use of systems biology and genome editing techniques to map out and engineer the cell pathways controlling mammalian cell growth, protein synthesis, and protein glycosylation.
You are also welcome to Erika Hagrot PhD thesis defence, for which Assoc. Prof. Nathan E Lewis will be Opponent. Erika's PhD thesis is entitled "Macroscopic models of Chinese hamster ovary cell cultures". Venue: November 13, 2019 10:00 - Albanova FB54 floor 5.