Michael Betenbaugh, professor of chemical and biomolecular engineering and lead PI of the Advanced Mammalian Biomanufacturing Innovation Center (AMBIC), is known for integrating systems biology with cellular, metabolic, and biochemical engineering for eukaryotic biotechnology applications.
Betenbaugh is one of the original pioneers of eukaryotic metabolic engineering and has made multiple landmark contributions in improving the efficiency and effectiveness of mammalian and insect production hosts, in fundamental discoveries in glycobiology, in applying systems biology to understand mammalian cells in biotechnology and biomedicine, and in advancing knowledge about sustainable algal bioprocessing for biofuels and other products.
AMBIC is an Industry-University Cooperative Research Center (IUCRC) funded by NSF and 20 industrial and governmental sponsors, including major biopharmaceutical manufacturers, contract manufacturers, and suppliers. Projects in the areas of upstream mammalian cell culture sponsored at Johns Hopkins include epigenomics, glycan analytics, reference cell line development, mathematical modeling, mammalian cell metabolism, and media optimization. Additional academic participants include Clemson University; University of Delaware; University of Massachusetts, Lowell; and University of Maryland, College Park.
Betenbaugh also led the JHU initiative to be one of the original academic members of the National Institute for Innovation in Manufacturing Biopharmaceuticals (NIIMBL), which uses federal and industry co-funding to fine-tune existing biopharmaceutical manufacturing techniques.
Betenbaugh’s most significant achievements include the application of chaperones and foldases to increase protein folding and product yields from insect cells; glycoengineering in insect and mammalian hosts to produce sialylated high-value glycoproteins; anti-apoptosis engineering to increase mammalian survival and productivity; genomics, proteomics, glycomics, and systems biology models of mammalian hosts; microRNA analysis and genome engineering in mammalian cells; and advancing sustainable microalgae processing.
In the 1990s, a major challenge in the cell culture field was the low yield obtained for secreted proteins. Betenbaugh’s research group hypothesized that a bottleneck existed at post-translational processing steps—including folding and assembly— in the secretory processing pathways of insect cells, and pioneered the co-expression of molecular chaperones and folding catalysts.
In the glycoengineering field, a major limitation to the wider application of many recombinant expression systems had been the absence of complex glycosylation capabilities and the presence of non-human glycoforms from these hosts. In order to characterize glycosylation processing, Betenbaugh and collaborators published a detailed composition of N-linked glycans from insect cells. His group and collaborators also developed a pioneering essay that quantifies all of the major intracellular sugar nucleotides, which has become a benchmark in the biotechnology industry. Their findings revealed a major limitation of insect cells glycoprocessing, a limitation the group later addressed using glycoengineering. Indeed, Betenbaugh’s group was the first to undertake whole pathway metabolic engineering to overcome glycosylation bottlenecks in one of the first projects funded as part of NSF’s Metabolic Engineering Program, a forerunner to current synthetic biology efforts.
His group was also one of the first to demonstrate apoptosis activation in industrial cell culture processes and is the world leader in controlling programmed death in cell culture processes.
In the area of sustainable microalgae processing, Betenbaugh has screened and identified microalgae species such as Chlorella that can achieve very high lipid content, representing potential biodiesel precursors, under varying phototrophic, heterotrophic, and mixotrophic conditions. His application of the latest genomics, analytics, and mathematical techniques has facilitated the study of intracellular pathways and enabled users to identify and overcome processing limitations in multiple eukaryotic systems including insect, mammalian, and microalgae.
Betenbaugh received the D.I.C. Wang Award for Excellence in Biochemical Engineering (2017), the Marvin J. Johnson (2015), and James Van Lanen awards from the American Chemical Society’s Division of Biochemical Technology, and the Cell Culture Engineering Award (2010). He served as a visiting scientist at the Kyoto Institute of Technology in 2001 and is an elected fellow of the American Institute for Medical and Biological Engineering (AIMBE).
He earned his BS in chemical engineering at the University of Virginia in 1981, and his PhD in chemical engineering at the University of Delaware in 1988.