|Molecular Bioprocessing Overview|
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CBIS researchers are exploiting their combined expertise in upstream and downstream bioprocessing to focus on the molecular level. This includes protein- and polysaccharide-based therapeutics, as well as novel small molecule diversity. An underlying theme is the integration of engineering science and technology with molecular and cellular biology.
Many biomolecules, particularly protein therapeutics, are complex glycoproteins that are typically manufactured in mammalian cells to achieve appropriate glycosylation and other forms of post-translational processing. There is currently very little fundamental understanding of how the cells, culture environment, nucleic acid sequences, and the biomolecules themselves, both their sequences and their structures, interact to affect productivity and product quality. For example, many monoclonal antibodies exhibit specific productivities of 50 to 100 picograms per cell per day with product titers exceeding 5 g/l; however many others do not, or they exhibit splice variants, abnormal truncation or other changes that make them unsuitable for therapeutic manufacturing. Moreover, some enzymatic therapeutics exhibit exceptionally low productivities (e.g. 1 to 5 picograms/cell/day), making viable commercial processes difficult. In addition, different cell clones producing the same product can exhibit widely different productivities, requiring extensive, labor-intensive screening of hundreds or thousands of cell clones to identify highly productive cell lines.
There is, thus, an urgent need for the development of novel bioprocesses for the efficient production of new generation biopharmaceuticals, which has led CBIS researchers to focus on the new interdisciplinary field of Molecular Bioprocessing. The unifying theme for this research program is to provide a molecular understanding of the interactions of biomolecules, particularly recombinant protein pharmaceuticals, with cellular systems, separations materials, ligands and other biomolecules (Figure 1). This improved fundamental understanding is helping to bridge critical technology challenges in bioprocessing, catalyzing the production of novel, life-saving drugs. This research area has a long and distinguished history at Rensselaer and has produced a large number of outstanding graduates who have gone to leadership positions in the biotechnology industry and academia.
Figure 1: Overview of molecular Bioprocessing of biotherapeutic proteins within CBIS. The unique environment at CBIS is ideal for this type of interdisciplinary research program and the addition of recent junior faculty promises to make this an even more dynamic research area in the future.
Through CBIS research, important bioprocessing questions are being addressed with far reaching implications such as why similar molecules have radically different levels of expression, why apparently similar molecules have different affinities for chromatographic materials, and why some proteins aggregate while others do not under bioprocessing conditions. The implications of this research are significant for both obtaining fundamental insight into biomolecular interactions and for the development of entirely new bioprocesses. CBIS researchers have extensive research expertise in fields related to cellular bioprocessing, biomolecular interactions and purification, and biomolecular stability and aggregation that enable us to address critical fundamental and technological challenges in molecular bioprocessing. This research is being carried out in teams comprised of biologists, chemists and chemical engineers. In the area of cellular bioprocessing, CBIS researchers are investigating genetic and epigenetic effects on protein productivity, effects of culture environment and cell physiology on protein product, and the relationship between protein sequence and stability on correct folding and post-translational processing in vivo.
Biomolecular purification plays a critical role in processes ranging from large-scale production of biopharmaceuticals to small scale complex proteomic separations. The requirement for large quantities of new antibody biopharmaceuticals at high purity makes the development of novel bioseparation processes of paramount importance. Critical challenges associated with the downstream processing of protein based therapeutics include: developing bioseparations processes that can handle very high volumes of high concentration products, reducing the number of downstream processing steps by integrating several unit operations into a single step and by developing more selective separation systems to remove key product impurities and developing new separation processes that can assure product quality (e.g. glycosylation, native conformation, and reduced aggregation). Research efforts in this area include: novel chromatographic, membrane, crystallization, precipitation, affinity, and genetic-based separation technologies.
Many biomolecules are inherently unstable and preventing their aggregation represents a critically important problem in the biopharmaceutical industry. Current research in Biomolecular Stability and Aggregation focuses on addressing two key challenges: the design of aggregation-resistant proteins through engineering of surface residues to optimize both conformational and colloidal stability; and analysis of novel excipients that inhibit and reverse protein aggregation.