Putting Biotechnology to Work Bioprocess Engineering (1992) / Chapter Skim
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4 Current Bioprocess Technology, Products, and Opportunities
4 Current Bioprocess Technology, Products, and Opportunities
Pages 50-76
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· Specialty products and industrial chemicals. Antibiotics, value-added food and agricultural products, and fuels, chemicals, and fiber from renewable resources.
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E cold is the microbial system of choice for the expression of heterologous proteins.
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54 PUTTING BIOTECHNOLOGY TO WORK Table 4.2 Conditions for Which Biotechnology-Derived Drugs are Under Development AIDS and AIDS-related complex (ARC) Chemotherapy effects Leukemia Aplastic anemia Cancer Bone marrow transplant Hematological neoplasms Neutropenia Myelodysplastic syndrome Infectious diseases Thermal injury Reperfusion injury related to myocardial infarction and renal transplantation Anemia secondary to kidney disease, AIDS, premature infants, chemotherapy, rheumatoid arthritis Autologous transfusion Hemophilia Corneal transplants Wound healing Chronic soft tissue ulcers Diabetes Wasting syndromes Nutritional and growth disorders Venous stasis Turner's stasis Burns Venereal warts Herpes simplex 2 Hepatitis-B, non-A non-B hepatitis Hypertension Platelet deficiencies Septic shock Pseudomonas infections Heart and liver transplant rejection Malaria Need for cervical ripening to facilitate childbirth Myocardial infarction Deep vein thrombosis Acute stroke Pulmonary embolism SOURCE: OTA, 1991, p.
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cold can now be designed for either intracellular accumulation of the heterologous protein in the cytoplasmic space or translocation of the protein across the cytoplasmic membrane from the cytoplasmic space into the periplasmic space. After translocation, the protein can accumulate within the periplasmic space or might be released to the surrounding medium.
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However, the system is often limited by its inability to produce intact, properly folded proteins and by a limited ability to yield posttranslational modifications, such as glycosylation and specific proteolytic modification. Nonetheless, the system has enabled the commercialization of such products as human insulin, human growth hormone, human oc-interferon, and human y-interferon.
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Alternatively, it might be possible to use molecular chaperones to repair and disaggregate proteins outside the cell before releasing them for refolding to the active monomer. 4.1.3 Mammalian Host Systems Production of heterologous proteins by mammalian cells has usually used CHO cells or hybridoma cells.
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Yeast has been used to produce rDNA proteins, such as IGF-1 and human serum albumin; in spite of substantial effort, it has not been used as extensively as E cold or CHO cells.
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Measurement of those contaminants requires sophisticated assays capable of detecting a spectrum of possible contaminants at a few parts per million of the product protein. The presence of undesired variants of the target protein has motivated the development of techniques to detect and separate (on a large scale)
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As additional glycoproteins are identified and cloned, there is an increasing need for more effective chromatographic methods, production systems that mimic mammalian glycosylation patterns, and fast, reproducible analytical methods to minimize microheterogeneity during manufacture. Variability in oligosaccharide biosynthesis has been found to be an important source of heterogeneity for glycoproteins produced by eukaryotic cells (Merino, 1989~.
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The development of appropriate process controls, analytical methods, and quality-control specifications to control lot-to-lot consistency will be complicated by the inherent microheterogeneity of glycoproteins. 4.1.8 Metabolic Engineering A powerful new approach to product development is the creative application of fermentation technology and molecular biology for "metabolic engineering." Examples of metabolic engineering for heterologous-protein production include deletion of proteases that eliminate product and production of factors that facilitate product maturation and secretion.
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4.1.9 Polymerase Chain Reaction Within the last 5 years, the polymerase chain reaction (PCR) has transformed the way DNA analysis is performed.
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The product protein must be in a form that is stable, is convenient to use, and allows the drug to be delivered in the desired manner. Several of the initial rDNA products were in lyophilized form, which is relatively stable, but inconvenient.
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Biological and biochemical tools are needed and will require research to · Develop tools for the expression, modification, and secretion of heterologous proteins from prokaryotic and eukaryotic cells. This includes the study of protein translocation and folding in E
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. · Develop rapid on-line and off-line assay capabilities for assessing contaminant host proteins and DNA at parts-per-million concentrations, variants of the product protein, and relative biological activity.
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Development of the appropriate, censored systems is probably the key element in the early stages of efficient computer-managed biological manufacturing systems. 4.2 SPECIALTY BIOPRODUCTS AND INDUSTRIAL CHEMICALS Specialty products are chemicals, proteins, microbial substances, and other biologically derived materials whose volume of annual domestic or worldwide use is measured in tons.
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That group of products is sensitive to processing costs, and manufacture is carried out at a scale in which bioprocess engineering is an important component of technology and design. Specialty products also include flavor enhancers, such as monosodium glutamate, and amino acids.
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Challenges that bioprocess engineering faces include specialty-equipment design that meets regulatory, biological, and economic constraints; integration of manufacturing processes into environmentally acceptable and economically feasible process concepts; and rapid purification and monitoring of purification processes to obtain high quality, high purity, and consistent output. Many specialty products are obtained through fermentation in dilute solution.
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For submerged fermentations, product inhibition presents an important challenge to bioprocess engineers, because it limits both the rate and the extent of product formation. Novel bioreactor designs, membrane-separation technologies, and processing aids could all improve the economics of producing specialty bioproducts.
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Subsurface Bioremediation uses microorganisms already in the soil and groundwater and adds oxygen and nutrients. Ex situ treatment involves the excavation of contaminated soil and its transfer to appropriate treatment sites, i.e., bioreactors.
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Regulations provide a market for bioremediation by dictating what must be cleaned up, how clean it must be, and which cleanup methods may be used; but regulations also hinder commercial development due to their sheer volume and the lack of standards for biological waste treatment. Although some research is being conducted on the use of genetically engineered organisms for use in bioremediation, today's bioremediation sector relies on naturally occurring micro-organisms.
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Most DNA work on animals focuses on altering livestock, poultry, or fish to improve reproductive performance, weight gain, or disease resistance. Planned introduction of genetically engineered organisms into the environment, often called deliberate release, was the focus of an earlier OTA report.
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Avian erythroblastosis Sindbis virus (sheep, cattle, chickens) Herbicide resistance or tolerance to: Glycophosphate Atrazine Imidazolinone Bromoxynil Phosphinotricin Disease resistance to: Crown gall disease (tobacco)
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Animals Livestock species engineered to enhance weight gain or growth rates, reproductive performance, disease resistance, or coat characteristics Livestock animals engineered to function as producers for pharmaceutical drugs Fish: Triploid salmon produced by heat shock for use as game fish in lakes and streams Fish with enhanced growth rates, cold tolerance, or disease resistance for use in aquaculture Triploid grass carp for use as aquatic weed control agents SOURCE: OTA, 1991. an Center for Mineral and Energy Technology is the leading government research agency in the field.
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4.3.6 Research Needs and Opportunities The committee concurs with the OTA report (OTA, 1991) that immediate opportunities for bioprocessing, particularly those which would use genetically engineered microorganisms, exist.
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1991. Recent advances in the polymerase chain reaction.
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