臺灣博碩士論文加值系統

重組大腸桿菌（Escherichia coli, E. coli）受啟動子（promoter）誘導調節，加入乳糖誘導劑（inducer）進行誘導可表現重組蛋白質。饋料批式發酵重組蛋白以模式為基礎的進料流率分佈最適化問題來討論，最適化程序採用進化演算法（Evolutionary Algorithm）之中的基因演算法（Genetic Algorithm），討論以最少乳糖進料量與最高重組蛋白產量為兩個目標函數的最適化結果。接著取最適化得到的乳糖最適進料流率去設計單一輸入單一輸出(Single-input Single-output；SISO)的控制。在含有干擾的真實程序下，以PI控制及模式預測控制（Model Predictive Control; MPC）都有達到控制效果。

Recombinant E. coli is induced under the control of the promoter, by feeding the lactose used as the inducer which can induce and express recombinant protein. A model-based feed-rate profile optimization problem is discussed for the fed-batch recombinant protein production. The optimization procedure, applying Genetic Algorithm, one of Evolutionary Algorithm methods, is discussed the results of the optimization that contains the two objective functions regarded as the fewest amount of the lactose feed and the highest amount of recombinant protein. After the optimization, we use the optimal lactose feed-rate to design Single-input Single-output（SISO）control. In the actual process with disturbance, the control is perfectly performed both by PI controller and MPC.

目錄
中文摘要………………………………………………………………….i
Abstract………………………………………………………………….ii
目錄……………………………………………………………………...iii
圖目錄……………………………………………………………………v
表目錄………………………………………………………………….viii
第一章 前言……………………………………………………………..1
1-1. 研究背景……………………………………………………………………1
1-2. 研究動機……………………………………………………………………2
1-3. 研究目的……………………………………………………………………2
1-4. 文獻回顧……………………………………………………………………3
1-4.1. 發酵程序的概念…………………………………………………….3
1-4.2. 細菌生長的數學模式……………………………………………….4
1-4.3. 多目標最適化……………………………………………………….5
1-4.4. 模式預測控制的發展……………………………………………...6
1-5. 研究貢獻……………………………………………………………………8
1-6. 組織章節……………………………………………………………………8
第二章 大腸桿菌的發酵程序與分析…………………………………..9
2-1. 程序說明……………………………………………………………………9
2-2. 數學模式…………………………………………………………………..11
2-3. 模擬結果與討論…………………………………………………………..14
2-4. 參數調控…………………………………………………………..………15
第三章 多目標最佳化…………………………………………………39
3-1. 多目標與單目標最佳化的意義…………………………………………..39
3-2. 概述基因演算法…………………………………………………………..42
第四章 最適化批式饋料培養大腸桿菌重組程序……………………49
4-1. 前言………………………………………………………………………..49
4-2. 多目標最適化……………………………………………………………..51
4-2.1 最適化目標…………………………………………………………51
4-2.2 結果與討論…………………………………………………………52
第五章 批式饋料培養大腸桿菌重組程序之控制設計………………68
5-1. 前言………………………………………………………………..………68
5-2. PI控制……………………………………………………………………...69
5-3. MPC控制…………………………………………………………………..73
第六章 未來展望與結論………………………………………………79
參考文獻………………………………………………………………..80

參考文獻

[1] Anderson, L.; Strandberg, L.; Haggstrom, L.; Enfors, O., “Modelling of high cell density fed batch cultivation.”FEMS. Microb. Rev., 1994, 14, 39–44.
[2] Andres-toro, B.; Giron-sierra, J.M.; Feranadez-blanco, P.; Lopez-orozc, J.A.; Besada-portas, E.,“Multiobjective optimization and multivariable control of the beer fermentation process with the use of evolutionary algorithms.”J Zhejang Univ SCI , 2004, 5, 4, 378-389.
[3] Baltes, M.; Schneider, R.; Sturn, C.; Reus, M.,“Optimal experimental design for parameter estimation in unstructured growth models.”Biotechnol. Prog. , 1994, 10, 480–488.
[4] Bangaa J. R., Eva Balsa-Cantob, Molesc C. G., Alonsoa A. A., “Dynamic optimization of bioprocesses: Efficient and robust numerical strategies.” Journal of Biotechnology, 2005, 117, 407–419.
[4] Bard, Y.; Lapidus, L., “Kinetic analysis by digital parameter estimation.” Catalysis Reviews, 1968, 2, 67-109.
[5] Balsa-Canto, E.; Banga, J. R.; Alonso, A. A.; Vassiliadis, V. S.,“Dynamic optimization of chemical and biochemical processes using restriced second-order information.” Computers and Chemical Engineering, 2001, 25, 539-546.
[6] Biegler, L.T.; Damiano, J.J., “Nonlinear parameter estimation : a case study comparison.” AIChE J., 1986, 32, 29-45.
[7] Buckel, P.; Hübner-Parajsz, C.; Lenz, H.; Haug, M.; Beaucamp, K.,“Cloning and nucleotide sequence of heavy- and light-chain cDNAs from a creatine-kinase-specific monoclonal antibody.” Gene , 1987, 51, 13−19.
[8] Camacho, F., and Bordons, C. Model Predictive Control. Springer, 2004.
[9] Chiou, J.P.; Wang, F.S., “Estimation of Monod model parameters by hybrid differential evolution.” Bioprocess and Biosystems Engineering, 2001, 24, 109-113.
[10] Clarke, D. W.; Mohtadi, C. and Tuffs, P. S., “Generalized Predictive Control Part I. The Basic Algorithm.” Automatica, 1987, 23 ,2 , 137-148.
[11] Clarke, D. W. and Gawthrop, P. J., “Self-tuning Control.” Proceedings IEEE, 1979, 123, 633-640.
[12] Cutler, C. R.; and Ramaker, B. C., “Dynamic Matrix Control-a Computer Control Algorithm.” In Automatic Control Conference, San Francisco, 1980.
[13] Deb, K.; Pratap, A.; Agarwal, S.; Meyarivan, T., “A fast and elitist multiobjective genetic algorithm: NSGA II.” Evolutionary Computation 6 , 2000, 182-194.
[14] Deb, K., “Multi-objective optimization using evolutionary algorithms.” John Wiley & Sons, Chichester, UK, 2001.
[15] De Keyser, R M.C. and Van Cuawenberghe, A.R., “Extended Prediction Self adaptive Control.” In IFAC Symp. On Identification and System Parameter Estimation ,” York, UK, 1985, 1317-1322.
[16] Diaz, C.; Lelong, P.; Dieu, P.; Feuillerat, C.; Salome´, M.,“On-line analysis and modeling of microbial growth using a hybrid system approach.”Proc. Biochem., 1999, 34, 39–47.
[17] Dietz, A.; Azzaro-Pantel, C.; Pibouleau, L.; Domenech, S., “Multiobjective optimization for multiproduct batch plant design under economic and environmental considerations.” Computers & Chemical Engineering, 2006, 30, 4, 599–613, 15 February.
[18] Fonseca, C., & Fleming, P., “Genetic algorithms for multiobjective optimization: formulation, discussion and generalisation.” Proceedings of the 5th International Conference on Genetic Algorithms, 1993, 416–423.
[19] Galvanauskas, V.; Simutis, R.; Volk, N.; Lübbert, A.,“Model based design of a biochemical cultivation process.” Bioproc. Eng., 1998, 18, 227-234.
[20] Galvanauskas, V.; Volk, N.; Simutis, R.; Lübbert, A.,“Design of recombinant protein production process.”Chem. Eng. Comm., 2004, 191, 732-748.
[21] Garcia, C., Prett, D., and Morari, M. Model predictive control: theory and practice 　a survey. Automatica (Journal of IFAC) 25, 1989, 3, 335–348.
[22] Garcia-Ochoa, F.; Santos, V.E.; Alcon, A.,“Metabolic structured kinetic model for xanthan production.” Enzyme Microb Technol, 1998, 23, 75–82.
[23] Garcia-Ochoa, F.; Santos, V.E.; Alcon, A.,“Chemical structured kinetic model for xanthan production.” Enzyme Microb Technol, 2004, 35, 284–292.
[24] Gombert, A.K. and Kilikian, B.V.,“Recombinant gene expression in Escherichia coli cultivation using lactose as inducer.”J. Biotechnol, 1998, 60, 47-54.
[25] Greco, C.; Menga, G.; Mosca, E. and Zappa, G., “Preformance Improvement of Self Tuning Controllers by Multistep Horizons: the MUSMAR approach.” Automatica, 1984, 20, 681-700.
[26] Han, K.; Levenspiel, O., “Extended Monod kinetics for substrate, product, and cell inhibition.” Biotechnol Bioeng, 1988, 32, 430-437.
[27] Heitzer, A.; Kohler, H.P.P.; Reichert, P.; Hamer, G.,“Utility of phenomenological models for describing temperature dependence of bacterial growth.”Appl Environ Microbiol , 1991, 57, 2656–2665.
[28] Henson, M.A. and Seborg, D.E., “Nonlinear Control Strategies for Continuous Fermentters.” Chem. Eng. Sci., 1992, 47, 4, 821-835.
[29] Holms, H., “Flux analysis and control of the central metabolic pathways in Escherichia coli.” FEMS Microbiol Rev , 1996, 19, 85-116.
[30] Horn, J., Nafpliotis, N., Goldberg, D., “ A niched Pareto genetic algorithm for multi-objective optimization.” In Proceedings of the 1st IEEE Conference on Evolutionary Computation, 1993, 1, 82–87.
[31] Jones, M.T., “AI Application Programming”, Charless River Media, INC., 2003.
[32] Korz D.J.; Rainas U.; Hellmuth K.; Sanders E.A. and Deckwer W.-D., “Simple fed-batch technique for high cell density cultivation of Escherichia coli.” Biotechnol Bioeng , 1994, 39, 59–65.
[33] Lendenmann, U.; Egli, T., “Kinetic models for the growth of E. coli with mixtures of sugars under C-limited conditions.” Biotechnol Bioeng , 1998, 59, 99–107.
[34] Lee, C.W.; Chang, H.N.,“Kinetics of ethanol fermentation in membrane cell recycle fermenters.” Biotechnol Bioeng, 1987, 29, 1105–1112.
[35] Lee, J.H.; Hong, J.; Lim, H.C., “Experimental optimization of fed-Batch culture for poly-b-hydroxybutyric acid production.” Biotechnol Bioeng, 1997, 56, 6, 697-705.
[36] Levisauskas, D.; Galvanauskas, V.; Simutis, R. and Lübbert, A.,“Model based calculation of substrate/inducer feed-rate profiles in fed-batch processes for recombinant protein production.” Biotechnology Techniques., 1999, 13, 37-42.
[37] Lee, S.Y., “High Cell-Density Culture of Escherichia coli (Review).” Treds. Biotech., 1992, 14, 98-105.
[38] Lefebvre, J.; Junter, G.L.; Vincent, J.C., “Graphics-associated Modeling of batch cultures of E. coli fermenting glucose.”Enzyme Microb Technol, 1994, 16, 163–169.
[39] Lemos, J. M. and Mosca, E., ”A Multipredictor-based LQ self-tunning Controller.”In IFAC Symp. On Identification and System Parameter Estimation York, UK, 1985, 137-141.
[40] Luli, G.W.; Strohl, W.R., “Comparison of growth, acetate production, and acetate inhibition of Escherichia coli strains in batch and fed-batch fermentations.” Appl. Environ. Microbiol., 1990, 56, 1004-1011.
[41]
[42] Mahadevan, R. and Doyle III, F.J., “On-Line Optimization of Recombinant Product in a Fed-Batch Bioreactor.” Biotechnol. Prog., 2003 , 19 , 639-646.
[43] Majewski, R.A.; Domach, M.M., “Simple constrained-optimization view of acetate overflow in E. coli.” Biotechnol Bioeng, 1990, 35, 732–738.
[44] Mendes, P.; Kell, D.B.,“Nonlinear optimization of biochemical pathways: applications to metabolic engineering and parameter estimation.”Bioimformatics, 1998, 14, 869-883.
[45] Neubauer, P.; Hofmann, K., “Efficient use of lactose for the lac promotercontrolled overexpression of the main antigenic protein of the foot and mouth disease virus in Escherichia coli under fed-batch fermentation conditions.” FEMS Microbiol. Rev., 1994, 14, 99-102.
[46] Nielsen, J.; Pedersen, A.G.; Strudsholm, K.; Villadsen, J.“Modeling fermentations with recombinant microorganisms: formulation of a structured model.” Biotechnol Bioeng , 1991, 37, 802–808.
[47] Pagni, M.; Egger, L.; Aragno, M.,“The relationship between kinetics of substrate-limited transitions and steady-state growth in continuous cultures of Aquaspirillum autotrophicum limited by piruvate.” Antonie van Leeuvenhoek, 1995, 68, 181–189.
[48] Panda, A.K. ; Khan, R.H. ; Mishra, S. ; Appa Rao, K.B.C. ; Totey, S. M., "Influences of yeast extract on specific cellular yield of ovine growth hormone during fed-batch fermentation of Escherichia coli." Bioproc. Eng., 2000, 22, 379-383.
[49] Peterka, V., “Predictor-based Self-tunning Control .” Automatica, 1984, 20, 1, 39-50.
[50] Propoi, A. I.; “Use of LP Methods for Synthesizing Sampled-Data Automatic Systems.” Automn Remote Control, vol. 24, 1963.
[51] Ramakrishna, R.; Ramkrishna, D.; Konopka, A.E.,“Cybernetic modeling of growth in mixed, substitutable substrate enviroments: preferential and simultaneous utilization.”Biotechnol Bioeng, 1996, 52, 141–151.
[52] Reuss, M.; Wagner, F., “Double limiting substrate in fermentation.” In: Dellweg H, editor. Proc 3rd Symp. Techn. Mikrobiol. Berlin: Technische Universitat, 1973, 89–102.
[53] Richalet, J.; Abu el Ata-Doss, S.; Arber, C.; Kuntze, H. B.; Jacubash, A. and Schill, W., “Predictive Functional Control. Application to fast and accurate robots .” In Proc. 10th IFAC Congress, Munich, 1987.
[54] Richalet, J.; Rault, A.; Testud, J. L.; and Papon, J., “Algorithmic Control of Industrial Processes.” In 4th IFAC symposium on Identification and System Parameter Estimation,” Tbilisi URSS, 1976.
[55] Richalet, J.; Rault, A.; Testud, J. L.; and Papon, J., “Model Predictive Heuristic Control: Applaction to Industrial Processes.” Automatica, 1978, 14, 2, 413 -428.

[56] Schaffer, J.D. “Multiple objective optimization with vector evaluated genetic algorithms.” In J.J. Grefenstette (Ed.), Proceedings of an International Conference on Genetic Algorithms and Their Applications. Pittsburgh, PA, 1985, 93–100. Sponsored by Texas Instruments and U.S. Navy Center for Applied Research in Artificial Intelligence (NCARAI).
[57] Schuegerl, K. and Bellgardt, K.H., “Bioreaction engineering, modeling and control.” Springer, Berlin Heidelberg New York, 2000.
[58] Shimizu, A. ; Fukuzono, S. ; Fujimori, K. ; Nishimura, N. ; Odawara, Y., "Fed-batch cultures of recombinant Escherichia coli with inhibitory substance concentration monitoring." J. Ferm. Technol., 1988, 66, 187-191.
[59] Shiue, Y.L.; Wang, F.S.; Lee, W. C., “Parameter estimation and sensitivity analysis for batch fermentation of recombinant cells.” Biotechnology techniques, 1995, 9, 12, 891-896.
[60] Sarkar, D. and Modak, J. M., “Optimization of fed-batch bioreactors using genetic algorithm, multiple control variables.” Computers and Chemical Engineering, 2004, 28, 789-798.
[61] Sarkar, D. and Modak, J. M., “Pareto-optimal solutions for multi-objective optimization of fed-batch bioreactors using nondominated sorting genetic algorithm.” Chemical Engineering Science, 2005, 60, 481-492.
[62] Shuler, M.L. and Kargi, F., “Bioprocess Engineering Basic Concepts.”
Prentice-Hall Inc., 1992, New Jersey.
[63] Skolpap, W.; Scharer, J.M.; Douglas, P.L.; Moo-Young, M.,“Fed-batch optimization of α-Amylase and protease-producing.”Biotechnol Bioeng, 2004, 86, 6, 706-717.
[64] Soeterboek, R., “Predictive Control. A unified approach.” Prentice-Hall, 1992.
[65] Srinivas, N., & Deb, K., “Multiobjective optimization using nondominated sorting in genetic algorithm.” Evolutionary Computation, 1994, 2(3), 221–248.
[66] Srinivas, N. and Deb, K., “Multi-objective function optimization using non-dominated sorting genetic algorithms” Evolutionary Computation, 1995, 2,221-2248.
[67] Tartakovsky, B.; Dainson, B.E.; Lewin , D.R.; Sheintuch, M., “Observer-based non-linear control of a fed-batch autoinductive fermentation process.” The Chemical Engineering Journal, 1996, 61, 139-148.
[68] Wang, F.S.; Sheu, J.W., “Multiobjective parameter estimation problems of fermentation processes using a high ethanol tolerance yeast.” Chemical Engineering Science, 2000, 55, 3685-3695.
[69] Wang, F.S.; Lin, K.J.,“Performance analysis and fuzzy optimization of a two-stage fermentation process with cell recycling including an extractor for lactic acid production.” Chemical Engineering Science, 2003, 58, 3753-3763.
[70] Ydstie, B. E., “Extended Horizon Adaptive Control.” In Proc. 9th IFAC World Congress,Budapest, Hungary, 1984.
[71] Zitzler, E.; Thiele, L., “Multiobjective evolutionary algorithms: a comparative case study and the strength Pareto approach.” IEEE Transactions on Evolutionary Computation, 1999, 3(4), 257–271.