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1、1. Biopharmaceuticals Pharmaceutical substances : Medicinal therapy Traditional pharmaceutical sectors: - Chemical-based drugs : chemical synthesis - Extraction or isolation from biological sources Biopharmaceuticals : A class of therapeutic agents produced by modern biotechnological techniques, lik
2、e recombinant DNA, protein engineering, and hybridoma technologies etc. (used in the 1980s) - Nucleic acids used for gene therapy and antisense technology - Proteins for in vivo diagnostics A Protein or nucleic acid-based pharmaceutical substances used for therapeutic or diagnostic purpose, which is
3、 produced by modern biotechnological techniques Form the backbone of medicinal agents in the modern biotech era Before 20th century:Naturally occurring substances : Medicinal herbs- Digitalis to stimulate heart muscle- Quinine for malaria - Pecacuanha for dysentery- Mercury to treat syphilis - Synth
4、esis of aspirin in 1895 by Bayer- Chemical synthesis of artificial dyes proved to be therapeutically useful Foundation of Bayer and HoechstHistory of the pharmaceutical industry 1930s ; Beginning of pharmaceutical industry- landmark discovery and synthesis of sulpha drugs against bacterial infection
5、s from the red dye, Prontosil rubrum (Fig. 1.1)- large-scale industrial production of insulin 1940s : Industrial-scale production of penicillin boosting the development of biopharmaceutical industry 1992 : Taxol approved by FDA for ovarian, lung, breast cancerTaxol from the bark of the Pacific yew t
6、ree by Bristol-Myers-Squibb(BMS) Opium poppyMorphine Foundation of the leading pharmaceutical companies - Ciba Geigy, Eli Lilly, Wellcome, Glaxo, Roche Current pharmaceutical industry - 10,000 pharmaceutical companies- 5,000 substances are used routinely in medicine- 500 potential drugs under clinic
7、al trials - $ 200 billion marketStory of TaxolPaclitaxel- Identified in 1967 by NCI from the bark of the Pacific Yew tree (Taxus brevifolia) : - Used by American Indian for treatment of inflammation- Developed as anti-cancer agent by Bristol-Myers-Squibb (BMS) 1955 : Plant screening project by NCI t
8、o discover new anticancer agents screening of 35,000 plants 1967 : Identification of cytotoxic ingredient from the bark of Pacific yew tree Taxol (Generic name) 1969 : 10 g of pure compound from 1,200 kg of bark 1979 : Mechanism of action in leukamic mice inhibition of cell division by stabilization
9、 of microtubules 1984 : Phase 1 clinical trial problem of supply 1988 : Phase 2 clinical trialsA remarkable response rate of 30% in patients with refractory ovarian cancerOutline All the ovarian cancer and melanoma cases in the US : destruction of 360,000 trees annually Ecological concerns about the
10、 impact on yew populations 1989 : Cooperative Research requires many milk bottles Bottle plant long growing cycle and labor intensive Submerged fermentation process : Challenges - Mold physiology : productivity vs conditions- Reactor design : reactor size and configuration,oxygen supply (low solubil
11、ity of oxygen, viscosity,mixing, mass transfer ), heat removal, agitator design, mechanical sealing, decontamination, Product recovery/purification : pH shift and liquid-liquid extraction First plant for commercial production by Pfizer 100,000 gal scale in 1945 Nobel prize in 1945 for three scientis
12、ts Accomplishment required a high level of multidisciplinary workEx) Merck assigned a engineer and microbiologist together to each aspect of the problem Continued progress with penicillin fermentation through physiology, metabolic pathway engineering, mold genetics, process control, reactor design:
13、- Increase from 0.001 to 100 g/L Production of penicillin derivatives with greater potency: Antibiotic resistance- Semi-synthetic antibiotics- Protein engineering to design relevant enzymes:More economically feasible processBiosynthesis of Penicillin G in FungusPenicillin GPenicillin nucleus(6-APA)P
14、enicillin FEnzymatic processNew antibiotics with greater potency Derivatives (rational design)Animal testClinical trials (Phase I, II, III) Protein EngineeringAmoxicillinAmpicillinMethicillinFlucloxacillinDicloxacillinCarbenicillinLessons from the penicillin story Penicillin process established a pa
15、radigm for bioprocess development and biotechnology Analysis of the failed experimental results in a critical way:Curiosity leads to a creative and original idea The development of biological process requires a high level of multidisciplinary work Current issue Emergence of antibiotic-resistance pat
16、hogens : Genes can be transferred between bacteria in a horizontal fashion by conjugation, transduction, or transformation A gene for antibiotic resistance that had evolved via natural selection can be shared Evolutionary stress such as exposure to antibiotics selects for the antibiotic resistant trait. Superbug : a bacterium with several resistance genes- MRSA (Methicillin-r
