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What is Biotechnology?
- Purposeful design and modification/assembly of bio-oriented materials (e.g., proteins/enzymes, microorganisms, plant/animal cells, tissues, stem cells etc..) and processes to benefit humans or produce valuable product for profit.
- the use of biological system (cells, tissues etc..) or biomolecules (enzymes/proteins, antibodies, DNA/RNA) for or in the manufacture of
products at commercial scale : cost-effectiveness economically feasible
• Basic Biology / Medical sciences
- To discover and elucidate the underlying mechanisms of behaviors and disorders in living organisms, and eventually a drug target
- Production of valuable products at commercial scale Therapeutic proteins, vaccines, drugs, biofuels, amino acids, vitamins, hormones, fine chemicals, etc..
- Development of tools and methodology
Recombinant DNA tech., Gene synthesis, Cell culture tech., Purification process, Formulation, Bioassay, Diagnosis, Delivery
Integration of biological sciences with Engineering principles
cost-effectiveness : Competiveness
- Process development/design/optimization Required disciplines
- Basic disciplines : molecular biology, immunology, cell biology,
- Practical disciplines : Engineering principles - Mass / Energy /Momentum balance
- Thermodynamics - Physical, organic chemistry / Pharmacology - Biochemical engineering : the extension of chemical engineering principles to biological system Bioreaction engineering and bio-separation
Computational modeling .DNA/Protein chips/ Proteomics technology . global warming Energy (Bio-energy) : depletion of petroleum source Agriculture : crop with reduced vulnerability to environmental stresses high productivity • Related key areas and technologies .Therapeutic protein development : safety.Cell culture engineering .• Major applications . and toxicity Health care / Diagnosis : early detection and prevention Environment : pollution.Nano-biotechnology . CO2 emission. standardized and well-characterized building block .Synthetic biology : Systematic. efficacy.Protein design/engineering : Rational design and creation of protein with desired property based on structural and mechanistic knowledge . bio- inspired system using robust.Metabolic pathway engineering .Separation / purification technology . hierarchical design of artificial.
Gas − CO2 − Organic vapor Bioprocessing Cell culture Biocatalyst Bioreactor Enzymatic Product Recovery product PRODUCT LINES Bio-processing Immobilized Enzymes Separation Cell culture /Purification ( Microorganisms.Organic − Sugar solution Solid − Biomass − Consumer Waste Culture media Bioreactors − Gaseous − Aqueous − Organic .Immobilized − Secondary − Free Media − Ambient to Extreme − Continuous System − Membrane − Batch or Fed-batch Product Therapeutic proteins Biofuels Amino acids Specialty Chemicals Vitamines Industrial enzymes Liquid . process mammalian cells) − In situ .General Bioprocess Feedstock GAS LIQUID SOLID Feedstock Gas − Syn.
Embrel : soluble TNF(Tumor necrosis factor) receptor .EPO (Erythropoetin) : stimulate the generation of RBCs treatment of anemia associated with chronic kidney failure or chemotherapy .Herceptin : Mab against epidermal growth factor receptor 2 .Typical examples of therapeutic proteins Company Amgen Roche Eli Lilly Genzyme Immunex Genentech Products EPO Interferons Avastin Insulin Cerezyme Embrel Herceptin World market : $ 50 Billion (2007) $ 80 Billion (2011) .Avastin : Mab against VEGF block angiogenesis in tumors .
000 annually .Therapeutic Enzymes Sales (US$Millions) Disease Product Developer Features Glucocerebrosidase Purified from human placenta Produced in CHO cells 3 Exoglycosidases process for Terminal Mannose alpha-galactosidase Mannose-6-phosphate for Glycotargeting alpha –L-iduronidase glucosidase alfa 2004 2007 N/A Ceredase® Gaucher’s Genzyme 443 932 (2005) 209 57 12 Cerezyme® Fabrazyme® Replagal MPS-1 Pompe Aldurazyme® Myozyme® Genzyme Genzyme TKT Genzyme Genzyme 1.048 397 168 204 Fabry’s Approved (2006) Treatment of Gaucher’s disease by Cerezyme costs up to $550.
Lysosomal Storage Disease .Found by Phillipe Gaucher in 1882 .Gaucher’s Disease.Biochemical basis for the disease in 1965 by Brady et al. Glucosyl Ceramide O=C-CH2-CH2-CH2-(CH2)nCH3 OH N CH2-CH-CH-CH=CH-(CH2)12-CH3 Glucocerebrosidase (b-glucosidase) O=C-CH2-CH2-CH2-(CH2)nCH3 OH N OH-CH2-CH-CH-CH=CH-(CH2)12CH3 Glucose Ceramide Autosomal recessive inheritance ..
8) within the lysosome is required for lysosomal enzymes to be active • Lysosome Lysosome with substrate accumulation (LSD) Nucleus Mitochondria (Normal cell) (LSD cell) .Lysosomal storage diseases (LSDs): Lysosomal Enzymes Lysosome : cells’ garbage disposal system • Digestive organelle in the cell • (1) The ER and Golgi apparatus make a lysosome (2) The lysosome fuses with a digestive vacuole (3) Activated acid hydrolases digest the contents Contains~40 hydrolytic enzyme Acidic pH (about pH4.
neurological complications etc. Normal cells glucocerebrosides Exocytosis Glucocerebrosidase + Digestive vacuole glucose ceramide Residual vacuole Distended abdomen Gaucher cells glucocerebrosides Incomplete digestion Residual vacuole accumulated Digestive vacuole No exocytosis . liver.000 (Jew 1/~500) swollen vacuoles Gaucher cells accumulation in spleen.. brain enlarged spleen and liver.000~60.Gaucher’s disease : Occurrence and symptoms 1/ 40. liver malfunction. kidney.
3-Propanediol Terephthalic acid Adipic acid Methanol Celanese / Diversa Cargill DuPont / Genencor Chevron / Maxygen .000 MT/yr) 1.Typical examples of Bio-Products Company BASF Eastman Chemical / Genencor Degussa Procucts Vitamin B-2 Methoxy isopropyl amine (chiral intermediate) Styrene oxide Amino acids Ascorbic acid Acrylamide Fatty acid – derived esters Polyglycerine ester Organo modified silicones and oleochemicals Acetic acid Polyunsaturated fatty acids Non-digestible starch Polylactic acid (PLA) Polylactic acid (PLA) (140.
protein microarray) Development and commercialization of target products .Gene (mRNA) expression profiling in a high throughput manner .New paradigms in Biotechnology .Bio-molecular interactions (Interactom) Proteomics (2-D gel.Global analysis : Genome or proteom wide analysis .High amounts of relevant knowledge : genome sequences Genomics (Gene chip) .Bioinformatics .Drug target identification via high throughput screening .Advent of Bio-based Economy Massive and high speed analysis system .Functional genomics .Genome and proteom-wide approach : Systemic approach .Integration of a high throughput system .
Exhaustion and soaring price of petroleum (> $ 100 /gallon) .Replacement of chemical process with Bio-based one White Biotechnology .Development of renewable source-based Bioprocess .Bio-based economy: Impact on global economy Shift from petroleum-based economy .Environmental issue Global warming (CO2 emission) Pollution .
Value chains from renewable sources .
Value Chain of White BT .
Increase in the yield and alcohol tolerance .Process development : Fermentor and operation .Design of enzymes in the pathway .Redesign of pathway way .Separation and concentration .Pathway of ethanol production in yeast .Source of starting substrate : starch or cellulose .Elucidation of enzyme mechanisms .Alternative energy source Production of biofuel (ethanol or butanol) from natural resources .
Potential Market Value of White BT White BT will account for 20 % of total chemical industry by 2010 $ 280 billion (McKinsey. 2003) .
Depletion of petroleum source .Limitation to CO2 emission (Kyoto protocol) Petrochemical-based economy Renewable source-based economy Chemical process Bio-based process Enzymes .Key role of enzymes in Bio-based economy Energy and Environmental issues .
Enzymes • • • Most proficient catalysts with high specificity Competitive and cost-effective processes Use for biosciences DNA polymerase: Thermostability. fidelity Restriction enzymes: Specificity Alkaline phosphatase Peroxidase Cleaning (Detergents) • • • • • • • • • Textiles Starch Processing Brewing Leather Baking Pulp and Paper Food and Specialties Animal feeds Cosmetics Industrial use for specialty chemicals Chiral drugs Chiral intermediates Semi-synthetic antibiotics Organic acids Therapeutics • Treatment of Gaucher’s disease .
Chemical company devoting to Biotechnology : BASF Emphasis on Bio-products mainly using Enzymes Ecoflex® .
Synthetic biology • • • Genome sequences of more than 200 organisms Knowledge on functions of genes/enzymes Design and construction of new biological entities such as enzymes. and the assembly of these smaller parts and devices into larger integrated systems that solve specific problems Design integrated circuits based on the known physical properties of materials and then fabricate functioning circuits and entire processors (with relatively high reliability) Create and build newly engineered biological systems • • . metabolic pathways. and tuned to meet specific performance criteria. genetic circuits. genetic circuits. and cells or the redesign of existing biological systems (expansion of genetic code) Focus on the design and construction of core components (parts of enzymes. etc.) that can be modeled. understood.
Artemisinin works by disabling a calcium pump in the malaria parasite Enemy within: haemoglobin in these red blood cells is being digested by the parasite that causes malaria. primarily children in Africa and Asia .as currently produced from plant sources : scarce and too expensive for large-scale use .Anti-malarial drug precursor artemisinic acid in engineered yeast .000 years by the Chinese as a herbal medicine called qinghaosu. more effective artemisinin-based drugs . . and has been used for more than 2.Malaria infects 300-500 million people and causes 1-2 million deaths a year.Artemisinin : extracted from the leaves of Artemisia annua. . .The parasite that causes malaria has become at least partly resistant to every other treatment tried so far.The faster-acting. or sweet wormwood.
effective. Biol. artemisinic acid by introducing three genes from Artemisia annua . . Nature Struct. 628–629.. Mol.Goal : To produce inexpensive. 12.Redesign of yeast to synthesize artemisinin precursor.Report that the mutation of a single amino acid was sufficient to confer resistance (Uhleman et al. anti-malarial drugs using synthetic biology approach .US $ 43-million dollar grant to a UC Berkeley group from the Seattle-based Bill & Melinda Gares Foundation . 2005).Production level by yeast culture: ~ 100 mg/L .
Nature (2009) ..FPP: Farnesyl pyrophosphate ADH : Amorphadiene synthase Green arrows : the biochemical pathway Leading from FPP to Artemisinic acid Ro et al.
life-style. and economy . requires interdisciplinary collaborations .Diagnosis : in vitro and in vivo • Biotechnology constitutes a variety of diverse areas and technologies.Perspective • Biotechnology will have the greatest impact on humans in the future in terms of health.Therapeutic proteins : Treatment of diseases .Bio-based economy : Environmental issue .
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