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IntroductionWhat 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
Biotechnology- Production of valuable products at commercial scale
Therapeutic proteins, vaccines, drugs, biofuels, amino acids, vitamins, hormones,
fine chemicals, etc..
- Development of tools and methodologyRecombinant DNA tech., Gene synthesis, Cell culture tech., Purification
process, Formulation, Bioassay, Diagnosis, Delivery
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Integration of biological sciences with Engineering principles
cost-effectiveness : Competiveness
- Process development/design/optimization
- Required disciplines
- Basic disciplines : molecular biology, immunology, cell biology,neurobiology etc..
-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
Basic Biology BiotechnologyBio-industry
- Commercialization- Scale-upEngineering principles
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Relatedkeyareas and technologies
- DNA/Protein chips/ Proteomics technology
- Protein design/engineering : Rational design and creation of protein
with desired property based on structural and mechanistic knowledge
- Metabolic pathway engineering
- Computational modeling
- Cell culture engineering
- Separation / purification technology
-Synthetic biology : Systematic, hierarchical design of artificial, bio-inspired system using robust, standardized and well-characterized building block
- Nano-biotechnology
Major applications
- Therapeutic protein development : safety, efficacy, and toxicity
- Health care / Diagnosis : early detection and prevention
- Environment : pollution, CO2 emission, global warming- Energy (Bio-energy) : depletion of petroleum source- Agriculture : crop with reduced vulnerability to environmental stresses
high productivity
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Cell culture
Enzymatic
Feedstock Bioprocessing Product
GAS
LIQUID
SOLID
PRODUCT
LINESBiocatalyst Bioreactor
Recovery
product
Feedstock Bio-processing
Gas Syn. Gas
CO2
Organic vapor Liquid
- Organic Sugar solution
Solid Biomass
Consumer Waste
Culture media
Immobilized Enzymes
Cell culture
( Microorganisms,
mammalian cells)- Immobilized Free
Ambient to Extreme
Bioreactors Continuous System
Membrane
Batch or Fed-batch
Separation
/Purification
process
In situ
Secondary
Media Gaseous
Aqueous
Organic
Therapeutic proteins
Biofuels
Amino acids Specialty Chemicals
Vitamines
Industrial enzymes
General Bioprocess
Product
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Typical examples of therapeutic proteins
Company ProductsAmgen EPO
Interferons
Roche Avastin
Eli Lilly Insulin
Genzyme CerezymeImmunex Embrel
Genentech Herceptin
World market : $ 50 Billion (2007) $ 80 Billion (2011)
- EPO (Erythropoetin) : stimulate the generation of RBCstreatment of anemia associated with chronic kidney failure or chemotherapy
- Avastin : Mab against VEGF block angiogenesis in tumors- Herceptin : Mab against epidermal growth factor receptor 2- Embrel : soluble TNF(Tumor necrosis factor) receptor
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Disease Product DeveloperSales
(US$Millions) Features
2004 2007
Gauchers
Ceredase Genzyme 443 N/A Glucocerebrosidase
Purified from human placenta
Cerezyme Genzyme 932(2005) 1,048
Produced in CHO cells
3 Exoglycosidases processfor Terminal Mannose
FabrysFabrazyme Genzyme 209 397 alpha-galactosidase
Mannose-6-phosphate forGlycotargetingReplagal
TKT 57 168
MPS-1 Aldurazyme Genzyme 12 204 alphaL-iduronidase
Pompe Myozyme GenzymeApproved
(2006) glucosidase alfa
Therapeutic Enzymes
Treatment of Gauchers disease by Cerezyme costs up to $550,000 annually
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Lysosomal storage diseases (LSDs):Lysosomal Enzymes
Lysosome :cells garbagedisposal system
Digestive organelle in the cell
Contains~40 hydrolytic enzyme
Acidic pH (about pH4.8) within
the lysosome is required forlysosomal enzymes to be active
(1) The ER and Golgi apparatus make a lysosome
(2) The lysosome fuses with a digestive vacuole
(3) Activated acid hydrolases digest the contents
(LSD)Lysosome
Nucleus
Mitochondria
Lysosome withsubstrateaccumulation
(Normal cell) (LSD cell)
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Normal cells
Gaucher cells
+
1/ 40,000~60,000 (Jew 1/~500)
swollen vacuoles Gaucher cells
accumulation in spleen, liver, kidney, brainenlarged spleen and liver, liver malfunction,
neurological complications etc..
Gauchers disease : Occurrence and symptoms
Distended abdomen
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Company Procucts
BASF Vitamin B-2 Methoxy isopropyl amine (chiral intermediate)
Styrene oxide
Amino acids
Eastman Chemical / Genencor Ascorbic acid
Degussa
Acrylamide
Fatty acid derived esters
Polyglycerine ester
Organo modified silicones and oleochemicals
Celanese / Diversa
Acetic acid
Polyunsaturated fatty acids
Non-digestible starch
Polylactic acid (PLA)
Cargill Polylactic acid (PLA) (140,000 MT/yr)
DuPont / Genencor 1,3-Propanediol
Terephthalic acid
Adipic acid
Chevron / Maxygen Methanol
Typical examples of Bio-Products
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New paradigms in Biotechnology
Massive and high speed analysis system- Genome and proteom-wide approach : Systemic approach
- High amounts of relevant knowledge : genome sequences
Genomics (Gene chip)- Gene (mRNA) expression profiling in a high throughput manner
Proteomics (2-D gel, protein microarray)
- Functional genomics- Bio-molecular interactions (Interactom)
Development and commercialization of target products- Bioinformatics- Drug target identification via high throughput screening
- Global analysis : Genome or proteom wide analysis
- Integration of a high throughput system
- Advent of Bio-based Economy
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Bio-based economy: Impact on global economy
Shift from petroleum-based economy
- Exhaustion and soaring price of petroleum (> $ 100 /gallon)
- Environmental issueGlobal warming (CO2 emission)
Pollution
- Development of renewable source-based Bioprocess- Replacement of chemical process with Bio-based one
White Biotechnology
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Value chains from renewable sources
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Value Chain of White BT
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Alternative energy source
Production of biofuel (ethanol or butanol) from naturalresources
- Increase in the yield and alcohol tolerance
- Pathway of ethanol production in yeast- Source of starting substrate : starch or cellulose
- Elucidation of enzyme mechanisms
- Redesign of pathway way
- Design of enzymes in the pathway
- Process development : Fermentor and operation
- Separation and concentration
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Key role of enzymes in Bio-based economy
Energy and Environmental issues
- Depletion of petroleum source- Limitation to CO2 emission (Kyoto protocol)
Renewable source-based economy
Enzymes
Petrochemical-based economy
Chemical process Bio-based process
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Enzymes
Cleaning (Detergents)
Textiles
Starch Processing
Brewing
Leather Baking
Pulp and Paper
Food and Specialties
Animal feeds
Cosmetics
Most proficient catalysts with high specificity
Competitive and cost-effective processes
Chiral drugs
Chiral intermediates
Semi-synthetic antibiotics
Organic acids
Industrial use for specialty chemicals
Use for biosciencesDNA polymerase: Thermostability, fidelity
Restriction enzymes: Specificity
Alkaline phosphatase
Peroxidase
Therapeutics
Treatment of Gauchers disease
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Chemical company devoting to Biotechnology : BASF
Ecoflex
Emphasis on Bio-products mainly using Enzymes
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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,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 ofenzymes, genetic circuits, metabolic pathways, etc.) that can be modeled,understood, and tuned to meet specific performance criteria, and theassembly of these smaller parts and devices into larger integrated systemsthat solve specific problems
Design integrated circuits based on the known physical properties ofmaterials and then fabricate functioning circuits and entire processors (withrelatively high reliability)
Createand build newly engineered biological systems
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- Malaria infects 300-500 million people and causes 1-2 million deaths a year, primarily
children in Africa and Asia
- Theparasite that causes malaria has become at least partly resistant to every othertreatment tried so far.
- The faster-acting, more effective artemisinin-based drugs - as currently produced
from plant sources : scarce and too expensive for large-scale use
- Artemisinin : extracted from the leaves ofArtemisia annua, or sweet wormwood, and
has beenused for more than 2,000 years by the Chinese as a herbal
medicine called qinghaosu.
-Artemisinin works by disabling a calcium pump in the malaria parasite
Anti-malarial drug precursor artemisinic acid in engineered yeast
Enemy within:
haemoglobin in these red blood cellsis being digested by the parasitethat causes malaria.
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- Goal To produce inexpensive, effective, anti-malarial drugs
using synthetic biology approach
- US $ 43-million dollar grant to a UC Berkeley group from the Seattle-basedBill & Melinda Gares Foundation
- Redesign of yeast to synthesize artemisinin precursor, artemisinic acidby introducing three genes from Artemisia annua
- Production level by yeast culture: ~ 100 mg/L
- Report that the mutation of a single amino acid was sufficient to
confer resistance (Uhleman et al. Nature Struct. Mol. Biol. 12, 628
629; 2005).
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Ro et al., Nature (2009)
FPP: Farnesyl pyrophosphateADH : Amorphadiene synthase
Green arrows : the biochemical pathwayLeading from FPP to Artemisinic acid
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Biotechnology will have the greatest impact on humans
in the future in terms of health, life-style, and economy
- Therapeutic proteins : Treatment of diseases
- Bio-based economy : Environmental issue
- Diagnosis : in vitro and in vivo
Biotechnology constitutes a variety of diverse areas andtechnologies, requires interdisciplinary collaborations
Perspective