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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
http://shop.arrayit.com/index.asp?PageAction=VIEWCATS&Category=272


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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

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