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DSM White Biotechnology

Emerging Business AreaEmerging Business Area

White BiotechnologyWhite Biotechnology

Industrial BiotechnologyIndustrial Biotechnology --

Towards Next GenerationTowards Next Generation BiorefineriesBiorefineries

Marcel WubboltsMarcel Wubbolts

DSM White BiotechnologyDSM White Biotechnology b.vb.v..

Delft, The NetherlandsDelft, The Netherlands

ChemelotChemelotColloquium, October 23Colloquium, October 23

thth

,, GeleenGeleen

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EBA Biomedical MaterialsUrmond, NL

DSM Innovation Center, HQ inDSM Innovation Center, HQ in UrmondUrmond

Staff

P&T

Licensing

EBA Personalized Nutrition

Parsippany, US

(Delft, NL)

EBA Specialty Packaging

Urmond, NL

EBA White BiotechnologyDelft, NL

Corporate

Technology

Business

Incubator

Venturing

Chief Innovation Officer

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Location of DSM White BiotechnologyLocation of DSM White Biotechnology b.vb.v..

DSM White Biotechnology b.v., HQ in Delft (NL)Part of DSM Innovation Center b.v.

Urmond (NL)

White BiotechnologyBeijing (CHN)White Biotechnology

Freemont, CA (US)

White BiotechnologyGeneseo, IL (US)

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Recent Press MessageRecent Press Message -- 211008211008

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Location of DSM White BiotechnologyLocation of DSM White Biotechnology b.vb.v..

DSM White Biotechnology b.v., HQ in Delft (NL)Part of DSM Innovation Center b.v.

Urmond (NL)

White BiotechnologyBeijing (CHN)White Biotechnology

Freemont, CA (US)

White BiotechnologyGeneseo, IL (US)

White BiotechnologyBelvidere, NY (US)

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ColoursColours in Biotechnologyin Biotechnology

White Biotechnology - Industrial Biotechnology

Red Biotechnology - Healthcare Biotechnology

Green Biotechnology Plant biotechnology

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What aboutWhat about White BiotechnologyWhite Biotechnology??

Industrial or WhiteBiotechnology is an emerging field

within modern biotechnology that serves industry. It uses

living cells like moulds, yeasts or bacteria, as well as

enzymes to produce goods and services

source:

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Living Cells & EnzymesLiving Cells & Enzymes

Cell

(mini-factory)

Enzyme

(catalyst)

Enzyme(structure canbe designedand changedby laboratoryevolution)

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Industrial (White) BiotechnologyIndustrial (White) Biotechnology

BioBasedChemicals

BioFuels

BioProducts

BioMaterials

StartingMaterial

Process Products

starchstarch

biomassbiomass

otherother

(renewable)(renewable)

materialsmaterials

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Why is White Biotechnology so Important to DSM?Why is White Biotechnology so Important to DSM?

White Biotechnology, in contrastto Petrochemistry, makes use ofa renewable resource: sunlight

via agricultural feedstocks

The use of crops / crop residues

as feedstock is an alternative tocrude oil (volatile prices) andleads lower CO2 emissions.

White Biotechnology is a powerful source of innovation for new products

and processes and is a barrier to entry for competitors. DSM has strong capabilities in White Biotechnology via its Life Sciences

technology base.

DSM has leading competences in Chemistry and Materials Sciences thatbecome increasingly integrated with Life Sciences.

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Crude Oil Prices (October 2008)Crude Oil Prices (October 2008)

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Industrial Biotechnology PenetrationIndustrial Biotechnology Penetration

Source:Ceasar, Industrial Biotechnology, March 2008

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Industrial Biotechnology SegmentsIndustrial Biotechnology Segments

More than BiofuelsMore than Biofuels

Source:Ceasar, Industrial Biotechnology, March 2008

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Innovation is ourInnovation is our SportSportTMTM

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EvolutionLife Science Products

Coal

Fertilizers

Petrochemicals

Performance Materials

Bioterials / Biologics

Chemical engineeringPolymer technology

Fine chemicals

Material science

Mechanical engineering

Biotechnology

Technological competences1902 1930 19701950 1990 2000 2010

DSM: Ability to changeDSM: Ability to change100 years of successful transformations100 years of successful transformations

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EvolutionLife Science Products

Coal

Fertilizers

Petrochemicals

Performance Materials

Bioterials / Biologics

Chemical engineeringPolymer technology

Fine chemicals

Material science

Mechanical engineering

ModernBiotechnology

Technological competences1902 1930 19701950 1990 2000 2010

DSM: Ability to changeDSM: Ability to change100 years of successful transformations100 years of successful transformations

ClassicalBiotechnology

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DSM has a long history in BiotechnologyDSM has a long history in Biotechnology

ClassicalBiotechnology (>1870s) Yeast, Ethanol, Yeast extracts, Vitamins, Penicillin,

Butanol (ABE), Enzymes, Citric acid

ModernBiotechnology (>1980s) Recombinant enzymes (e.g. Chymosin, Phytase)

Metabolic engineering (e.g. Vitamin B2, Cephalexin)

Biocatalysis (e.g. pharmaceutical intermediates)

Cell culture (e.g. PerC6TM human cell line)

WhiteBiotechnology (>2005)

1. Enzymes & Yeast for next generation biorefineries

2. Renewable processes for chemicals, materialsand biofuels.

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20m

DSM Nutrition Biotechnology Process: Vitamin BDSM Nutrition Biotechnology Process: Vitamin B22Fermentation of aFermentation of a NaturalNaturalCompoundCompound

Sugar

Metabolic

Engineering

BacillusBacillussubtilissubtilis

Vitamin B2

1212 rawraw materialsmaterials replacedreplaced byby sugarsugar

7 solvents7 solvents replacedreplaced byby waterwater

wastewaste reductionreduction of over 75%of over 75%

costcost reductionreduction of over 20%of over 20%

environmentalenvironmental impactimpact 40%40% lowerlower

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DSMDSM PharmaPharma Biotechnology Process:Biotechnology Process: CephalexinCephalexin antibioticantibioticFermentation of aFermentation of a NonNon--NaturalNaturalCompoundCompound

13 chemical steps2 enzymatic steps

TraditionalFermentation

Sugar

MetabolicEngineering

Sugar

Old Route New Route PenicilliumPenicillium

chrysogenumchrysogenum1313 chemicalchemical stepssteps

replacedreplaced byby::

11 fermentationfermentation ++

22 enzymaticenzymatic stepssteps

65% less65% less energyenergy andand materialsmaterials50% lower50% lower costcost

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Vision for EBA White BiotechnologyVision for EBA White Biotechnology

DSM to build a leadership position in selectedWhite Biotechnology Fields by enhancing existinginternal capabilitiesthrough key externalpartnerships:

BioBased Chemicals and Advanced BioFuels inpartnership with upstream and downstreamplayers

Provider of Yeast and Enzymes for cellulosicethanol production

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White Biotechnology andWhite Biotechnology and

Tools for BiofuelsTools for Biofuels

Provider of Yeast and Enzymes forProvider of Yeast and Enzymes for

cellulosic ethanol productioncellulosic ethanol production

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BiomassBiomassOilOilCoalCoal

Non-renewable Renewable

RawRaw materialmaterial transitiontransition

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GHG Emissions (COGHG Emissions (CO22 eqeq.).)

Source: http://ngm.nationalgeographic.com/2007/10/biofuels/biofuels-interactive
http://ngm.nationalgeographic.com/2007/10/biofuels/biofuels-interactivehttp://ngm.nationalgeographic.com/2007/10/biofuels/biofuels-interactive

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Amount of CropAmount of Crop ResiduesResiduesAvailable: OriginAvailable: OriginCorrected for need to prevent erosion / fertilizer

Source: LMC Starch & Fermentation Analysis, June 2008

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Industrial Biotechnology Trend towards CellulosicsIndustrial Biotechnology Trend towards Cellulosics

Second generation biorefineries (based on waste biomass, 2nd

generation) for chemicals and fuels production are crucial to cope withcrude oil shortages andavoid (perceived) food competition.

Intelligent use of biomass is needed to address issues:

- Land use- Food versusFuel

- Water consumption

- Sustainability certification for Biomass

Innovations needed to make this happen

- Higher efficiency in agricultural productions (globally)

- Efficient use of biomass

- Innovations in cellulosics processing, hydrolysis and fermentation

- New (and existing) biobased products

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OilOil--RefineriesRefineries vsvsBioBio--RefineriesRefineriesStep Up in Efficiency RequiredStep Up in Efficiency Required

Oil-refinery: Crude oil (finite) as input

Established technology Very efficient use of raws

Bio-refinery (1st generation): Starch / Sugar (renewable) as input Technology established Efficient use of feedstock

Bio-refinery (2nd generation):

Biomass (renewable) as input Logistics? Technology very much in development (Enzymes &

Fermentation Organisms) What do we do with byproducts?

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StarchStarch C6 SugarC6 Sugar

Current (Current (11stst) and Future () and Future (22ndnd generationgeneration) Feedstock Use) Feedstock Use

Corn as an ExampleCorn as an Example

Other

BioSuccinic

BioEthanol

CornCorn

C6 YeastC6 Yeast

CornCorn

KernelsKernels

StarchStarch

EnzymesEnzymes

Pre-treatment

BiomassHydrolysateC5 sugarsC6 sugar

CelluloseEnzymes

C5 Yeast

C5 Yeast

Bacteria

Current (1st)

Future (2nd)

Residue

BioButanol

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Popular method: mild acid pretreatment (0,5 vol. % H2SO4, 180-190C)- Short residence time

- Cellulose intact, hemicellulose hydrolysis

- Some inhibitor formation (acetic acid, furfural, HMF)

- Waste production (CaSO4)

Pre-treatmentRoom for innovation

Source:Michael R. Ladisch, Nathan Mosier, Gary Welch, Bruce Dien, Andy Aden, Phil Shane, Purdue University

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Enzymatic hydrolysis (30 L)Enzymatic hydrolysis (30 L)

high solids required: operational challenges

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Cellulosic Material as FeedstockCellulosic Material as Feedstock

Innovations needed for 2Innovations needed for 2ndnd generation to happen!generation to happen!

It is not that easy at all and requires substantial innovations

CelluloseEnzymes

C5 Yeast

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DSM Enzymes for Wave 2 FeedstocksDSM Enzymes for Wave 2 FeedstocksLeveragingLeveraging DSMDSMss Enzyme TechnologyEnzyme Technology

DSM has large collection of hydrolases (cellulase,

hemicellulase, pectinase) and fermentation

processes developed for various business

segments

Several existing DSM in houseenzyme products

of value for cellulose processing

US DoE awarded R&D grant to DSM White

Biotechnology for further development ofenzymes for second generationfeedstocks

CelluloseEnzymes

A. nigersequence: Pel et al. (2007) Nature Biotechnology 25, 221

P. chrysogenumsequence: van den Berg et al. (2008) Nature Biotech. 26, 1161

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DSM White BiotechnologyDSM White Biotechnology

PressPress

Cellulose processing enzymes: DSM and Abengoa NewEnergy (DoE grant awarded tot DSM, 27 February 2008)

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HowHow toto developdevelop thethe rightright enzymesenzymes??

Key to success:

Diversity- Large libraries of (bio)catalysts required (in house/ partners)

- Access to genomes and meta-genomes (incl. bioinformatics)

- Directed evolution to optimize biocatalysts Screening power

- Automation and miniaturization

- High through-put screening

- Fast, reliable and generic analysis (NMR, LC-MS/MS)

Process optimization & scale-up- PluGbugTM

- High through-put experimentation (Table Top Biorefinery)

- Engineering & modeling

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GenericGeneric AnalysisAnalysis:: FlowFlow InjectionInjection NMRNMR

Joint development of DSM-Gist and Bruker: BEST-NMR BrukerEffcient Sample Transfer (based on Gilson XL215)

Now commercially available

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Screening & Strain Development

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Pretreatment Ethanol fermentation (AFM)

Table Top BiorefineryTable Top Biorefinery

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Corn Fiber PretreatmentCorn Fiber Pretreatment

Pretreatment & enzyme treatment result: strongly reduced viscosity

Original90% DM

Milled90% DM

Destarched25% DM

Cooked &Saccharified12.5% DM

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EschweilerEschweiler 10L10L FermentorsFermentors in Delftin Delft

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4m4m33 -- 100m100m33 FermentorsFermentors

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Proprietary DSM Enzymes applied inProprietary DSM Enzymes applied inLignocelluloseLignocellulose HydrolysisHydrolysis

Dilute acid pretreatedlignocellulosic feedstockconverted at 10% dry matter

DSM cellulases added andincubated for 16 hrs at 65 C,

pH 5.0 to reduce viscosity andproduce monomeric sugars forfermentation

DSM C6-Yeast inSimultaneous Saccharificationand Fermentation for 150 hrsat 33 C

Complete cellulose conversion in Simultaneous Saccharification andFermentation (SSF)

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((LignoLigno) Cellulosic Feedstock Composition) Cellulosic Feedstock Composition

Corn as an ExampleCorn as an Example

Cellulose 20-45% (C6)

Hemicellulose 20-55% (C5)

C6C6

C5C5

C6C6

C5C5

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Fermentation Organisms for 2Fermentation Organisms for 2ndnd Generation FeedstocksGeneration Feedstocks

Leveraging DSMs Bakers Yeast Technology Position

C5 Yeast

TraditionalEthanol Yeast Long history of safe industrial use Fermentation and strain development tools well developed Robust organism Used at low pH, which prevents infections (non-sterile) Facultative anaerobe (no aeration needed, lower CAPEX, energy input

low) First eukaryotic genome sequenced (1998) >40 mio tpa fuel ethanol applications for > 30 years Efficient fermentation of C6 sugars (1st generation)

However, traditionalYeast only uses C6 sugars and it does notefficiently produce BioEthanol on cellulose feedstock (C5 sugars)

DSM C5 Ethanol Yeast DSM is developing Yeast that consumes cellulose hydrolysates

(C5 Yeast), suited for 2nd generation biorefineries

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Example of Metabolic Engineering of Utilization ofExample of Metabolic Engineering of Utilization of

C5 Substrates inC5 Substrates in SaccharomycesSaccharomycescerevisiaecerevisiae

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BioBasedBioBasedChemicalsChemicals

BioSuccinicBioSuccinic AcidAcid

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Environmental Advantages ofEnvironmental Advantages of BiobasedBiobased ChemicalsChemicalsGreen House Gas (GHG) Emission Reductions ofGreen House Gas (GHG) Emission Reductions of BioBio--succinic Acidsuccinic Acid

Succinic acid from renewable feedstocks vspetrochemical feedstocks

Source: Patel et al. (2006). BREW Report; and Hermann, Blok and Patel (2007). Environ. Sci. Technol. 41, 7915-7921.

0

1

2

3

4

5

6

7

Petro

chem

ical

Corn

-starch

Suga

rcane

Today Today Today

GHGe

missions(t

CO2,eq

/tproduct)

-50% -65%

Today's technology (2005)

0

1

2

3

4

5

6

7

Petro

chem

ical

Corn

-starch

Suga

rcane

Corn

stove

r

(2nd

Gen

.)

Future Future Future Future

GHGe

missions(t

CO

2,eq

/tproduct)

-65% -80% 75%

Future technology (2030)

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DSM White BiotechnologyDSM White Biotechnology

PressPress

Biosuccinic acid: DSM and Roquette (18th January, 2008;BioHUB program)

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DSMDSM--RoquetteRoquette Partnership for BioPartnership for Bio--Succinic AcidSuccinic Acid

BiorenewableBiorenewable

PolymersPolymers (e.g.(e.g. PBSPBS))

RenewableFeedstock

Bio-SAFermentation

ExistingExisting largelarge--volumevolume

productsproducts likelike butanediolbutanediol ((BDOBDO))

BioBio--SASA derivativesderivatives (e.g.(e.g.

solvents,solvents, variousvarious esters)esters)

RQ-DSMAlliance

DSM & downstream partners

BioBio--Succinic Acid IntermediateSuccinic Acid Intermediate

forfor BioBasedBioBased MaterialsMaterials

RQ

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BioBasedBioBasedChemicalsChemicals

BioButanolBioButanol

BiobasedBiobased Chemical and aChemical and a

PotentialPotentialAdvanced BiofuelAdvanced Biofuel

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Global Butanol Demand:Global Butanol Demand:

Approximately 3000Approximately 3000 ktkt -- $4 billion market$4 billion market

Central and South.America only 80 kt

Sources: SRI/NEXANT & DSM analysis

China 695China 1115

USA 790

USA 940Asia 630

Asia 745Europe 600

Europe 720

ROW 345

ROW 420

0

5 00

1 0 0 0

1 5 0 0

2 0 0 0

2 5 0 0

3 0 0 0

3 5 0 0

4 0 0 0

4 5 0 0

2 0 07 2 01 5

Volum

e

(kt

)

3060

3940

CHN: largest growth

& planned capacityexpansions

+420

+115

+150

+120

+75

GROWTH

3%- 4% / yr.

Supply gap in Chinaand Europe despiteplanned expansions

+880 KT

Quality will be important for chemical market penetration

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MaterialsMaterials

BioBased Chemicals and Advanced BioFuels in partnership withupstream and downstream players

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A New Value Chain is EmergingA New Value Chain is Emerging

FeedstockProvision

FeedstockProcessing

PrimaryConversion

SecondaryConversion

BioCompounds& Formulation

Converters

Grain seed milling

Biomass pretreatment- enzymatic conversion

Farming

Storage

Distribution

Fermentation

Chemical conversion

Enzymatic conversion

Polymerization

Chemical Synthesis

Compounding

Formulation

Reactive Extrusion

Moulding

Film extrusion

DSM has multiple capabilities that extend across several stages in the value-chain that extend into multiple product and market combinations.

MaterialMaterialSciencesSciences

Life SciencesLife Sciences

Food & Feed Bio Medical

Personal Care

Coatings Automotive

ElectricalPharma

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ConclusionsConclusions

BioprocessBioprocess economicseconomics andand environmental advantagesenvironmental advantages such assuch asfossil energy savings and greenhouse gas reductions make thefossil energy savings and greenhouse gas reductions make theproduction of biobased chemicals, biofuels and materials usingproduction of biobased chemicals, biofuels and materials usingWhite Biotechnology desirableWhite Biotechnology desirable

Life Sciences and Materials Sciences are becomingLife Sciences and Materials Sciences are becoming increasinglyincreasingly

integratedintegrated, opening new opportunities for Industrial, opening new opportunities for IndustrialBiotechnology. At DSM most of the required competences areBiotechnology. At DSM most of the required competences are

availableavailable in housein house..

AdditionalAdditional development and innovations at multiple positions indevelopment and innovations at multiple positions in

the value chain, including lignocellulosic feedstockthe value chain, including lignocellulosic feedstock (2(2ndnd

generation)generation) processingprocessing, are needed to fully exploit the potential, are needed to fully exploit the potentialof Industrial Biotechnology in chemicals, biofuels and materialsof Industrial Biotechnology in chemicals, biofuels and materials

applicationsapplications

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