irgc - guidelines for the appropriate risk governance of ......international risk governance council...

Policy Brief

international risk governance council

Guidelines for the Appropriate Risk Governance of Synthetic Biology

international risk governance council Guidelines for the Appropriate Risk Governance of Synthetic Biology

P 2

ATC AirTrafficControl

BWC BiologicalWeaponsConvention

CCS CarbonCaptureandStorage

COP ConferenceoftheParties

CBD ConventiononBiologicalDiversity

DNA Deoxyribonucleicacid

ENMOD EnvironmentalModificationConvention

EPA USEnvironmentalProtectionAgency

EU EuropeanUnion

FAO UNFoodandAgricultureOrganization

FDA USFoodandDrugAdministration

GATT GeneralAgreementonTariffsandTrade

GM Geneticallymodified

GMO Geneticallymodifiedorganism

GURTs Geneticuse-restrictiontechnologies

IASB InternationalAssociationforSyntheticBiology

ICGEB InternationalCentreforGeneticEngineeringandBiotechnology

ICT Informationandcommunicationtechnologies

IP Intellectualproperty

IRGC InternationalRiskGovernanceCouncil

LMO Livingmodifiedorganism

NIH USNationalInstitutesofHealth

NGO Non-GovernmentalOrganisation

OECD OrganisationforEconomicCo-operationandDevelopment

RNA Ribonucleicacid

SRM SolarRadiationManagement

TRIPS Trade-RelatedAspectsofIntellectualPropertyRights

UN UnitedNations

US UnitedStatesofAmerica

USDA USDepartmentofAgriculture

WTO WorldTradeOrganization

©InternationalRiskGovernanceCouncil,2010.ReproductionoforiginalIRGCmaterialisauthorisedprovidedthatIRGCisacknowledgedasthesource.ISBN978-2-9700672-6-9

Abbreviations used in the text:

international risk governance councilGuidelines for the Appropriate Risk Governance of Synthetic Biology

P 3

Contents

PrefaceExecutive summaryIntroduction

1. What is synthetic biology?Box: Genetics and molecular biology

2. Current developments in synthetic biology2.1 Current and past activities

2.2 Some potential future applications

3. Risks of synthetic biology

4. Existing policy and regulatory frameworks, and their deficits4.1 Regulatory and governance contexts

4.2 Risk Governance Deficits

5. Risk governance in synthetic biology5.1 The concept of appropriate risk governance

5.2 Regulation and governance of first-generation synthetic biology

5.3 Policy and regulatory strategies in biosafety and biosecurity related to research,

innovation and technology development

5.4 Intellectual property (IP) issues and maintaining incentives for innovation

5.5 Risk regulation and barriers to innovation

5.6 Local, regional and international perspectives on regulatory oversight and risks

5.7 Technological risk management options

5.8 Policy and regulatory strategies related to public and stakeholder dialogue

6. Guidelines – Avoiding future risk governance deficits for synthetic biology6.1 Guidelines relevant to research and technology development

6.2 Guidelines relevant to public and stakeholder engagement

6.3 Systemic guidelines

ConclusionReferences and bibliographyAcknowledgementsAbout IRGC

4

5

7

9

11

14

14

18

21

24

24

26

29

29

29

30

33

34

35

36

37

40

40

41

42

43

44

50

51


P 4

TheInternationalRiskGovernanceCouncil(IRGC)aimstoimprovethegovernanceofemerging,systemicrisksthroughhelpingdecision-makers,particularlygovernments,toanticipateandunderstandsuch risksand theoptions formanaging thembeforethey become urgent policy priorities. IRGC’s risk governance recommendationsare communicated to policymakers to inform their work in designing policies andregulations,drawingtheirattentiontoaspectsoftheissuethatmightbeinappropriatelyneglectedorignored.

IRGC’scoreprocessinworkingonsyntheticbiologycomprisedthefollowing:Analysing the scientific and technological developments and their associated•opportunitiesandrisks,aswellastheinstitutionsandriskgovernancestructuresandprocessesthatarecurrentlyinplaceforassessingandmanagingthese;Identifyingpotentialissuesofconcernattheearliestpossibletime;•Identifyingandunderstandingriskgovernancedeficitswhichappeartohinderthe•efficacyoftheexistingriskgovernancestructuresandprocesses;Developingguidelinesthataddressthesedeficits.•

ThispolicybriefonsyntheticbiologyispartofIRGC’sworkontheriskgovernanceofinnovativetechnologies.PreviousIRGCprojectsonsuchtechnologiesincludeworkonnanotechnology,carboncaptureandstorage(CCS)andsolarradiationmanagement(SRM).IRGChasidentifiedsyntheticbiologyasanewtechnologyforwhichtheremaybesignificantdeficitsinriskgovernancestructuresandprocesses,inpartbecauseofuncertaintiesaboutthedirectionsthatthetechnologymighttake.

OfparticularconcerntoIRGCisthatimportantsocialandeconomicbenefitsofferedbyinnovativetechnologiesarenotcompromisedbyinadequateriskgovernance,whichcould result in unduly restrictive regulation. Synthetic biology has the potential toprovidepotentialsolutionstosomeofthechallengesthattheworldfacesinthefieldsofenvironmentalprotection(e.g.,detectingandremovingcontaminants),health(e.g.,diagnostics,vaccinesanddrugs)andenergyandindustry(e.g.,biofuels).Atthesametime, IRGC aims to ensure that risks are not underestimated by those developingthe field, and it recognises that some potentially severe risks might demand therecommendationofnewprecautionarymeasures.

InOctober2009, IRGCorganisedamulti-stakeholderworkshop inGenevaentitled‘RiskGovernance ofSyntheticBiology’, atwhichmany of the issues raised in thispolicybriefwerediscussed.Itwasattendedby24participantsfromtheUnitedStates(US),Canada,ChinaandmanyEuropeancountries,includingexpertsfromacademia,governments, non-governmental organisations (NGOs) and the private sector. AnIRGC concept note [IRGC, 2009b] was published as a briefing document for thisworkshop(availableonIRGC’swebsite,www.irgc.org.)

Thispolicybriefdoesnotintendtoproposeawideandexhaustivereviewofthefieldofsyntheticbiology,buttoreflectandelaborateonthediscussionsattheworkshopandsubsequent riskgovernancedevelopments in thefield.Moreover, IRGCrecognisesthatgovernments,industryandothersectorsarealreadyseekingwaystoresolvetheuncertaintiesassociatedwiththeriskgovernanceofsyntheticbiology.Theaimofthispolicybriefistoprovideguidancetodecision-makerstoachievethisgoal.

Preface


P 5

Executive summary

Synthetic biology is a new scientific discipline emerging from the convergence ofbiotechnology,geneticsandadvancesinthesystems-scalefundamentalunderstandingoflivingorganisms,alongwithaspectsofphysics,chemistryandcomputerscience.Itispredicatedonanengineeringapproachtobiology:anunderstandingofthemechanismsbywhichlivingcellsfunction,coupledtotheavailabilityoftoolsforinterveninginandalteringthesefunctionsat thegenetic level–orevenforrebuildingsomebiologicalentitiesandprocessesfromscratchusingchemicalmethods.Thisismakingitpossibleto‘design’lifeinmuchthesamewayaswemightdesignanautomobileoranelectroniccircuit.Insteadofrelyingonhaphazardtinkeringorsmall-scalegeneticmodificationtodirectlivingsystemstowardsnewobjectives,itmaybecomepossibletoradicallyalterwhatcellsandorganismscanachieveinarational,systematicway.

Thisdisciplineoffersgreatpromiseinareassuchashealthandmedicine,chemicalmanufacturingandenergygenerationandconversion.Butthereareattendantrisks,notjustintermsofthesafetyofengineeredor‘synthetic’organismsbutalsoinabroadersenseofhowsuchapowerfultechnologicalcapacitymighttransformtheenvironmentand society, affect economic development, and alter existing power relationshipsbetweenbasicscience,industry,consumers,governments,andnations.

This document develops the concept of appropriate risk governance: one that isenablingof innovation,minimisesrisktopeopleandtheenvironment,andbalances theinterestsandvaluesofallrelevantstakeholders.Itprovidessuggestionsforhowan appropriate trade-off between these factorsmight be attained, and argues thatregulationmustnotsimplyprohibitorrestrictanydevelopmentforwhichpotentialriskscanbeadducedbutshouldseektherightbalancebetweenpotentialsocialbenefitsanddangers–eventhoughthesemaybothbeuncertainandspeculativeatthisearlystageinthefield’sevolution.

Someofthenear-termresearchinandapplicationsofsyntheticbiologywillbealreadygovernedbyexistingregulatoryframeworks.However,thesearenotalwaysmutuallycompatible or consistent, and there are some areas of potential conflict betweendifferent aims and priorities. Moreover, such frameworks have shortcomings andloopholeswhenappliedtosomeofthepotentialoutcomesofsyntheticbiology–forexample, safety risks for geneticallymodified organismsmight not be best judgedfromthebehaviouroftheparentorganism,oncemodificationispursuedatthe‘deep’systemic level that synthetic biology should enable. The objective here is to seekways of addressing such risk governance deficits that allow a voice to all relevantstakeholdergroups.

Withthisinmind,thepolicybriefoffersaseriesofguidelinesforpolicymakersinvolvedin regulating or otherwise guiding or affecting the course of synthetic biology. Theguidelinesaddressfactorsrangingfrombiosecurityrisksinthefundamentalresearchand development stages, to the question of how to balance transparency againsttheneedforcommercialconfidentiality.Amongthekeyconsiderationsare thatnewregulations should not repeat themistakes of existing ones, that they should takecarenottoforeclosefutureadvancesthatcouldbeofsignificantsocialbenefit,and


P 6

thatthereshouldbeaninternationalefforttostandardiseproceduresandregulationswhilerecognisingthatparticularregionsandnationsmayhavespecificrequirementsorvulnerabilities.

Furthermore,aneffectiveapproachtoriskgovernanceofsyntheticbiologymustbecapableofevolvingasscientificandtechnicalknowledgeexpandsandaslessonsarelearnedaboutthemostappropriateformsofregulationandgovernance:forexample,ifandhowthetechnologycanregulateitself,andhowintellectual-propertyframeworksmightbeststimulateinnovationinasustainableway.Thisrequiresflexibilityinthefaceofuncertaintyabouttheeventualapplications,products,processes,benefitsandrisks,whilerecognisingthedangersofirreversibleharms.


P 7

Introduction

SyntheticbiologyisoneofarangeofdevelopmentsinscienceandtechnologythatIRGChasidentifiedasraisingchallengesforriskgovernance.Buildingondevelopmentsinthelifesciencesoverthepastseveraldecades,inessenceitinvolvestherepositioningofbiologyasanengineeringdiscipline, so that livingorganismsbecomeamenabletorationaldesignandsynthesis.Advancesinbiotechnologyandgeneticengineeringin thepast several decadeshavepresaged theemergenceof thisnewfield, but itnowpromisestotaketheirapproachtoanewlevelinourabilitytoplan,controlandmanipulatelivingsystems.

Synthetic biology represents just one illustration of how rapid advances in the lifesciencesareopeningupahostofpotentiallydramaticnewapplicationsinmedicineandhealthcare,agriculture,industrialchemistryandenergyproduction,amongotherfields. These developments also introduce possible new risks that are necessarilyspeculativeandhardtoassess.Yetthereisoftenpressurefordecision-makingaboutriskgovernanceandregulationtobeginmanyyearsbeforeactualproductsappearonthemarket.Errorsofjudgementattheseearlystagescanhaveamajorimpactonthetrajectoryofanewtechnology,aswellasontheeffectivenessandefficiencyofriskgovernanceitself[Tait,2007].

Such decisions, taken in a context of high uncertainty, also affect the investmentenvironmentforinnovativetechnology.Complexregulatorysystemsgiverisetolongleadtimesfornewproductsandthustotheneedforlong-terminvestmenttosupportdevelopment. But investors are reluctant to commit funding without knowing whatfutureregulatorysystemswilllooklike–andthuswhatthelikelycostsofcompliancewillbe.

These pressures on policy-makers to take early decisions about risk governance,basedonincompleteormerelyspeculativeinformationaboutthescaleoftheactualrisks,makeitdifficult toapplyconventionalriskgovernanceapproaches.Thereisaneedforflexibility,includingacapacitytomodifyearlydecisionsinthelightofemergingevidenceaboutrisksandopportunities.Suchanadaptiveapproachmust,however,alsoacknowledgetheneedto identifyandavoidpotential irreversibleharms,whichcannotbeamelioratedbylateradjustmentsinpolicy.

Theconceptofriskgovernancethatweadoptheretakesabroadviewofrisk.Itincludesbothwhathasbeentermed‘riskmanagement’or‘riskanalysis’,aswellasconsidering‘howrisk-relateddecision-makingunfoldswhenarangeofactorsisinvolved,requiringcoordinationandpossibly reconciliationbetweenaprofusionof roles,perspectives,goalsandactivities’ [IRGC,2005].Ourgoal is todevelopguidelines forappropriaterisk governance of innovative technology that integrate in-depth, independentunderstanding of three key areas and their interactions: (i) strategies for scientificresearchandinnovationstrategiesinthepublicandprivatesectors;(ii)regulationandgovernanceofnewtechnology;and(iii) the interestsandperspectivesof thepublicandotherstakeholders[Wield,2008].Ithaslongbeenunderstoodthatdecisionsonriskregulationaredeterminedbyinteractionsamongthesethreeconstituencies;here


P 8

weaimtoassesstheiroutcomesintermsofsocietalbenefitsdeliveredorforegone.Thetargetaudienceforthispolicybriefincludespolicymakers,politicians,companiesandresearcherswith interests inbiotechnology,energy,health,agriculture,climate,environment,tradeandsecurity.

Policy-makers and regulators can increasingly be seen as shaping, rather thanresponding to, innovative science and technology. They may influence the futuredevelopmentofthescience,guideproductdevelopmentincertaindirections,andeithergenerateordiminishconflictbetweenstakeholdergroups.Theguidelinesproposedherefocusonwhatpolicy-makersandregulatorscanachieveinthiscontext.Whilewecannotpredicthowthefieldwillevolve,someregulatoryrethinkingmaybeneededifsyntheticbiologyistogrowintoamature,safeandacceptedsetoftechnologies,withinnovativeandsociallyvaluableproductsbroughttomarket[Rodemeyer,2009].

Section 1 of this policy brief outlines the scope andmeaning of synthetic biology,and Section 2 describes current developments and potential applications. Section3 considers the associated risks, and Section 4 outlines the existing regulatoryframeworks for handling these and identifies potential risk governance deficits. InSection5weconsider the issueofappropriateriskgovernanceofsyntheticbiologyand suggest approaches or guidelines for risk assessment and management thatcouldenablethepotentialbenefitsofsyntheticbiologytobedeliveredwhileavoidingor minimising associated risks and ensuring proper accountability. Section 6 thenproposesasetofguidelinestosupportpolicydecision-making.Twopreviousconceptnotes[IRGC,2008;2009b],andalsoanIRGCworkshopinvolvingdiverseexpertsinsyntheticbiology,haveprovidedbackgroundmaterial.


P 9

1. What is synthetic biology?

Syntheticbiologyappliestheprinciplesofengineeringtolivingorganisms,regardingthemassystemsthatareamenabletodesignandfabricationforpredictableandcloselyspecifiedfunctions.Bytailoringthe‘parts’ofanorganism–thegeneticinstructions,themoleculesandmolecularassemblies,and the interactionsbetweendifferentgenes,moleculesandcells–itaimstocreateorganismsthatfunctionandbehaveinwaysquitedifferentfromthenaturalspeciesonwhichtheyarebased.

Throughout the twentieth century, cell biologists have steadily characterised themolecularcomponentsof life in increasingdetail. It isapparent that lifearises fromtheinteractionsoftheseparts:genesencodedinDNA,proteinsencodedingenes,aswellascellularcompartments,ionsandothersubstancesinthecellfluid(cytoplasm),smallRNAmoleculesalsoencodedinthegenome,andothercomponents.Howthoseinteractionsareorchestratedremainsoneofthebigquestionsofmolecularbiology,inparticularhowinformationandorganisationaretransmittedthroughoutahierarchyofsizescalesfromindividualmoleculestothewholeorganism.

At the same time, biologists have sought to intervene in and to modify theseinteractions, changinganorganism’s functionandphysiology– to influencehumanhealth,forexample,ortoalterthepropertiesofagriculturalcrops,ortoconferusefultechnologicalbehavioursonmicro-organisms.Theseeffortshaveresultedinaviewoflife’smechanismsthatowesastrongdebttoengineering.Theuseoftermssuchasbioengineeringandgeneticengineeringtestifiestothewaytheengineeringparadigm,whichinvokesprinciplesofdesignandcontrol,hasalreadyimposeditselfonthelifesciences.Nonetheless,onthewholeour interventions inbiologyhavetendedtobedirectedtowardseithercrude‘sabotage’oftheprocessesoflife–preventingmicro-organismsorcancercellsfromproliferating,say–orminor,adhocmodificationsofexistingbehavioursinwhichmuchofthe‘mechanics’remainsa‘blackbox’.

Syntheticbiologynowaimstousetheengineeringparadigmformuchmoredramaticandsystematicinterventioninbiology:toapplyingbasicdesignprinciplesinordertoproducepredictableandrobustbiologicalsystemswithnovelfunctionsandpropertiesthat do not exist in nature. It has been described as ‘the engineer’s approach tobiology’[Breithaupt,2006]andsomesyntheticbiologistsclaimthattheiraspirationistomakebiologyintoanengineeringdiscipline[Endy,2005;ArkinandFletcher,2006],somethingthatrequiresareductionistunderstandingofbiologicalcomplexity[Pleiss,2006].Thisengineeringapproachtobiology,combinedwithsyntheticbiology’sheavyreliance on information technologies, makes the field intrinsically interdisciplinary.Althoughsomeresearchersapproachsyntheticbiologyasa‘discoveryscience’–atoolforinvestigatinghownatureworks–itisultimatelylikelytobecomeamanufacturingtechnology,offeringnewsyntheticroutestosuchthingsasmedicines,newmaterialsandfuels,environmentalorphysiologicalsensors,andmicro-organismsthatcleanuppollutants.

Severalofthefundamentalscientificissuesandcurrentappliedobjectivesofsyntheticbiologyoverlapwiththoseinother,morematurefields,especiallybiotechnology and

Synthetic biology aims to apply basic design principles in order to produce predictable and robust biological systems with novel functions and properties that do not exist in nature

It is ultimately likely to become a manufacturing technology, offering new synthetic routes to such things as medicines, new materials and fuels

Atypicalanimalcellwithitsspecialisedcompartments


P 10

systems biology.Traditionally, biotechnology involves themanipulationof biologicalmolecules, cells or whole organisms to address technological challenges. But thedegreeofmodificationinvolvedhastendedtobesmallandoftenbasedonastronglyempiricalapproachthatdoesnotredesignanorganismorcomponentatadeeplevel.Forexample,therearenowwelldevelopedwaystointroducegenesfromonespeciesintothegenomesofanotherandtostimulatetheexpressionofthoseforeigngenestoproduceanexcessoftheproteinproduct.Butwhenanaturallysynthesisedcompoundinvolvesthecoordinatedactionofmanygenes,thesetechniquesstruggletoachievetherequiredcoordinationintimeandspace,inpartbecausetheinteractionsofgenesarepoorlyunderstood.Thislimitsthescopeofwhatbiotechnologycando.

Itishopedthatmuchoftheunderstandingneededformoredramaticinterventionsandredesignofbiologicalsystemswillcomefromthedisciplineofsystemsbiology[Ideker,2004;Kitano,2002].Thisinvolvesthemappingofpathwaysandnetworksofinteractionbetweengenes,proteinsandotherbiomolecularcomponents,soastoascertainthe‘logiccircuitry’ofnaturalorganismsatthelevelofcellsandsub-cellularcompartments,tissuesandthewholeorganism.Whilecellandmolecularbiologyandgeneticshavebeenlargelyconcernedsofarwithstudyingindividualcomponentsandsmallgroupsoftheminisolation,systemsbiologyaimstodiscoverhowtheyallfittogetherinarobust,functionalsystem.Assuch,itshouldprovidetheanalyticalframeworkinwhichsyntheticbiologywilloperate.Simulationtoolsandmodelsdevelopedinsystemsbiologywillbeusedinsyntheticbiologytodesignandengineernovelcircuitsorcomponents[Barrettetal.,2006].Inthisrespect,syntheticbiologywillinvolveusingsystemsbiologynotfor‘pureunderstanding’ofnaturalsystemsbutforpracticaldesignofsemi-synthetic,andultimatelyperhapswhollysynthetic,ones.

It is important toemphasise that, as is common for anemerging technology, thereis no consensus aboutwhere the boundaries of synthetic biology lie orwhat formitmightmostproductively take. Itmay (andatpresent,generallydoes) involve theuseandmodificationofexistingorganisms;butthede novodesignandsynthesisoforganisms isalsoagoalofsome researchers. It iswidelybelieved that thedesignelementshouldinvolvetheuseofstandardisedpartsandfollowaformaliseddesignprocess [ArkinandFletcher, 2006] that takes it beyond the capabilitiesof previousformsofgeneticengineering.Greatersophisticationandcomplexitymighttherebybeachieved,offeringtheabilitytomovefrominsertingonegeneatatimeintoanexistingbiologicalsystemtotheconstructionandinsertionofwholespecialisedmetabolicunits[Stone,2006].Syntheticbiology isnot restricted tousinggeneticorotherbiologicalmaterialfromexistingorganisms[POST,2008],andinvolves‘tinkeringwiththewholesysteminsteadofindividualcomponents’[Breithaupt,2006:22].

Despitethediversityandfluiddefinitionsofsyntheticbiology,fourinter-relatedresearchareascanbeidentifiedthatcurrentlycontributeitsmajorthemes:

Electronicdevicesaredesignedtoperforminawell-definedwaywheninserted1.intoanycircuit.Itiswidelythoughtthatthe‘genecircuitcomponents’ofsynthetic

Synthetic biology involves ‘tinkering

with the whole system instead

of individual components’

There is no consensus

about where the boundaries of

synthetic biology lie or what form

it might most productively take


P 11

biology,whichmightforexampleturnothergenesonandofforotherwisemodulatetheiractivity,willhavetobesimilarlystandardisedandreliable,sothattheycanbesimplypluggedintocircuitsandperformpredictably.Theengineeringprinciplesofstandardisation,decouplingandabstraction [Endy,2005]maybeadopted todevelop biological components that are interchangeable, functionally discreteandcapableofbeingeasilyandreliablycombinedinamodularfashiontoenablepredictableperformanceinawidevarietyoforganisms.

Genome-drivencellengineeringfocussesonthedesignandsynthesisofwhole2.genomes – something that has beenmade possible by advances in chemicaltechnology that will rapidly synthesise long stretches of DNA with a specifiedsequence (the linear order of thebasic chemical units,which encodesgeneticinformation). DNA synthesis is now a commercial technology and offers DNAsequences approaching the length of entire bacterial genomes. To use theseconstructs forsyntheticbiology involveseither ‘editing’ thegenomicsequencesofexistinggenomestomakeamorestreamlinedandefficientgenetic‘chassis’,whichcouldprovideaplatformformakingorganismswithnewgenomes[Gibsonetal.,2010],or (moreambitiously) thewhollydenovodesignandsynthesisofgenomes.

Thechemicalcreationof‘protocells’withlifelikefunctionssuchasreplicationand3.metabolism,forexamplebyinsertingnaturalormodifiedbiomolecularcomponentsintoartificial,hollow,cell-likesacscalledvesicles[Szostaketal.,2001].

Morerevolutionaryresearchapproachesincludeattemptstocreateanalternative4.genetic alphabet with new nucleotides beyond the four found in natural DNA.This could lead to pseudo-biomolecules or even synthetic proto-organismsthat are ‘invisible’ to natural biological systems, aswell as suggestingwaysofcommandeeringnaturalcellularmachinerytomakesubstanceswithachemicalbasisdifferentfromthosefoundinnature.

Someoftheseareasareexplainedinmoredetailinthenextsection.

Box: Genetics and molecular biology

InthetraditionalpictureofgeneticsdevelopedsincethediscoveryofDNA’schemical structure in 1953, the double-helical molecule of DNA encodesin its sequence of chemical building blocks (called nucleotide bases) theinformationneededtoconstructaproteinmoleculefromaminoacids.Mostoftheseproteinsareenzymesthatenablebiochemicalprocessesinthecelltotakeplace.Eachproteinisencodedbyaseparategene,andthenucleotidesequenceofageneonDNAistranslated(‘expressed’)bycellularmolecularmachineryintoasequenceofaminoacidsthatdeterminesthecorrespondingprotein’sshapeandfunction(Figure1).ThusDNAwasseenasarepositoryofencodedproteinstructures.

DNAdoublehelix


P 12

While this basic picture still holds, itis now complicated in many ways.Most importantly, the interaction ofgenesandproteins is two-way:someproteinswill attach themselves (bind)to DNA to regulate the way othergenesareexpressed (turningagene‘on’or‘off’,say),sothatineffectgenescaninfluenceothergenes.Thiscross-talk between genes means that theyare linked into a complex network ofinteractions,leadingsomeresearcherstodescribegeneticsusingmetaphorssuch as a ‘society’ of genes, ratherthan the traditionalpictureofa ‘book’ofinformation(Figure2).Tracing

these interaction networks – in effect, deducing the ‘wiring diagram’ of thecell’sgeneticcircuitry(Figure3)– isakeyaimofsystemsbiology,andthisinformationisessentialifwearetodesignnew‘genenetworks’withspecificfunctions,whichcanbeinsertedintogenomesusingthecuttingandsplicingtoolsofbiotechnology.

Figure 1:Thetraditionalpictureofgenetics:howgeneticinformationofDNAisconverted,viaRNA,intoproteinstructureswithawell-defined

shapeandfunction.

Figure 2:PartofthenetworkofgenesrelatedtothefunctionofaproteincalledDISC1,whichplaysavarietyofrolesinthefunctioningofcells.Mostgenesandtheircorrespondingproteinsareembeddedinnetworksofinteractionlikethis

one.[Copyright:©2009Hennah,Porteous;originalsource:http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0004906]


P 13

Figure 3:ThegenenetworkthatregulatesthebehaviourofTcells,involvedintheimmuneresponse.Thefeedbacksandinteractionsareanalogoustothoseincomputerlogiccircuits[FromGeorgescuetal.,2008;Copyright(2008)National

AcademyofSciences,USA]


P 14

Parallelshavebeendrawnbetween today’ssyntheticbiologyand theearlydaysofthecomputerindustry.Ontheonehand,thisimpliesthatthetechnologicalrevolutionbroughtbysyntheticbiologywillbeasimportantastherevolutionininformationandcommunication technologies (ICT) brought about by electrical engineering [NEST,2005; NEST, 2007; Royal Society, 2008]. On the other hand, it suggests that thepreciseformandcontentofthatrevolutionisashardtopredictatthismomentasitwasforICTinthe1970s.

Becauseofthefundamentalchangethatitproposestointroduceinthemethodologyfor modifying living organisms, synthetic biologymay be able to fulfil many of thepromises that traditional biotechnology is still struggling to fulfil, in such importantareasasbiomedicine, thesynthesisofpharmaceuticals, thesustainableproductionof chemicals and energy, and safeguarding against bioterrorism. While traditionalbiotechnologyhashadsomenotableachievements in severalof theseareas, theyhavegenerally been slowandexpensive todevelop. In contrast, synthetic biology,with its rational, knowledge-based approach to biological design,might attain suchgoalsmorequicklyandcheaply.Itwillalsoenabledevelopmentsthatarenotobviouslyfeasiblewithconventionalbiotechnologicaltools,suchasthecoordinationofcomplexsequences of enzymatic processes in the cell-based synthesis of useful organiccompounds.Thus,while ‘first-generation’syntheticbiology is likely tosimplyenablestraightforwardextensionsofwhat today’sbiotechnologycanachieve,ultimately itsgoalsanditscapabilitieswillnotbemereextrapolationsofthissortbutmaydifferinqualitativeways, probably bringing about applications thatwe cannot yet envisage[IRGC,2008].Examplesofsomeofthecurrentachievementsandprojectedaimsaredetailedbelow[seealsoNEST,2005].

2.1 Current and past activities

2.1.1 Synthetic gene circuitsMostofthekeyearlyworkinsyntheticbiologyinvolveddevisingsimplesynthetic‘genecircuits’andusingthetechniquesofbiotechnologytoinsertthemintobacterialgenomesand look for the corresponding changes in the behaviour of the cells [Elowitz andLeibler,2000;Gardneretal.,2000;Weiss,2004].Manyofthesecircuitswereinspiredbythoseusedinelectronicengineeringforthe‘logic’operationsofcomputation:forexample,switchestoturnothergenesonoroff,oroscillatorsthatinduceregularburstsoftheproductionofcertainproteins.Inoneinstance,oscillationsinthesynthesisofafluorescentproteinproducedbybacterialcellscausethemtoflashwithasteadypulsewhenilluminatedwithultravioletlight[ElowitzandLeibler,2000].

Aswellasdemonstratinga‘proofofprinciple’–thefeasibilityofdesigninggenecircuitsthatcancontrolcellbiochemistryinpre-determinedways–theseeffortsmighthavegenuine technological and biological applications. They might enable genes to beactivatedandreactivatedatwill,orinresponsetooutsidesignals.Theycanbeusedtotesttheoriesofhow‘informationprocessing’worksinnaturalcells–forexample,

Parallels have been drawn between

today’s synthetic biology and the early days of the computer

industry

Synthetic biology may be able to

fulfil many of the promises

that traditional biotechnology is still

struggling to fulfil

Greenfluorescentproteinexpressedinthecellsofaleaf

[FromSantaCruzetal.,1996);Copyright(1996)NationalAcademy

ofSciences,USA

2. Current developments in synthetic biology


P 15

howthedetectionofparticularchemicalsignalsatthecellsurfacetriggersachangeincellbehaviour.Logic-processingoperationsincellsmightalsobeusedtodevelopnewkindsofbiologicalsensorsthatsignalthepresenceofpollutantsorbiomoleculesintheenvironmentorthebody,andtoenablebacteriatocommunicatewithoneanotherinnewways[Butleretal.,2004].Theengineeringoflogicgatesinmammaliancellsmightsignificantlyextendtherealmofsyntheticbiologytomedicalapplications.

To develop these capabilities in a systematic way analogous to the evolution ofmicroelectronic circuitry, it seems fruitful to learn the lessons of the electronicsindustry: tocreatestandardisedcomponents(suchasswitchesandoscillators) thatcanbereliablypluggedintoanycircuit,forexample,andtoestablishalibraryofwell-characterisedgenedevices.Somestandardisedbiologicalparts,devicesandsystems(sometimescalledBioBricks)arebeingmadefreelyavailableonlineinanopenaccesslibrary called the Registry of Standard Biological Parts. BioBricks can be used forcreatinggeneticcircuits, forexamplebyusing logicgatesandoscillators, revealingdirectanalogieswithelectronicengineering[Lowrie,2010].

Oneexampleofthewaysuchresearchmightbeappliedisanattempttodevelopaplantwhose leafshapeorflowercolourchangeswhena landmine isburiedbelowit,bygeneticallyalteringtheplantrootstodetectexplosivestracesinthesoilandtocommunicatethatinformationtotheleavesorflowers[Antunesetal.,2006].

2.1.2 Creation of synthetic organismsTheannouncementofa‘syntheticorganism’in2010byCraigVenterandhisco-workers[Gibsonet al., 2010] highlighted, amongother things, howambiguous this term is.Venterandcolleaguesdidnotbyanymeansbuildabacterialcellfromscratch;rather,theyreplacedthegenomeofanexistingcell(aparticularlysimpleformofbacteriaofthegenusMycoplasma,whichhasanunusually small genome)withonedesignedandmadebychemicalmethods.Thisnewgenomewasbasedon thenaturalone,butwithsomeadditionsanddeletions.Thus theMycoplasmacellswereessentially‘reprogrammed’withanewsetofgenetic instructions,whichhad themselvesbeendesignedandmadeinthelaboratory.

Thiswasanaturalandanticipateddevelopment inexplorationsof theconceptofa‘minimal genome’,whichVenter’s group and others had been pursuing for severalyears[Glassetal.,2006;Glassetal.,2007;Lartigueetal.,2007;Gibsonetal.,2008].The idea is that a genome stripped down to the bare minimum of genes neededto ensure the organism’s survival could act as a ‘chassis’ onwhich new genomescouldbedesignedandbuilttoconfernewfunctions–biosynthesisofanewfuelfromnaturalsources,say–ontheorganism.Theverynotionofaminimalgenomeisitselfambiguous–whatgenesacellneedsmaydependonwhatenvironmentalchallengesitwillface–buttheunderlyingconceptthatbacterialgenomescanbesimplifiedandtailorednowseemstobevindicated.However,itremainstobeseenwhetherwecanunderstandthe‘genecircuitry’ofeventhesesimplebacterialgenomeswellenoughtoenablewide-rangingandsystematicdesignofnewones.

The underlying concept that bacterial genomes can be simplified and tailored now seems to be vindicated

New kinds of biological sensors that signal the presence of pollutants or biomolecules in theenvironment or the body


P 16

2.1.3 Biological computationThewayinwhichgeneticinformationisencodedandreadoutincellsisakindofdigitalcomputation.Thishasledtosuggestionsthatsuch‘logic’mightbeusedbothtocontrolandmodifybiological processes in cells, formedicine say [Benensonet al., 2004],and to use biological systems for purely technological information processing, forexampleinsensortechnologies.Onegroupisexploringcomplexlogicsystemsbasedonribozymes(catalytic formsofRNA)thatwillenableexternalmolecularsignals toactivatedrugs[StojanovicandStefanovic,2003].OthershaveshownthatartificialDNAmoleculescanbedesignedtoperformlogicoperations,computationsandcontrollablebehaviouringeneral[LaBeanetal.,1999;Seeman,2003;Rothemund,2006].Syntheticbiologymightpermitsuchsystems,whichhavebeenmadeandinvestigatedinvitro,tobeincorporatedinlivingcells.

2.1.4 Building artificial cells or compartments from scratchIncontrasttothe‘top-down’re-engineeringofnaturalorganismsexemplifiedbytheworkofCraigVenter’sgroup,someresearchersarepursuingthegoalofmakingcell-likeentitiesfromscratch,puttingthemtogetherfromeithernaturalorsyntheticmolecularcomponents [Szostak et al, 2001; see http://www.protocell.org]. This ‘bottom-up’constructionofartificial‘protocells’couldofferatestinggroundforideasabouthowlifebeganonEarth,forexamplebyelucidatingtheminimalrequirementsoflife-likesystemsthatcangrow,divideandevolve.Such ‘cells’mayalsohavepracticalapplications,forexampleactingas‘factories’forthesynthesisofbiologicalmolecules–muchasgeneticallyengineeredmicro-organismscan,exceptthatsuchartificialsystemswouldbemuchsimplerandthereforeeasiertodesign,control,adaptandsustain.Asysteminwhichmicroscopiccompartments(vesicles)thatassemblethemselvesfromthelipidmoleculesthatconstitutecellmembranesencapsulatepared-downgeneticmachinery(DNAandRNA)hasbeenshown togenerateproteinswhenprovidedwith the rawingredients[NoireauxandLibchaber,2004].

Onekeyaimistodevelopsynthetic‘protocells’thatcanreplicateandpassongeneticinformation,probablyusingmodifiedformsofthegeneticmachineryofnaturalcells.Very simple forms of self-replication have already been reported, for example invesicleslikethosementionedabovebutmadefromself-assemblingmoleculeswhoseformationiscatalysedbythevesiclesthemselves[Luisi,2006;Luisietal.,2006].

2.1.5 Materials and nanotechnologyOneprominent theme in nanotechnology involves themimicry of naturalmolecularsystems that have evolved effective solutions to ‘engineering’ problems of a sortencountered in technology, such as storing information, harvesting light ormakingmaterialswith atomic-scale precision. But it sometimes turns out that such naturalsystems can themselves be commandeered for that purpose, often with chemicalmodificationsthatmightbeimplementedatthelevelofthegenesthatencodethem.Inthisrespect,syntheticbiologypotentiallyhasmuchtooffermolecularnanotechnology[Ball,2005].

Some researchers are pursuing the

goal of making cell-like entities from

scratch

This ‘bottom-up’construction could

offer a testing ground for ideas

about how life began on Earth


P 17

Forexample,protein-likemoleculeshavebeengeneratedusing‘directedevolution’ofbiosyntheticpathwaysthatwillrecogniseandbindtoarangeofinorganicmaterials(forexample,semiconductors)andthatcanactastemplatesand‘adhesives’forassemblingfunctionalinorganicparticlesandthinfilms,providingapotentialinterfacebetweenthebiologicalandinorganicworlds[Whaleyetal.,2000;Sarikayaetal.,2003].Molecularrotarymotorproteinshavebeenusedtorotatemicroscopicmetalblades[Soongetal.,2000],andtheproteinsresponsiblefortransportingsmallpacketsandobjectsaroundincellshavebeenharnessedfor thecontrolled transportofartificialsmallparticles,offering‘molecularshuttles’thatmightbeusedtocreatecomplexmaterials,repairtinydefectsonsurfacesor in livingcells,and tostoreandretrieve information [Hessetal.,2001].Chemicallymodifiedviruseshavebeenusedastemplatesforcrystallisingmetallic and magnetic nanowires [Mao et al., 2003]. All these uses of biological‘molecularparts’mightgaininpowerandversatilityfromtheuseofsyntheticbiologytoassisttheirsynthesisincellsandtheirorganisation.

2.1.6 Developing genomes from using non-natural nucleotides, proteins from non-natural amino acidsAlthoughproteinsandnucleicacidsareastonishinglydiverseintheirstructuresandfunctions,theyincorporateonlyaverylimitedrangeofbasicbuildingblocks:20(aminoacids) for proteins, four (nucleotides) forDNA. It is possible that their repertoire offunctionsmightbewidenedbyincludingmorediversebuildingblocks–forexample,makingproteinsmorewater-repellentortemperature-resistant,ormakingDNAmoreelectricallyconducting.ExpandingthegeneticcodeofDNAcouldalsoallownewtypesofinformationtobeencoded.Severalgroupshavemanagedtoincorporatenon-naturalaminoacidsintoproteins[Wangetal.,2001;Chinetal.,2003,MontclareandTirrell,2006]andnon-naturalnucleotides intoDNAandRNA [Kool,2002].Onegrouphasmodifiedbothbacterialandyeastcellstogeneticallyencodenon-naturalaminoacidssothat theymaybe inserted intoproteinsatspecified locations[Wangetal.,2001;Chinetal.,2003].Insomecases,thecellsareabletomakethenewaminoacidsfromsimplerawingredientsintheenvironment.

Partofthemotivationforsuchworkisfundamental:toexplorethelimitsofbiologicalinformation transferor the ‘structurespace’ofproteinmolecules.But thesestudieshaveimportantpotentialapplicationstoo:forexample,drugsthatinteractwithnaturalproteinsandnucleicacidsinnewways,orprotein-basedmaterialswithnewstructuresand properties. For example, one aim of some artificial genetic coding schemesthatusenon-naturalnucleotides [Kool,2002] is tousechemicallymodifiedDNA todetect thesmall geneticmutations that causecanceranddrug resistance.Artificialgenes incorporated intomicrobes can encode non-natural proteinswith interestingmaterialproperties(forexample,onesthatformliquidcrystalsandmaterialsfortissueengineering),includingsomewithnon-naturalaminoacids[Tirrelletal.,1991].

2.1.7 In-cell synthesis of chemicals and materialsThereisawell-establishedfieldcalled‘metabolicengineering’,whichaimstogenetically

Anaminoacid


P 18

engineer themetabolicprocessesof simpleorganismsso that theyproduceusefulchemicalsonan industrial scale–somevitaminsandfinechemicals, forexample,aremadethisway.However, thishasoftenreliedon ‘tinkering’ rather thanrational,design-basedstrategies,frequentlyleadingtoonlyminorchangestothecells’syntheticcapabilities.

Syntheticbiologycouldgivethisapproachthemorerationalflavouroftrueengineering.Theabilitytoharness,combine,modifyandadaptthegeneticallyencodedroutesbywhichcellsmakecomplexorganicmoleculeswill openupnewandefficient routesto natural and non-natural compounds with medicinal and industrial value. Thesemodulesmightbeengineeredintobacteriatogreatlyexpandthepowerofthekindsof fermentationprocessescurrentlyusedwithgeneticallymodifiedbacteriatomakepharmaceuticals.SomesuccesswiththisapproachhasalreadybeendemonstratedwiththeengineeringofE.colibacteriatoproducetheantimalarialartemisinin,anaturalproductfoundinverysmallquantitiesinaspeciesofplant[Martinetal.,2003;WithersandKeasling,2007].Becauseofthemulti-stagenatureofthesynthesisofartemisinininplants,thisre-engineeringofbacteriaisbeyondthereachofconventionalgeneticmodification,requiringacomplicatedredesignofthebacterialgenome.

2.2 Some potential future applicationsThe developments described above open up some new, often rather speculative,possibilitiesforsyntheticbiology.Someareasfollows.

2.2.1 BiomedicineA smart drug would be one that contains an autonomous diagnostic capability; itcoulddirectlysensemoleculardiseaseindicators,whichmayinitiatedrugactivationorrelease. Ideally,asmartdrugwouldbedeliveredtoapatient likearegulardrug,but would only become active in cells affected by a disease. The techniques andphilosophyofsyntheticbiologyhavealreadybeenusedtodevelopprototypesofsuchdrugsbasedonakindofcomputationperformedbysyntheticstrandsofDNA.

Synthetic biology could help in the design of biocompatible devices, e.g., smallassembliesofmoleculesthatwillsensechangesinparticularbiochemicalsignalssuchashormonesandwillproceedtosecreteachemicalorbiologicalcompoundinresponse[Benensonetal.,2004].Thiskindofdevicecouldbeusedtosensedamagetobodytissuessuchasbloodvesselsorbone,and to repair them.Syntheticbiologycouldprovidewaystogeneratethesedevicesthemselvesin situwithincellsinresponsetophysiologicalsignalsofdamageordistress.

Modifiedvirusesarecurrentlybeingexploredas transportagents forgene therapy,which can penetrate cells and deliver ‘healthy’ genes to the target tissue in awaythatpromotes their integrationwith thecell’sgenome.Syntheticbiologymightoffergreatflexibilityforthedesignandmodificationofsuch‘virusvectors’.Theymight,forexample,betailoredtorecognisespecificcellsandtarget themfordrugdeliveryordestruction.

Synthetic biology could open up new

and efficient routes to natural and non-natural compounds with medicinal and

industrial value

A smart drug would be delivered

to a patient like a regular drug,

but would only become active in

cells affected by a disease

Artemisiaannua


P 19

Onevisionofpersonalisedmedicineistodevelopdrugsthatareadaptedintheirmodeof action, formulation, dosage, and release rates to the individual requirements ofthepatient.Butthisisfeasibleonlyifsuchmedicineswithsubtledifferencescanbemanufacturedreliablyatasmallscale.Syntheticbiologymightbeusedtodevisecellsthatwillmanufacturesuchdrugsaccordingtoprecisegeneticspecifications.

It ispossiblethatwewillbeabletomodifyhumancells togivethemnewfunctionsnotpresentinourbody.Onemightimagine,forexample,cellsinvolvedintheimmuneresponse being programmedby design to recognise and attack specific viruses orbacteria. Not only would this address the growing problem of antibiotic-resistantpathogenic bacteria but it could also reduce the chance of resistance spreadingrapidly.

2.2.2 Applications of non-natural biopolymersThereiscurrentlygreatinterestindevelopingdrugsfromnucleicacids,suchassmallRNAmoleculesthatinterferewiththeexpressionofgenes.Modifiednucleicacidswithanon-naturalchemicalcompositionmightbegivenadvantageouscharacteristicsfromapharmaceuticalperspective,forexamplepassingmoreeasilyacrosscellmembranes.Organismswithanexpandedgeneticcodethatallowsmorethanthe20naturalaminoacidstobeincorporatedintoproteinsshouldlikewiseenablethemanufactureofproteindrugswithnovelorenhancedproperties,forexamplebylengtheningtheir‘shelf-life’ormakingthemlessormorepronetointerfereinunintentionalwayswithbiochemicalprocesses.Enzymeswithnon-natural aminoacidsmightalsoshowgreateror lesscatalyticactivitywhenusedfortheproductionofpharmaceuticals.

Pseudo-biomolecules with non-natural chemical structures could be designed tobe ‘invisible’ to thenaturalchemistryof thecell, forexampleenablingthedesignofbiomolecularsensors thatoperate independently fromnaturalproteinnetworksandpathways.Amongthepotentialusesofsuchinvivomolecularsensorsmightbethevery early detection of cancer signals. Encoding genetic information in non-naturalnucleicacidsmightalsoreducetherisksofgeneticmodificationofnaturalorganisms,becausetheuseoftheaddedgenescouldthenbemadedependentonanexternalsupplyoftheingredientsneededtomakethenon-naturalnucleicacids:withoutthem,theaddedgenescouldnotbereplicated.Thiswouldofferasimplewaytoswitchthegeneticmodification‘on’and‘off’,forexamplebywithholdingthenecessaryingredientsfromatransgenicplant.

Nucleic acids have been recognised as versatile components for the synthesis ofnanoscale structures and devices [Seeman, 2003; see above]. Expanded geneticalphabetsshouldallowthecell-basedsynthesisandreplicationofDNAnanodeviceswithawiderrangeofproperties:greaterrobustness,say,ortheabilitytointeractwithinorganiccomponents.

Synthetic biology might be used to devise cells that will manufacture drugs according to precise genetic specifications


P 20

2.2.3 Sustainable chemicals manufacturing and energy productionTheinevitabledwindlingoffossil-fuelreservesduringthiscenturywillforceindustrialchemistrytofindanewsourceofrawmaterialsformakingproductssuchasdrugs,fuelsandplastics.Oneofthecurrentgoalsinsyntheticbiologyistodevelopengineeredmicro-organisms thatcangenerateusefulcarbon-based (organic)chemicals,of thesortcurrentlyobtainedfrompetroleum,fromnewfeedstockssuchasbiomass.Thisis a particularly valuable objective in the arena of fuel production,wheremicrobialproductioncouldbebasedonrenewablesources.Oneofthekeyaimsofthe‘minimalgenome’approach to synthetic organisms [Glasset al., 2006] is todesign them toturnbiomass, perhapsespecially the recalcitrant parts of plants that arenot easilydegradedbyexistingmicro-organisms,intobiofuelssuchasethanol.

2.2.4 Environmental remediationBioremediation–theuseofnaturallyoccurringorganismssuchasbacteriaandfungitobreakdownorganicpollutantssuchasoilandsewage,ortoconcentratetoxicheavymetals fromsoils–hasemerged in recentdecadesasoneof thebest techniquesfor decontaminating natural and man-made environments. Synthetic biology mightenablesuchorganismstoberationallydesigned,bothtoimprovetheirefficiencyandtobroadentherangeofpollutantsthattheycandegradeorremove.

2.2.5 Systems-scale molecular nanotechnologyAsshownabove, thereareseveralways inwhichengineeredproteins,virusesandorganismsmightassist inthedevelopmentofnewmaterials,suchasthoseusedinbiomedicine,microelectronics,mechanicalengineeringandenergyconversion.

So far, much of the work in this area has demonstrated specific functions usingindividualbiologicalcomponents:forexample,desalinationorfiltrationusingproteinsthatperformananalogousfunctionincellmembranes,ortransportofnanoparticlesusingmotorproteins.But in livingcells, suchsystemsare tightlycoupled toothersinan integrated,autonomousmolecularassembly thatbuildsand repairs itselfandgeneratesitsenergyfromambientsources.Itwouldbedesirabletoachievethissortofintegrationinsyntheticsystems[Ball,2005].Forexample,couplingphotosyntheticdevicestomotorproteinscouldenablelight-drivenmolecularmotion.Itisconceivablethatthebestwaytodothiswillbetoincorporateallofthecomponentsintothegeneticprogramsofengineeredorganisms. Inotherwords,syntheticbiologymighthelpustomimicnotjustsomeofthe‘molecularengineering’principlesoflivingcellsbuttheirsystems-scaleoperation.

One of the key aims of the ‘minimal

genome’ approach to synthetic

organisms is to design them to

turn biomass into biofuels such as

ethanol


P 21

Syntheticbiologyisanemergingdisciplinewithhugepotentialandscope.However,thereisnodirectcorrespondencebetweenthenatureandextentofthebenefitsandtheassociatedsafetyandsecurityrisks.Eachnewdevelopmentwillneedtobeassessedon its merits, balancing risks and benefits and, where necessary or appropriate,considering innovativeapproachestoenabling innovationwhileavoidinghazardstopeopleortheenvironment.

IRGChasidentifiedtwo‘frames’ofsyntheticbiologydevelopment:

first-generation• ‘evolutionary’syntheticbiologythatbuildsonexistingapplicationsof genetic engineering, deploying more rapid development methodologiesaccessibletoawiderrangeofactorsatreducedcosts;andsecond-generation• ‘revolutionary’ developments where feasible forms ofinnovationandapplicationareasarelesscertain.

Eachoftheseregimeswillhaveadistinctsetofrisks,withtheformerobviouslylessspeculativeandmorewell-definedthanthelatter[Mukundaetal.,2009].Adistinctionalsoneedstobemadebetweenthechallengesofregulatingtheconduct ofsyntheticbiologyresearchitselfandtheneedtoregulatetheproducts and practical outcomes of that research. For basic research and knowledge generation, risk governanceshouldfocusmainlyontheresearchprocessesthatarelikelytogiverisetohazards.Forproductsandotherapplicationsarisingfromthisknowledge,ontheotherhand,governanceshouldfocuslessontheprocesses involvedandmoreontheproductsandoutcomesthemselves.

Inconsideringproductsandpotentialapplications, thispolicybrief focusesonfirst-generation developments, for which we do have some information on likely futureoutcomes.However,commentsontheconductofbasicresearchonsyntheticbiologywouldapplytobothfirst-andsecond-generationdevelopments.

Reportsassessingpotentialrisksassociatedwithsyntheticbiologyhavebeenpreparedbyanexceptionallydiversesetoforganisations.Theseincludeofficialgovernmentalbodies[NSABB,2006;POST,2008],nationalacademies[RoyalAcademyofEngineering2009;RoyalSociety2008,2009;DFG,2009],foundation-and/orgovernment-fundedconsortia[BalmerandMartin,2008;Caruso,2008;Gaisser,etal.,2008;Garfinkel,etal.,2007;NEST,2007;Rodemeyer,2009]andNGOs[FriendsoftheEarth,2010;ETC,2010].Thesereportshavefocussedonthefollowingareas:

Insufficient basic knowledge about the potential risks posed by designed and1.syntheticorganisms.Forexample,arecentEuropeanUnion(EU)reporthasraisedquestionsaboutourabilitytoassessthesafetyoforganismsthatcombinegeneticelementsfrommultiplesources,thatcontaingenesandproteinsthathaveneverexistedtogetherinabiologicalorganism,orthatincorporatebiologicalfunctionsthatdonotexistinnature[EuropeanCommission,2009].

Uncontrolled release of novel genetically modified organisms with potential2.environmentalorhumanhealthimplications,eitherarisingfromaccidentalrelease

Each new development will need to be assessed on its merits

Regulating •the conduct of synthetic biology researchRegulating •the products and practical outcomes of that research

3. Risks of synthetic biology


P 22

intotheenvironmentorfromapplicationsentailingdeliberaterelease(forexample,bioremediation and some varieties of living therapeutics) [e.g. Friends of theEarth,2010].Areexistingbiosafetymeasuresadequate?Whoisresponsibleforascertainingandquantifyingrisks,andforimplementinganyclean-upmeasuresthatmightneedtobeundertaken?

Bio-terrorism,biologicalwarfareandtheconstructionofnovelorganismsdesigned3.tobehostiletohumaninterests.Geneticmanipulationoforganismscanbeused,orcanresultbychance,inpotentiallydangerousmodificationsforhumanhealthortheenvironment.Bioterroristsmight,forexample,createnewpathogenicstrainsor organisms resistant to existing defences. It has even been suggested thatpathogensmight be engineered to attack only a particular genetic subset of apopulation[Garfinkeletal.,2007].Itisbynomeansclearthatsuchabusescouldbeentirelyeliminated,anymorethantheycanbeforother‘dual-use’technologies.

Asidefromtheriskofabusescoordinatedbygovernmentsororganisedgroups,4.there are concerns about the emergence of a ‘bio-hacker’ culture in whichlone individuals develop dangerous organisms much as they currently createcomputerviruses.Thebasictechnologiesforsystematicgeneticmodificationoforganisms arewidely available and are becoming cheaper, although it is easytounderestimate thedegreeof technicalproficiency,experienceand resourcesneededtomakeeffectiveuseofthem.Manyresearchersinthefieldanticipatethattherealharmsthatmightbeinflictedbysuch‘hacker’activitiesareprobablysmall,buttheynonethelesswarrantcarefulconsideration,anditishardtoseehowtheymightbeprevented–thequestionismoreaboutlawenforcementthanscientificprotocol.Onesuggestionistoaimtoremovethe‘glamour’which,byanalogywithcomputerviruses,mightbecomeattachedtobio-hacking.

Patentingandthecreationofmonopolies,inhibitingbasicresearchandrestricting5.productdevelopmenttolargecompanies.

Trade and global justice, for example exploitation of indigenous resources by6.enabling chemical synthesis of valuable products in industrial countries (e.g.artemisininproductionformalariatreatment),ordistorting land-useagendasforgeneticallyengineeredbiomass[FriendsoftheEarth,2010;ETC,2010].

Claims that synthetic biology is involved in creating artificial life, and related7.philosophicalandreligiousconcerns.Theaccusationof‘playingGod’[Peters,2002]hasalreadybeenlevelledatsyntheticbiologyinthewakeofthefirstorganismwitha‘synthetic’genome[Gibsonetal.,2010;VandenBelt,2009].Aswithreproductivetechnologiesandstem-cellresearch,thelackofasharedconceptualframeworkmakesithardtodebatethisissueamongthevariousinterestedparties:thesciencemayhaveoutstrippedourethicalpointsofreference.

Many of these ethical and safety issues have already been acknowledged anddiscussed extensively by the synthetic-biology community [Schmidt, 2009b]. TheincreasinglyactivedebatearoundtherisksofsyntheticbiologyfocussesinEuropeontheexperienceofsimilardebatesaboutgeneticallymodified(GM)crops[Tait,2009b],

Genetic manipulation of organisms can be used, or can

result by chance, in potentially

dangerous modifications for

human health or the environment


P 23

whichhaveresultedinadefactomoratoriumonmanypotentialapplications.IntheUS,publicattitudestoGMcropshavebeenmuchmorepermissive.Ananalogyisoftenmadeinthesynthetic-biologycommunitywiththeAsilomarConferenceonRecombinantDNAin1975,atwhichguidelineswereagreedonhowthistechnologymightbeused,andavoluntarymoratoriumwasestablishedoncertainkindsofexperiments,suchasthecloningofDNAfrompathogenicorganisms.

It is easy (and perhaps appropriate) for an enumeration of the potential risks ofsyntheticbiologytosoundalarming.Butthesemustbeweighedagainstthebenefits,notleastinthesensethatthereisanethicalcomponenttothedecisiontoforegoanewtechnologytoo:therecanbesociallysignificantpenaltiestotheseemingly‘safe’option of ‘doing nothing.’ For one thing, the powerful capabilities synthetic biologymightprovidefordevelopingandmanufacturingdrugs,includingonessorelyneededindevelopingcountries,shouldnotlightlybesetaside,justaswedonotprohibitalldrugsthathaveside-effects.Itisconceivablethatinthelong-term,syntheticbiologymightofferoneofthemostpowerfulapproachesforamelioratingnaturalbiologicalandecologicalhazardssuchasthespreadofinfectiousdiseases[Mukundaetal.,2009].

Moreover,sincethebasictechniquesnecessaryforconductingsomeformofsyntheticbiologyalreadyexistandarepubliclyaccessible,curtailingscientificresearchinthisareaprovidesnoguaranteeagainstpotentialabuses. It is likely thatmisuse for thepurposesof,say,bioterrorismandbiowarfaremightbemosteffectivelypreventedorremediatedbythetechniquesofsyntheticbiologyitself.(Itcouldalsooffernewwaystocounteralreadyexistingmanifestationsofthesethreatstoo.)Inshort,thegenieisalreadyoutofthebottle:thetechnologymightbecomeitsownbestsafeguardagainstsomeofitsrisks.

It is easy for an enumeration of the potential risks of synthetic biology to sound alarming. But these must be weighed against the benefits

The technology might become its own best safeguard against some of its risks


P 24

4.1 Regulatory and governance contexts

The Organisation for Economic Co-operation and Development (OECD) viewssynthetic biology as a potentially revolutionary technology that could transformbiology and biotechnology from a largely scientific to an engineering discipline. Inthenear-term(to2015), theOECDsees theuseofmetabolic-pathwayengineeringtoproducechemicalsthatpreviouslycouldnotbeproducedbiologicallyasthemostlikelycommercialapplicationofsyntheticbiology. In the longer-term,applicationsofsyntheticbiologyinprimaryindustrialmanufacturingandinhealthcaremaybecomewidespread.Commercialisationof these latter useswas consideredunlikely before2015,becausesuchapplicationswillbesubjecttothesameregulatoryproceduresasotherbiotechnologyproducts,whichgenerallyrequirealeadtimeofbetween5and7years[OECD,2009a].

Thereiscurrentlyacomplexarrayofnationalandinternationalregulatoryinstrumentsthatmayberelevantfor,oractasprecedentsfor,theregulationofsyntheticbiology,particularlyfirst-generationproducts [e.g.ByersandCasagrande,2010].There isahistoryofdecisionsbeingtakeninveryearlystagesofproductdevelopmentthatturnouttohaveunforeseenandoftencounter-productiveoutcomeswhicharethendifficulttochange.Thisisparticularlyevidentwhereregulationhasbeendesignedtoreassurethepublicratherthantoaddressgenuineexpectedrisks,aswasthecaseforGMcropsinEurope.Also,wherearegulatoryregimehasevolvedoveralongperiodoftimeinresponsetoseveralgenerationsofscientificdevelopment,itcanbecomeinflexibleanddifficulttomodifyinwaysappropriatetothelatestadvancesandopportunities[ByersandCasagrande,2010].Thiscanunnecessarilylimitopportunitiesforinnovationandrepresentagovernancedeficitinitself[IRGC,2009a].Theappropriateriskgovernanceof innovative technologies thus needs to be informed by an understanding of howgovernanceandengagementapproachesinteractwithinnovationprocesses.

TheEuropean viewon risk regulation in synthetic biology is that itwill be coveredby existing regulations for geneticmodification and release ofGM products to theenvironment [Royal Academy of Engineering, 2009]. However, these regulationsare themselves controversial (see Section 5.2) and are already inhibiting thecommercialisation of potentially beneficial GM products, such as pest- or drought-resistantcrops[WagnerandMcHughen,2010].

Internationallawhasanimportantbearingontradeinbiotechnologicalproducts,themostfamiliarexamplebeingtherestrictionsontradeingeneticallymodifiedorganisms(GMOs)orproductsderivedfromthem.Someregulationsmayberelevanttoproposedapplicationsofsyntheticbiology,suchastheglobalmoratoriumonoceanfertilisation(foramelioratingclimatechangebypromotingoceaniccarbondioxideuptake)undertheConventiononBiologicalDiversityandtheprovisionsoftheBiologicalWeaponsConvention (BWC). The next review conference of the BWCwill be held in 2011,providing theopportunity for the internationalcommunity tomakebindingdecisionson the oversight of synthetic biology. The Environmental Modification Convention

There is currently a complex array of national and

international regulatory

instruments that may be relevant for,

or act as precedents for, the regulation of

synthetic biology

The appropriate risk governance

of innovative technologies needs

to be informed by an understanding

of how governance and engagement

approaches interact with innovation

processes

4. Existing policy and regulatory frameworks, and their deficits


P 25

(ENMOD), an international treaty prohibiting the military or other hostile use ofenvironmental modification techniques such as alterations to weather patterns oroceancirculation,mayalsoapplytosomepossibleusesofsyntheticbiology.

TheAgreementonTrade-RelatedAspectsofIntellectualPropertyRights(TRIPS)isthemostcomprehensivemultilateralagreementonintellectualproperty,settingstandardsto be met in domestic patent law. Most applications and techniques of syntheticbiologywouldbepatentableunderArticle27.3(b)oftheagreement,whichdealswithintellectualproperty(IP)protectionofgeneticresources.

Limitson theexploitationof IP rightsstem fromotherfieldsof law,suchashumanrightslawandinternationalenvironmentallaw.Trade-offsmayberequiredwheresuchissuesaspublicaccesstoinnovativemedicinesareatstake.Inthisregard,compulsorylicensing remainsanoptionunder theTRIPSagreement forpatents inanyfield. Inthe2001DohaDeclarationonTRIPSandPublicHealth,WorldTradeOrganization(WTO)membergovernmentsstressedthatitisimportanttoimplementandinterprettheTRIPSAgreementinawaythatsupportspublichealth.

TherearepotentialconflictsbetweentheTRIPSpatentingregimeandtheConventiononBiologicalDiversity,aswellastheInternationalUndertakingonWorldFoodSecuritynegotiated at the United Nations Food andAgriculture Organisation (FAO). Theseconflicts are generally seen as political rather than legal, andmay lead to disputeundertheWTOdispute-settlementsystem.

TheCartagenaProtocolonBiosafetytotheConventiononBiologicalDiversityregulatesinternationaltradeingeneticallyengineeredproducts.TheProtocolestablishescoreproceduresandasetofstandardsrelatingtotheimportandexportoflivingmodifiedorganisms(LMOs).AlthoughtheCartagenaProtocolrecognisesinitspreamblethattradeandenvironmentagreementsshouldbemutuallysupportive,itisgroundedinamorerobustapplicationoftheprecautionaryapproachthantheWTOrules.Currently,157nationalpartiesparticipateintheProtocol,includingChina,Brazil,IndiaandmostEuropean nations, but not theUS (where significant research and development insyntheticbiology is takingplace)orotherpotentially important internationalplayerssuchasAustralia,Russia,ArgentinaandCanada.

ThereareclearareasofoverlapbetweentheProtocolandtheWTOrules.InadditiontoTRIPS, theAgreementonTechnicalBarriers toTradeand theAgreementon theApplicationofSanitaryandPhytosanitaryStandardsare relevant.ArticleXXof theGeneralAgreementonTariffsandTrade(GATT)providesforexceptionsfromGATTrulesinordertoprotecthealthortheenvironment.TheseagreementsformedthebasisofthedisputeraisedbytheUS,CanadaandArgentinaundertheWTOsystemovertheEuropeanCommission’sregulationofGMOs.Thedifferentfundamentalobjectivesof the international trade and environmental regimes may lead to conflicts in theregulatorymeasurestakentoachievetheseobjectives.Strengtheningthecoherenceof these twosystems requiresmeasures tobe takenatnationalandsupranationallevelstoensuretheyareimplementedinamutuallysupportivemanner.


P 26

Developments in synthetic biology could lead to gaps in the risk assessmentframeworksetoutintheCartagenaProtocol,sinceestablishedpracticesmaynotbecapableofdealingwithcomplexhybridsofgeneticmaterial(includingsomethatarewhollysyntheticindesignandorigin)andthepropertiesandeffectstheydisplay.Thesameproblem is facedbynon-participating states. In theUS, the risk assessmentframework in the National Institutes for Health Guidelines for Research involvingRecombinantDNAMolecules[NIHGuidelines,2009;ByersandCasagrande,2010]isconsideredbyregulatorstobesufficientatpresentforhandlingrisksthatmightariseinsyntheticbiologyattheresearchstage.Theframeworkusestheriskgroupoftheparentorganismasastartingpointfordeterminingthenecessarycontainmentlevel;but synthetic techniquesmayenable thedevelopment ofmore complexorganismsforwhich the risksof theparentorganismarenotanappropriateprecedent [ByersandCasagrande,2010].Notenoughisknownatpresentforrobustriskassessmentsrelatedtocontainmentofpartiallyorwhollysyntheticorganisms.Thereisalsosomeconcern that intellectual property rights claims could be used to restrict access torisk-related informationand therebycompromise thecredibilityof riskassessmentsinfuture.

4.2 Risk Governance Deficits

Severalaspectsofriskgovernancerelevanttoinnovativetechnologiesareconsideredhereinrelationtosyntheticbiology:

Theuncertaintyaboutfutureresearchandindustrialdevelopments,andthusabout•theactualopportunitiesandrisks.Theinhibitingeffectoninnovationofuncertaintyaboutfutureregulatorysystems,•particularly for products with long lead times for delivery from conception tomarket.The need for a better understanding of how different regulatory approaches•interactwithinnovationprocessestodeterminethefateofinnovations,includingtherelativecompetitiveadvantagegainedbycompaniesandcountriesoperatingindifferentregulatoryregimes.Thepotentialtoadaptexistingregulatorysystemsandtoapplythesetoinnovative•technology, and in particular the importance of adopting the most appropriateregulatoryprecedent.The potential for lack of harmonisation between different national regulatory•systemstoleadtotrade-relatedandotherconflicts.Problemsofstakeholderandpublicengagementaboutinnovationswhere,forall•partiesinvolvedindiscussionanddecision-making,thereisignoranceoratbestuncertaintyabouttheeventualnatureofnewproductsandprocesses.Thevolatilenatureofpublicopinionaboutinnovativetechnology,sothatdecisions•basedonthebalanceofstakeholderattitudestodaymayfaceaverydifferentsetoffuturepublicopinions.The need to take decisions on a balanced basis, particularly where there is•irreconcilable or ideologically based conflict over innovative technology and itsapplication.

Not enough is known at present

for robust risk assessments related

to containment of partially or wholly

synthetic organisms

There is concern that intellectual property rights

claims could be used to restrict access

to risk-related information and

thereby compromise the credibility of

risk assessments in future


P 27

These considerations suggest that any effective approach to risk governance ofsyntheticbiologymustbecapableofevolvingasscientificandtechnicalknowledgeexpands, requiring flexibility in the faceof uncertaintyabout theeventual natureofproducts,processes,benefitsand risks.Wehave focussedhereon theconceptofrisk governance deficits1 – deficiencies or failures in risk governance processesor structures – and have aimed to identify weak spots in how risks are assessedandmanaged in the keyareasof policyand regulation, innovationand technologydevelopment,andpublicandstakeholderengagement[IRGC,2009a].

ParticipantsattheIRGCworkshoponsyntheticbiologysoughttofindanappropriatebalance between current scientific knowledge and uncertainty about futuredevelopments,andtheneedtorealisticallyassessthepotentialofthefield.Abalanceisalsoneededforpolicyandregulatoryoptions, includingthepotential totransformexisting policies and regulatory frameworks that may be difficult to adapt to thechallenges raised by innovative technologies. The participants were concerned toensurethattheopportunitiesofferedbysyntheticbiologyasthetechnologydevelopsbekeptopen,butalsorecognisedthatthereispotentialheretoopenupnewmodelsofpublicandstakeholderengagement.

One general theme to emerge from theworkshopwas the concern that ‘syntheticbiology’wasalreadybecomingtoobroadasetofdevelopmentstobedealtwithunderone heading. As is already the case with nanotechnology, this diversification willmakeitincreasinglynecessarytogoverntheareausingadiverseandflexiblesetofregulatoryprecedentstailoredtoarangeofspecifichazardsandtheneedsofdifferentindustrysectors.

Theworkshopdiscussionsalsoexploredpotentialinteractionsamongriskregulatoryprocesses,innovationsystems,andstakeholderandpublicperspectivesinrelationtosyntheticbiologydevelopments.They identified the followingdeficits [IRGC,2009a,pp.64-65]asbeingmost relevant topotential developments in syntheticbiology (inorderofperceivedimportance).TheguidelinesproposedinSection6aredesignedtohelppolicy-makersandregulatorstoavoidorreducethesedeficits.

Potential deficits in risk assessment: Lackofknowledge, includingtheprobabilitiesofvariousdiscoveries, inventions•and events and the associated economic, human health, environmental andsocietalconsequences.Lackofknowledgeaboutvalues,beliefsand interestsandthereforeabouthow•risksareperceivedbystakeholders.Failuretoidentifyandinvolverelevantstakeholdersinriskassessmentinorderto•improveinformationinputandconferlegitimacyontheprocess.Theprovisionofbiased,selectiveorincompleteinformation.•Lackofappreciationofthemultipledimensionsofariskandhowinter-connected•risksystemscanentailcomplexandsometimesunforeseeableinteractions.Failure toovercomecognitivebarriers to imaginingeventsoutsideof accepted•paradigms.

(1)TheconceptandalistofthemostcommonlyobserveddeficitsinriskgovernancehavebeendescribedinanIRGCreportavailableathttp://www.irgc.org/IMG/pdf/IRGC_rgd_web_final.pdf.

Any effective approach to risk governance of synthetic biology must be capable of evolving as scientific and technical knowledge expands


P 28

Potential deficits in risk management:Insufficientflexibilityinthefaceofunexpectedrisksituations.•Failure to balance transparency (which can foster stakeholder trust) and•confidentiality(whichcanprotectsecurityandmaintainincentivesforinnovation).Failure of the many organisations responsible for risk management to act•cohesively.Failuretomusterthewillandresourcestoimplementriskmanagementpolicies•anddecisions.Failure to design risk management strategies that adequately balance•alternatives.Failure of managers to respond and take action when risk assessors have•determinedfromearlysignalsthatariskisemerging.

Diversification willmake it increasingly necessary to govern

the area using a diverse and flexible

set of regulatory precedents


P 29

5.1 The concept of appropriate risk governance

IRGCdefines ‘appropriate riskgovernance’as thatwhich, in the fieldof innovativetechnologies,enables innovation,minimisesrisktopeopleandtheenvironment,andbalancestheinterestsandvaluesofallrelevantstakeholders[Tait,2007],whileavoidingsimplisticcomparisonsacrosssectorsandtechnologies.TheIRGCriskgovernanceframework[IRGC,2005]hasbeenappliedverysuccessfullytoarangeofriskissues,including forexample ‘NanotechnologyApplications inFoodandCosmetics’ [IRGC,2009c].However,syntheticbiologypresentschallengesfortheusualapproachestoriskgovernance.Initscurrent,earlydevelopmentalstage,bothbenefitsandrisksofsyntheticbiologyarelargelyconjecturalandmostpreviousreportsonthisissuehavethereforefocussedonaspectsthatarecoveredonly intheinitial(‘pre-assessment’)phaseoftheIRGCframework–specifically,

howrisksareframedbystakeholders;•whether thereareanyapplicable legalorotherexistingrulesorprocesses that•covertechnologydevelopments;thescientificcharacteristicsofthetechnologyanditspotentialapplications;•thehopesandconcernsofmajorstakeholdergroups.•

Regulationof basic researchon synthetic biology shouldbe considered separatelyfromproductregulation.Giventhelikelyrangeofapplicationsofsyntheticbiologyindifferentindustrysectors,however,itwouldbeunwisetoattempttodeviseanoverallframework for riskgovernanceofsyntheticbiology. Instead, riskgovernancehas tobeapproachedonaproduct-by-productbasis,payingparticularattention tocurrentregulatoryapproaches,theextenttowhichtheyaretransferabletothenewproducts,and the implications of such choices for the options for future development. Forexample,products thathaveapplications tohumanoranimalmedicine,agriculturalcrop development and the production of biofuels will come under the scrutiny ofdifferentexistingregulatorysystems.

However,someareasofsyntheticbiologywillnotbecoveredbythisapproach.Forexample,tradingin‘bio-bricks’(genesequencesthatcanbeusedbybothresearchersandcommercial companies todevelopnewgenecircuitry) canbedealtwithusingregulatoryinitiativessimilartothosebeingdevelopedtoregulatetheresearchstage.Ontheotherhand,whensyntheticbiologyisusedtodevelopnewprocessesforthemanufactureofcomplexbiologicalmolecules,theresultingmoleculesthemselvescanberegulatedbyexistingsystemsfordrugsorotherchemicals,butnewregulationmayalsobeneededforthenovelorganismsusedintheproductionprocess.

5.2 Regulation and governance of first-generation synthetic biology

Forsomelikelynear-termapplicationsofsyntheticbiology–forexample,inbiofuelsand industrial applications, pharmaceuticals and health diagnostics, and genetic

Risk governance has to be approached on a product-by-product basis, tailored to a range of specific hazards and the needs of different industry sectors

5. Risk governance in synthetic biology


P 30

modification of plants and organisms for agriculture and food production – well-developed risk governance approaches are already in place. The challenge is to choose the most appropriate regulatory precedent and to avoid reinforcing currently inadequate regulatory systems.

For example, the emerging consensus related to the use of synthetic biology to develop more sophisticated GM micro-organisms or plants, is that regulatory systems for existing GMOs will be the appropriate regulatory precedent. However, there are contentious differences between the US and EU approaches to GM risk governance. The latter is regarded by some to be unnecessarily demanding and inhibiting of innovation, while the former is seen as inadequate to deal with some of the risks emerging from current GM crop innovations, such as using GM food crops to produce pharmaceutical products. Ideally, the process of adapting these regulatory systems to accommodate the needs and opportunities presented by synthetic biology could at the same time resolve some of these outstanding and so far intractable issues arising from previous regulatory decisions.

Considering institutional and human dimensions to regulatory development, building regulatory capacity to deal with the issues presented by synthetic biology is both an experience issue and a skills issue. In terms of developing an appropriate knowledge base, the capacity to record ‘near misses’ is becoming recognised as a policy field in its own right and offers a structured approach to learning from early projects in order to develop adaptive governance frameworks [OECD, 2009b]. Furthermore, the risk assessment and governance of synthetic biology (in common with other areas of technological convergence) requires multi-disciplinary teams with skills across the scientific fields from which synthetic biology is emerging.

5.3 Policy and regulatory strategies in biosafety and biosecurity related to research, innovation and technology development

The ready availability of DNA sequence data and online explanations of the techniques of molecular biology, combined with the ease of purchasing a specified DNA sequence from the many commercial companies that now offer this service, means that these technologies can be readily acquired by amateur scientists or potential terrorists [Garfinkel, et al., 2007; de Vriend, 2006]. Even in the hands of legitimate and well-intentioned researchers, health and environmental risks could arise from unintended dispersion of modified organisms.

The synthetic biology community has generally supported approaches to oversight that rely on voluntary measures developed and implemented by the community itself [Campos, 2009]. In formalising such measures, decision-makers, particularly in the US and EU [Bennett, et al., 2009], are investigating approaches to screening all gene sequence orders sent by commercial DNA synthesis companies to

The challenge is to choose the

most appropriate regulatory

precedent and to avoid reinforcing

currently inadequate regulatory systems


P 31

research laboratories or other commercial companies. This approach is supported by some scientists, who point out that the likely control of DNA synthesis and other key technologies by a small number of very efficient companies [Bhattacharjee, 2007] could make such monitoring relatively easy and reduce biosafety concerns.

As the gene-synthesis market has become more competitive, two groups of companies have proposed different standards for screening orders for gene sequences to enable identification of any that could present a potential biological hazard [Hayden, 2009]. The International Association for Synthetic Biology (IASB) code of conduct [IASB, 2009] includes a review step by an expert in the field, while DNA 2.0/Geneart has suggested an automated process. The Federation of American Scientists has considered this problem of multiple standards, and is working towards a consensus, at least among American scientists and companies [FAS, 2010], on how screening might be done. Guidelines for screening of DNA synthesis have been formulated by the US Department of Health and Human Services [DHHS, 2010], but these are voluntary, apply only to double-stranded DNA, and have been criticised by some researchers as representing no improvement to the security risk [Ledford, 2010].

Furthermore, if these technologies become ever more accessible [Carlson, 2010], so that gene sequences can be procured by means other than through companies with sophisticated screening procedures, this will create stiffer challenges for risk management. Some feel that the threat may be much greater from state-sponsored terrorism (for which DNA synthesis would be hard to control or monitor) than from amateur activities. However, it is important not to underestimate the difficulty of moving from research in a laboratory, let alone a ‘bio-hacker’s’ garage, to a functioning product that can be disseminated widely. Incorporating engineering techniques into research on biology does not mean that the resulting products can be developed as if they were just another piece of hardware or software.

The dissemination of the technology, knowledge and capabilities involved in synthetic biology beyond the professional biotechnology community will have two (potentially overlapping) strands:

Professional groups such as engineers and computer scientists, educated in 1. disciplines that do not routinely entail formal training in biosafety, may acquire these capabilities. In consequence, there needs to be a dialogue among all relevant researchers on what responsible conduct might entail in this field, and education about the risks of, and guidance on best practice for, biosafety principles and practices applicable to synthetic biology. A review of biosafety standards should also be conducted to identify differences between standards and actual laboratory practices.

Dissemination may extend beyond academic and professional circles as biological 2. engineering becomes more accessible [Mukunda et al., 2009]. This may include less responsible individuals and organisations. Moreover, the most appropriate

The synthetic biology community has generally supported approaches to oversight that rely on voluntary measures developed and implemented by the community itself


P 32

balancebetweenpromotinginnovationandcontainingriskwillnotbethesameinallpartsoftheworld.Legitimateresearcherscanhelpgovernmentsandregulatorstofindwaystopreventotheractorsfromusingthetechnologyforillicitpurposes.Anappropriatebalancealsoneedstobefoundbetweentop-downcommandandcontrolandbottom-upeducationandawarenessinitiatives,includingthefosteringof a culture of responsibility and the de-glamorisation of the kind of antisocialactivitiesalreadyevidentinthecreationofcomputerviruses.

A summary of US Federal Regulations that relate to synthetic biology [Byers andCasagrande, 2010] haspointed to several inadequacies, includingNIHGuidelines,EPA,USDAandFDARegulations,DepartmentofCommerceRegulationsandSelectAgentRules,ascurrentlyapplied todevelopments in syntheticbiology that involvemicro-organisms.Thecurrentapproachtothedefinitionandclassificationoforganismsaccordingtoperceivedhazardlevelswillnotcovertherangeofpossiblemodificationsarisingfromsyntheticbiology,whetherlegitimateormalicious.Theruleswillneedtobeadaptedtonewcircumstances.

Policy-makers need to take a lead in developing and implementing standardisedprocedures and preferred practices for screening sequences and for mitigatingbiosecurityrisksasawhole.TherecentlypublishedUSNationalStrategyforCounteringBiologicalThreats [USNationalSecurityCouncil, 2009] isan important step in thisdirection. In thecontextofbiological threatsofall kinds, includinganyarising fromsynthetic biology, the strategy advocates an international, systemically organisedapproachthatseekstopromotea‘cultureofresponsibility’inthelifesciences,backedup by legal mechanisms, coupled with surveillance and improving intelligence ondeliberatethreats.

Oneofthekeyissues,whichlacksanycurrentconsensus,istowhatextentavoidanceofbiosafetyriskscanbeensuredbyvoluntarymeasures(forscreeningofcommercialDNAsynthesis,say)asopposed to top-down regulation.Forexample,Mukundaetal.recommendtheadoptionofa ‘safetyhold’normofthesortcurrentlyusedbyAirTrafficControl(ATC)systems,wherebyanyproposedchangetoATCsystemscanbeblockedbyanymemberofthecommunitywhobelievesthattheyarelikelytocausesafetyconcerns[Mukundaetal.,2009].

Amajorplankofthestrategyproposedhereistherecognitionthatusingthelifesciencestocombatbothnaturalandmaliciousthreatsmaybethebestwaytominimiseharm,giventhatthereisnofoolproofwaytoforestallmalicioususeofthetechnology.Thiscould include theuseofmethods insyntheticbiology todevelop improveddiseasediagnosticsandvaccines.Inthiscontext,itisimportanttorecognisethattheriskstohumanityfromnaturallyoccurringzoonoses(infectiousdiseasesthatcanbetransmittedfromanimalstohumans)andotheremergingpathogensarelikelytobegreaterthanthosearisingfrommalicioususeofsyntheticbiology.

The most appropriate balance between promoting

innovation and containing risk will not be the same in

all parts of the world

One of the key issues, which

lacks any current consensus, is to what extent

avoidance of biosafety risks

can be ensured by voluntary measures

as opposed to top-down regulation


P 33

5.4 Intellectual property (IP) issues and maintaining incentives for innovation

In any innovative technology, the granting of limited exclusive rights in intellectualpropertycansupportinnovationbutcarriesthedangerofcreatingadisproportionateconcentrationofmarketpower.Inareasoftechnologicalconvergence,IPrightsmaybefragmentedacrossmanyowners,andaresometimesgivenanexcessivelybroadinterpretation, which can pose obstacles to the development of the basic science.Moreover,wherescienceisdevelopingrapidly,theneedsoftheresearchcommunityforIPprotectionarenotnecessarilyalignedwiththoseofproductdevelopers.

Manyscientistsworkinginsyntheticbiologyhaveexpressedaprincipledcommitmenttoan ‘opensource’ethos,modelledon theopen-softwaremovement in ICT [HellerandEisenberg,1998].Suchstronglyheldviewscanmakeitmoredifficulttobalancethesocietaltrade-offsthatneedtobemadebetweenopenaccesstoinformationandcommercialrealities,particularlyinthecontextofthelengthyandonerousregulatoryprocesses that apply in many areas of life sciences (which tend to impose highdevelopmentcosts).Theclaimoftenmadeforopen-sourcebiotechnology–thatitcanrealisethebenefitsofcommercialtechnologytransferwhilecreatingarobustscienceandtechnologycommonsthatcansustaininnovation–hasyettobetestedincaseslikesyntheticbiology.

Aswellasawhollyopen-accessapproach,variousotheroptionshavebeenproposedforhandlingintellectualpropertyinsyntheticbiologythatgobeyondthetraditionaloptionofpatenting,typicalofbiotechnologyandthepharmaceuticalindustrytoday[RaiandBoyle,2007].Therecould,forexample,beprovisionforcopyrightingofinnovations,for contracts togovern their use, or for highly specificsui generis strategies.Eachhasadvantagesanddisadvantages,andnoneisobviouslypreferabletotheothers.OyeandWellhausenarguethatcurrentapproachescanbedistinguishedbothbythedegreeofpublicversusprivateownershipofIPandbytheextenttowhichpropertyrightsareeither clearlyorambiguouslydefined [OyeandWellhausen,2009].Theypointoutthatthereisnoconsensusontheseissuesamongresearchersinthefieldofsyntheticbiology,partlybecausethereisnoagreementontheextenttowhichprivateownershipisneededasanincentivetoinnovation.Intheshort-term,privatisationofIPmaybeimposedbytheinstitutionaldemandsoftheresearchers,butasapplicationsof synthetic biology in areas such as energy and climate gain pace, internationalpressuresmayencourageashifttoamorecommons-basedapproach. For near-term applications that resemble those in current genetic engineering andwhichrequirelargeinvestmentstobringaproducttomarket,patentingseemslikelytopredominate.Andaspatentapplicationsinthefieldofsyntheticbiologyarelikelytocontainclaimsforbiologicalmoleculesormicro-organisms,andformethodsofproducingandapplying them, theywillbemostly indistinguishable fromsimilarapplications inotherareasofbiotechnology.Patentauthoritiesholdprimaryresponsibilityforensuring

The needs of the research community for IP protection are not necessarily aligned with those of product developers


P 34

patentquality. Initiativessuchas the ‘Raising theBar’programmeof theEuropeanPatentOfficeaimto‘front-load’legalcertaintybyensuringahighqualitystandardofpatentsgranted[Nurton,2009].

Variousmeasureshavebeensuggestedforsupportingthesharingof informationinsyntheticbiologyinthelong-termwhilemaintainingincentivesforinnovation[HenkelandMaurer,2009].Companiescanbeencouragedtouseunpatentedbiologicalpartswherepossibleanddonatepartstothecommons,andpublicfundinginstitutionscanexercisetheirinfluenceonthelicensingconditionsfortheresultingpatents,sothatforexamplewherethisfundingisusedtodevelopfoundationaltoolsandtechniques, itcarriesanobligationtoshareinformation.However,thisapproachcouldstillinhibitthecommercialinvestmentnecessarytotakeaproducttomarket.

Regulatorshavearangeoftoolstodealwith,forexample,thecontrolofanti-competitivebehaviour,andprovisionsforaccesstomedicinesandcompulsorylicensingremainsanoptionunderTRIPS.Animportantconsiderationintermsofbalancingtransparencyand confidentiality is that IP rights should not be allowed to restrict access to thescientificdataneededforriskassessment,ashashappenedintheUSwithsomeGMcropvarieties[ScientificAmerican,2009].Thisisparticularlyimportantwherethereisnodejureresearchexemptionfortheuseofpatentedsubjectmatter(althoughsuchanexemptionmayberecognisedinpractice).

Amorenuancedregulatoryregime,ratherthanframingthedebateas ‘opensourceversuspatentingandcommercialisation’,couldtaketheneedsofallpartiesintoaccountsothatpolicyresponsesfavourresearchersandproductdevelopersequally,allowingtheflexibilitythatwouldenableinterestedpartiestoaccessinformationorbiologicalpartsonthetermswhichtheyrequiretoconducttheirresearchand/orinvestment.Asthesyntheticbiologyindustrydevelops,morestudieswillbeneededontheeffectsthatpatentingof inventionshasoncompetition, includingsuchphenomenaasstrategicpatentingandpatentclusters.

5.5 Risk regulation and barriers to innovation

Theshapeofemergingsynthetic-biologyindustrieswillbeinfluencedbytheregulatoryand investmentenvironmentswithinwhich theyoperate.Governanceproblemscanariseifthereisafailuretothinkthroughhowthepotentialbenefitscanbedeliveredin a way that balances public and commercial needs and agendas [Tait, 2009a].Policyapproachesoftenlackcross-functionalcoordination,forexamplebetweenriskregulation,IPprotectionandstakeholderperspectives,andmaynotrecognisesomeofthecounter-intuitiveimplicationsthatregulationmighthaveforinnovation.Regulationtends inevitably to be onerous and lengthy, which favours very large companiesby raising high barriers to newmarket entrants. Large companies are often highlyinnovative, but only within the restricted area that supports their overall companystrategy[Tait,2007].Syntheticbiologyislikelytoofferground-breakingopportunitiesformultinationalcompanies,butitispreciselythesedevelopmentsthatcouldbemost

IP rights should not be allowed to restrict access to the scientific data

needed for risk assessment

Governance problems can arise

if there is a failure to think through

how the potential benefits can be

delivered in a way that balances public

and commercial needs and agendas


P 35

atriskfromearlyregulatoryinitiatives.Forexample,thedecisiontocategorisestem-cell therapiesas ‘drugs’ for regulatorypurposesmilitatesagainst theirdevelopmentbysmallcompaniesworkingwith technology related tosurgicalprocedures.Wherethereisachoiceofregulatorysystems,anappropriateprecedentwouldbethesystemrelatedtotheindustrysectorforwhichthetechnologywouldbepath-dependent[Tait,2007].

Ingeneral,thechallengeistofindtheappropriatebalancebetween:

theinhibitingeffectofuncertaintyaboutfutureregulatorysystemsoninvestment•innewtechnology,particularlyforproductswithlongleadtimesfromconceptiontomarket;

regulation/innovationinteractionsthatdeterminethefateofindividualinnovations•andalsotherelativecompetitiveadvantageofcompaniesindifferentsectors;

thepotentialforalackofharmonisationacrossnationalregulatorysystems,which•couldcreatetrade-relatedandotherconflicts.

Becauseradical,path-breakinginnovationsgenerallyrequireinfrastructurechanges,pavingthewayforthemwilloftenrequireconcertedeffortstocreateamarket,foresightresearch,andinfrastructureinvestment.Regulatorscouldconsiderstreamliningmarketauthorisation,forexamplebysettingupa‘fasttrack’forproductsthatsatisfyaparticularpublicdemandorarecapableofreducingtheriskspresentedbycurrent-generationproducts.Aregulatorypolicythatenables positivechangeinindustrystrategiesanddiscriminatesamongproductsonthebasisofsociallyandscientificallyrelevantcriteriaislikelytobemoreeffectiveandefficientthanonewhichis indiscriminateandattemptsmerelytoconstrainundesirablebehaviour[Tait,2007].

5.6 Local, regional and international perspectives on regulatory oversight and risks

Divergent national approaches to the regulation of GM crops have created manyproblemsforbothlargeandsmallcountries,withlessonsforthegovernanceofsyntheticbiology.Regulatoryoptionsforsyntheticbiologywillhavetotakeaccountofacomplex,multi-layeredregulatoryenvironment(local,regional,nationalandsupra-national)andvarious specialised regimes. The law uses various frameworks to regulate genetictechnology,suchasindividualrightsandduties,scientificregulationbyadministrativeagencies, and legislative pre-emption. Each framework involves different decision-makersandisdesignedtooverseeadifferentaspectofgenetictechnology.

International trade law can prevent some conflicts, but the trading system is notthe appropriate place for harmonising environmental, social or other non-trade-related standards,or for determining itsmembers’ policiesonbiotechnology.Whilestatesmustfindtheirownappropriatebalanceonthesematters(takingintoaccountinternationallegalobligations,especiallymultilateralenvironmentalagreementssuchas theCartagenaProtocol), it is desirable that internationally applicable regulatory

Stemcellsinculture


P 36

principlesandguidelinesbeestablished,alongwithwaystointerfacetheapproachesofdifferentstates.

Synthetic biology offers different opportunities and risks in different parts of theworld. An important consideration is how to coordinate the international planningand collaboration required for effective governance of an innovative life-sciencetechnology,whileencouragingheterogeneityinafieldwithwidelyvaryingtechniquesandapplications.

It is also vital to acknowledge varying capacities to administer complicated riskregulatory regimes: this might, for example, be more challenging in developingcountries.Thesevariations in capacityhavebeen recognisedasan impediment totheeffectiveimplementationoftheriskassessmentandriskmanagementprovisionsof the Cartagena Protocol. To deal with these problems, developing countries willneedsupportandaccess to technical resources.Buildingup the researchcapacityofdevelopingcountries,and fosteringsmallerstart-upcompanies,couldhelp thesecountries to reap the benefits that the technology offers while at the same timecontributingtosolvingtheirpressingeconomicandsocialproblems.InstitutionssuchastheInternationalCentreforGeneticEngineeringandBiotechnology(ICGEB),whichwascreatedin1983topromoteinternationalcooperationindevelopingandapplyingpeacefulusesofgeneticengineeringandbiotechnology,mayhaveapart toplay inthis.Inanyevent,afailuretomatchtheregulatorycapacityofsmallcountrieswiththeirtechnologicalcapacitycouldcreatebiosecurityrisks.

It is not clear how countries that are currently undergoing rapid economic andtechnological development, such as China, India and Brazil, might function in thefuture as regulators, producers, and markets. To take just one example, in 2009AmyrisBiotechnologiesopenedaplantinCampinas,Brazil,forlarge-scaleproductionofhydrocarbons fromsugarcaneprocessedusinggeneticallyengineeredmicrobes[Bourzac, 2009]. These countries aremoving towards stronger regulatory systemsforproductssuchaspharmaceuticals.Countriesthatalreadyhaverobustregulatorysystemsshouldassistinthisprocess,withthewidergoalofimprovingallregulatorysystemsratherthanallowingpotentialbottlenecksandflawsinexistingmodelstobereplicatedinnewsystems.

5.7 Technological risk management options

Syntheticbiologymightcreateways tomitigatesomeof the risksofproductssuchas drugs orGM crops that are addressed by current regulatory frameworks, or tocontribute to improved standards for biofuels. Some of the challenges posed bythesetechnologiesmightbecomeamenabletotechnological,ratherthanregulatory,solutions, and as a result synthetic biology might motivate regulatory reform andrevision.Similarly, forsomeof thepotential risksof syntheticbiology, technologicalmeans toassuresafetymaybemoreappropriate thansettingupanewregulatorysystemorextendinganexistingone.

Synthetic biology offers different

opportunities and risks in different

parts of the world

It is also vital to acknowledge

varying capacities to administer

complicated risk regulatory regimes


P 37

The introduction of concepts from systems engineering, especially from safetyengineering, tobiologyhasbeensuggestedasoneway inwhichsyntheticbiologyitselfmayhelptoovercomeexistingandpossiblefuturebiosafetyproblems[Schmidt,2009a].Topreventtheuncontrollableproliferationofnovelorganisms,forexample,itmightbefeasibletomakethemdependentonnutrientsnotfoundinnature,ortoequipthemwith self-destructmechanisms [Endy, 2005; Church, 2005], or to incorporatemultiplesourcesofdependency thatwillminimise theirsurvivability in thewild.Andmakingtheseorganismschemicallydistinctfromnaturalones,thepossibilitiesfortheirinteractionmightberestricted.Proposalstobuildinsafetybydesignarecontroversial,however,partlybecauseofthedefactomoratoriumagreedongeneticuse-restrictiontechnologies (GURTs) in 2000 at the FifthConference of theParties (COP) to theConventiononBiologicalDiversity(CBD)(SectionIIIofDecisionV/5onAgriculturalBiologicalDiversity).

Inprinciple,theincorporationofGURTsintotransgenicsisinkeepingwiththeaimsoftheCartagenaProtocol(Article2),sincetheywouldblockgeneflow.Butthemoratoriumrecommendsthatfieldtestingandcommercialuseshouldnotbeapprovedatpresent.InMarch2006,theCOP8totheCBDrejectedcallstoregulateGURTsbasedonacase-by-caseriskassessmentapproach(DecisionVIII/23ofCOP8).Rather,partieswereurgedto“continuetoundertakefurtherresearch[...]ontheimpactsofgeneticuse-restrictiontechnologies, includingtheirecological,social,economicandculturalimpacts,particularlyonindigenousandlocalcommunities”.Moreneedstobeknownabout GURTs and their potential value in developing containment strategies forsyntheticbiology.

5.8 Policy and regulatory strategies related to public and stakeholder dialogue

[For this paper, we define ‘stakeholders’ as organised representatives of particularconstituencies with shared interests and/or values. This includes trade bodiesrepresenting companies, patient groups representing sufferers from particulardiseases,andNGOs involved inadvocacy related tohealthorenvironmental risks.Theterm‘public’referstocitizensactingasindividualswhomayormaynothaveaninterestinsyntheticbiologyanditsproducts.]

Aprominent themeat the IRGCworkshoponsyntheticbiologywas the ‘fearof thefearofthepublic’–aconcernamongthoseworkingonsyntheticbiologythatthekindofpublicresponsetoGMcropsthatemergedinEuropeinthelate1990swouldbetransferred,perhapsinamorevirulentform,tosyntheticbiology.Sincethe1990stherehavebeenmajor improvementsinengagementapproaches[DietzandStern,2008;EPA,2001].However, it isstillchallengingtofindwaysofreconcilingfundamentallyconflictingvaluesorideologies[Tait,2001].Also,wheretherearestrongdifferencesofopinionattheoutsetofadebate,itishardtomanagetheprocessinsuchawayastoavoidfurtherpolarisationofviewsandexacerbationofconflict[Sunstein,2009].

For some of the potential risks of synthetic biology, technological means to assure safety may be more appropriate than setting up a new regulatory system or extending an existing one

A prominent theme at the IRGC workshop on synthetic biology was the ‘fear of the fear of the public’


P 38

Ontheotherhand,workshopparticipantsalsoexpressedthehopethatsomeofthecharacteristicsandpotentialapplicationsofsyntheticbiologywouldenableittoavoidtheideologicallymotivatedrejectionthatwas,andstillis,aprominentpartofEuropeanopposition to GM organisms. For example, it would be desirable to move from aparadigminwhichinnovativetechnologiesaresimplyeitherrejectedoracceptedtoaformofpartnershipthatguidesdevelopment,suchasoccursbetweenpatientgroupsandpharmaceuticalcompaniesinthedevelopmentofnewdrugs.

Researchinsyntheticbiologyisthuslikelytoproceedwithinacontextofopendialogueaboutitspotentialbenefitsanditssocial,economicandethicalimplications,atatimewhenalloftheseoutcomeswillstillbehighlyuncertain.Thisraisesquestionsofhowand when to incorporate stakeholder concerns into decision-making about futuredevelopments, what power and influence state and non-state actors (both expertand lay) shouldhave, andhowwidely thedialogueshouldbe framed.On this lastpoint,thereisaneedtopromoteunderstandingnotjustofthescienceandtechnologyinvolved but also of the processes of innovation and technology development, therelevantregulatoryregimes,andhowtheyinteractwithoneanother.Abroaderframingof public and stakeholder engagement is thus required that includes debate aboutthesesocioeconomicissues.

Thisisacomplextask,butthatinitselfcouldencouragenewformsofcommunicationanddisseminationthatreachbeyondthetraditionallydidacticapproachesofthe‘publicunderstandingofscience’.Someofthebasicscientificissuesindesignandbiosafetyhavealreadybeenpresentedincomic-stripform[Endyetal.,2005];thereisalsonowawealthof experience that canbe tapped inexploring the interactionsof science,technology, policy and society using theatre, enactments and structured debate, inareassuchasclimatechange,sustainability,healthandgenetics(see,forexample,http://www.wellcome.ac.uk/Funding/Public-engagement/Funded-projects/Profiles/index.htm;http://www.kandu-arts.com/).

Innovation-related dialogue or engagement is particularly difficult, however, whenthereisignoranceoruncertainty among all parties involvedabouttheeventualnatureofnewproducts,processes,benefitsandrisks.Insuchcases,thewaythetechnologyanditsapplicationsareframedcanbehighlyspeculative,andthereisthedangerofdebating illusoryrisksbasedonassumptionsandpreconceptionsmore thanonthedirectionstheresearchisactuallytaking(compare,forexample,earlydiscussionsofself-replicating‘nanobots’,dubbed‘greygoo’,innanotechnology,whichwereneveranexplicitorimmediatelyfeasibleobjective).

Publicandstakeholderengagementactivitiescouldbeviewedintwostages:

A structured dialogue between risk assessors, scientists, regulators and the•full range of stakeholders to identify relevant developments, evaluate theappropriateness of current risk assessment and regulatory frameworks, anddiscusspotentialriskmanagementoptionsandtheirinteractionswithtechnologydevelopmentasabasisonwhichtobuildriskgovernancestrategies.

It would be desirable to move from a paradigm

in which innovative technologies are

simply either rejected or

accepted to a form of partnership

that guides development


P 39

Theknowledgebasefromtheaboveprocesswouldinformawiderdialogueand•engagementwithcitizensandstakeholdersaboutemergingapplications,makingjudgementsonabroadbasisrelatedtoperceivedbenefitsandrisks.

Asnotedabove,engagementanddialoguecanleadtopolarisationofviewsandmoreentrenchedconflictratherthanconsensus,andpolicymakersmightconsiderwhetherclear‘rulesforengagement’shouldbeestablished[Tait,2009b],forexampleonthestandards of quality and breadth of evidence considered and thewillingness of allparticipantstolistentoandrespecteachothers’views.Polarisationofviewsismuchless likely tooccurwhereallsides inadebatehaveacommoninterest inreachingconsensusandwillaccommodatetheneedsandinterestsofothersinordertoreachthat consensus: compare, for example, the discussions that regularly take placebetweenpatientgroupsanddrugdevelopers.

Dialoguearoundsharedinterestscouldleadtomorecreativeregulatorysolutionsthattakeintoaccountpublicdemandsandexpectationsbutarenotdominatedbytheviewsofvocalminoritiesorthedegreeofactivismandpoliticalinfluencethatstakeholdersareabletomobilise.Ultimately,thepolicyaimshouldbetoenablepeople,organisations,policymakers and governments tomake informed choiceswithin the constraints ofeffectiveregulatorysystems,andtoavoidtheimpositionofasinglesetofvaluesthatunnecessarilyconstrainstheopportunitiesavailabletosocietyatlarge.

Engagement and dialogue can lead to polarisation of views and more entrenched conflict rather than consensus, and policymakers might consider whether clear ‘rules for engagement’ should be established


P 40

AsnotedintheIntroduction,policymakersandregulatorscanincreasinglybeseenasshapingratherthanreactingtoinnovativescienceandtechnology.Withthisinmind,we propose the following guidelines that should help policymakers and regulatorsavoid future risk governance deficits in research and technology development andpublicandstakeholderengagement.

Thefirstsetofguidelinesrelatesparticularlytoresearchandtechnologydevelopment;thesecondtostakeholderengagement;andthethirdtosystemicinteractionsacrossinnovation,governanceandstakeholderconstituencies.TheguidelinesrelatetotheriskgovernancedeficitsidentifiedinSection4andarebasedonabroadunderstandingofdevelopments insyntheticbiology, includingdiscussionsat IRGCworkshopsandwithawiderangeofexpertsinthisarea.

Wehaveaimedtomaintainbalance,tobaseriskgovernanceasfaraspossibleonevidenceofharm,andtoaccommodatethevaluesandinterestsofallsocietalgroups,maximisingthescopeforchoiceamongarangeof technologyoptions.Wewant tohelppolicymakersavoidirrevocablecommitmentstoparticularformsofregulationthatwillthemselvesleadtoriskgovernancedeficitsinthefuture.

6.1 Guidelines relevant to research and technology development

6.1.1 Biosecurity risksGuideline1Developandimplementinternationallystandardisedproceduresandpreferredpracticesformitigating biosecurity risks as awhole, and in particular for screening requeststo commercial companies to supply gene sequences; and create an international,systemicallyorganisedapproachtopromotinga‘cultureofresponsibility’,backedupbylegalmechanisms,alongwithsurveillanceandintelligenceondeliberatethreats.

Guideline2In assigning hazard and containment levels tomicro-organisms, consider both theproperties of the parent organism (as in current provisions) and the nature of themodification, recognising that sufficiently extensivemodificationmight result in theparentorganismnolongerbeingtheappropriatepointofreference.

Guideline3Conduct regular reviews of biosafety standards in synthetic biology laboratories toidentifydifferencesbetweenmandatedandactuallaboratorypractice.

Guideline4Avoidimposingrestrictionsonresearchersthatwould,inthelongrun,inhibitsociety’scapacitytorespondbothtonaturalandtointentionalbiosecuritythreats;andsupporttheuseofsyntheticbiologytodevelopimproveddiseasediagnosticsandvaccinesasameansofcombatingillicituseofthistechnology.

6. Guidelines – Avoiding future risk governance deficits for synthetic biology

Policymakers and regulators

can increasingly be seen as

shaping rather than reacting to

innovative science and technology


P 41

Guideline5For researchers working in synthetic biology who do not have previous training inbiosafety: establish a dialogue on the nature of responsible conduct in this field,and provide education about experimental risks, including biosafety principles andpractices.

6.1.2 Choosing an appropriate regulatory precedentGuideline6For products arising from first-generation synthetic biology, choose the mostappropriate regulatoryprecedent (e.g., forvaccines,diagnostic techniques,biofuelsorplants)andavoidreinforcingregulatorysystemsthatmostimportantstakeholderscurrentlyfindinadequate.Thiswillentailcarefulevaluationoftheextenttowhichsuchregulatory frameworksare transferable tonewproducts fromsyntheticbiology,andof the implicationsof such choices for futuredevelopment options.Aim touse thisopportunitytoassessandimprovecurrentregulatorysystemsandtopreventpotentialbottlenecksandflawsinexistingmodelsfrombeingreplicatedinnewsystems.

Guideline7Where new organisms capable of autonomous replication are used in productionprocessesorwhere theyarepartofafinalproduct, introducedesignelements thatrestrict as far as possible their ability to survive in a natural environment. In thiscontext,reconsiderthecircumstancesunderwhichtheuseofgeneticuserestrictiontechnologiescouldbedevelopedwithintheconstraintssetupbytheConventiononBiologicalDiversity.

6.1.3 Balancing transparency and confidentiality Guideline8Ensure that intellectual property rights claims cannot be used to restrict access toinformationneededforeffectiveriskregulation.

6.1.4 The need for flexibility in the face of unexpected outcomesGuideline9Inthefaceofuncertaintyaboutfuturerisks,ensureflexibilityinallinterimregulatoryinitiatives, and include proposals for adaptation and revision on the basis of newevidence.

6.2 Guidelines relevant to public and stakeholder engagement

Guideline10Developbetterprocedures to involveabalanced rangeofstakeholders indialogueaboutnewdevelopmentsinsyntheticbiology,includingscientists,companymanagers,interestgroups(forexample,patientsandfarmers),NGOsandcitizens.Inadditionto


P 42

dialoguewithpublicgroupsmotivatedbysharedvalues,ensurethatequalprominenceis given to groups with interests in the development of technology – for example,relevantpatientgroupsindrugdevelopment.

Guideline11Inadditiontotheusualfocusonthescienceandrisksofpotentialproducts,includeinthedialoguediscussionaboutinnovationandregulatoryprocessesandhowthesecansafeguardagainstfuturerisks(sothat,forexample,the‘slipperyslope’argumentthatextrapolatesintoanimaginarylandscapeofrisksandfearscannotbeusedtosupportundulyrestrictiveprohibitionsatanearlystage).

6.3 Systemic guidelines

Guideline12Encourageunderstandingamongallrelevantactorsoftheinteractionsbetweenriskgovernance,regulation,marketpracticesandinnovationsystemssothatpolicymakersmight aim to achieve a balanced resolution of various trade-offs, for example byexplainingtherisksofnotdoingaswellasofdoing.Wherethedevelopmentofcertainproducts(suchasnewdrugs)carriesastrongpotentialsocialbenefit,considerusingpolicyincentives,suchasmarketmechanisms,infrastructureinvestmentorregulatory‘fasttracks’,toavoidunnecessarydelaysongroundsofrisk.

Guideline13Allowregulatory frameworksscope foradaptability tonewknowledgeand technicalcapability, while recognising the danger of irreversible harms that could not beredressedbyfutureadjustments.

Guideline14Support international dialogue on regulatory oversight and the development ofinternationallyapplicableprinciples,particularlyinrelationtobiosafetyandbiosecurityrisks.An importantpartof thisprocesswillbe tosupport thegrowthofknowledge,infrastructureandimplementationcapacityindevelopingcountries.


P 43

Synthetic biology offers the potential to help us both further our understanding ofnaturalbiologicalsystemsandalsodevelopnewbiologically-basedsystemstotacklepressingenvironmentalandpublichealthneeds.Inordertorealiseitsfulleconomicand social potential, the field needs to be subject to partnershipsand internationalcollaborations between technology developers, policymakers, regulators and publicandstakeholdergroups.

Credible,effectiveandappropriategovernancesystemsareakeypartofensuringthatthebenefitsofsyntheticbiologyare realisedwhileminimising risks.Todevisesuchsystems, policymakers need tomakedecisions that balance potential benefits andharmsinthefaceofuncertaintyabouttheeventualnatureofproductsandprocesses.WehopetheseGuidelineswillhelptoidentifyandpromotepoliciesandpracticesthatassureresponsibleconductofresearchandinnovationinthefield.

Conclusion


P 44

[Antunesetal.,2006]Antunes,M.S.,Ha,S.B.,Tewari-Singh,N.,Morey,K.J.,Trofka,A.M.,Kugrens,P.,Deyholos,M.andMedford,J.I.,Asyntheticde-greeninggenecircuitprovidesareportingsystemthatisremotelydetectableandhasare-setcapacity,Plant Biotechnology Journal4,605-622

[ArkinandFletcher,2006]Arkin,A.P.andFletcher,D.A.,Fast,cheapandsomewhatincontrol,Genome Biology7(114)http://genomebiology.com/2006/7/8/114

[Ball,2005]Ball,P.,Syntheticbiologyfornanotechnology,Nanotechnology16,R1-R8

[BalmerandMartin,2008]Balmer,A.andMartin,P.,SyntheticBiology:SocialandEthicalChallenges,http://www.bbsrc.ac.uk/organisation/policies/reviews/scientific_areas/0806_synthetic_biology.pdf

[Barrettetal.,2006]Barrett,C.L.,Kim,T.Y.,Kim,H.U.,Palsson,B.Ø.andLee,S.Y.,Systemsbiologyasafoundationforgenome-scalesyntheticbiology,Current Opinion Biotechnology17,1–5

[Benensonetal.,2004]Benenson,Y.,Gil,B.,Ben-Dor,U.,Adar,R.andShapiro,E.,Anautonomousmolecularcomputerforlogicalcontrolofgeneexpression, Nature429,423-429

[Bennett,etal.,2009]Bennett,G.,Gilman,N.,Stavrianakis,A.andRabinow,P.,Fromsyntheticbiologytobiohacking:areweprepared?,Nature Biotechnology 27,1109-1111

[Bhattacharjee,2007],Bhattacharjee,Y.,Gene-synthesiscompaniesjoinforcestoself-regulate,Science316,1682

[Bourzac,2009]Bourzac,K.,BiofuelPlantOpensinBrazil:Amyris’slarge-scaledemonstrationplantwillmakedieselfromsugarcane,Technology Review,July9,2009http://www.technologyreview.com/business/22976/?nlid=2164

[Breithaupt,2006]Breithaupt,H.,Theengineer’sapproachtobiology,EMBO Report,7(1)21-23

[Butleretal.,2004]Butler,T.,Lee,S.-G.,Wong,W.W.C.,Fung,E.,Connor,M.R.andLiao,J.C.,Designofartificialcell–cellcommunicationusinggeneandmetabolicnetworks,Proceedings of the National Academy of Sciences of the USA,101,2299-2304

[ByersandCasagrande,2010]Byers,J.andCasagrande,R.,TheRegulationofSyntheticBiology:AConciseGuidetoU.S.FederalGuidelines,RulesandRegulations,April2010

[Campos,2009]Campos,L.,Thatwasthesyntheticbiologythatwas,In:SyntheticBiology:TheTechnoScienceanditsSocietalConsequences,SchmidtM.,KelleA.,Ganguli-MitraA.anddeVriendH.(eds),Heidelberg,Springer,5-21

[Carlson,2010]CarlsonR.,BiologyisTechnology,Cambridge,MA,HarvardUniversityPress

[Caruso,2008]Caruso,D.,SyntheticBiology:Anoverviewandrecommendationsforanticipatingandaddressingemergingrisks,Science Progress,Nov12,2008,http://www.scienceprogress.org/2008/11/synthetic-biology/

[Cello,etal.,2002]Cello,J.,Paul,A.V.andWimmer,E.,ChemicalSynthesisofPolioviruscDNA:GenerationofInfectiousVirusintheAbsenceofNaturalTemplate,Science 297,1016-1018

[Chinetal.,2003]Chin,J.W.,Cropp,T.A.,Anderson,J.C.,Zhang,Z.andSchultz,P.G.,Anexpandedeukaryoticgeneticcode,Science301,964-967

[Church,2005]Church,G.,Letusgoforthandsafelymultiply,Nature 438,423

[Deamer,2005]Deamer,D.,Agiantsteptowardsartificiallife?,Trends in Biotechnology23,336–338

References and bibliography

http://www.bbsrc.ac.uk/organisation/policies/reviews/scientific_areas/0806_synthetic_biology.pdf


P 45

[deVriend,2006]deVriend,H.,Constructinglife:earlysocialreflectionsontheemergingfieldofsyntheticbiology,TheHague,TheNetherlands,RathenauInstitute

[DFG,2009]DeutscheForschungsgemeinschaft,SynthetischeBiologie:Stellungnahme,July2009http://www.dfg.de/download/pdf/dfg_im_profil/reden_stellungnahmen/2009/stellungnahme_synthetische_biologie.pdf

[DHHS,2010]USDepartmentofHealthandHumanServices,ScreeningFrameworkGuidanceforProvidersofSyntheticDouble-Stranded DNA, October 2010 http://www.phe.gov/Preparedness/legal/guidance/syndna/Documents/syndna-guidance.pdf

[DietzandStern,2008]Dietz,R.andStern,P.C.(eds),PublicParticipationinEnvironmentalAssessmentandDecisionMaking,Committeeon theHumanDimensionsofGlobalChange(CDGC),NationalResearchCouncilof theNationalAcademies,WashingtonDC,NationalAcademiesPress

[Elowitz andLeibler, 2000]Elowitz,M.B. andLeibler,S.,A synthetic oscillatory networkof transcriptional regulators,Nature403,335-338

[Endy,2005]Endy,D.,Foundationsforengineeringbiology,Nature438,449–453

[Endy et al., 2005] Endy, D., Deese, I. andWadey, C.,Adventures in synthetic biology, http://openwetware.org/wiki/Adventures

[EPA, 2001] Environmental Protection Agency, Improved Science-based Environmental Stakeholder Processes, USEnvironmentalProtectionAgencyScienceAdvisoryBoard,WashingtonDC,EPA-SAB-EC-COM-1-006,Oct,2001,www.epa.gov/sab

[ETC,2010]TheNewBiomassters:SyntheticBiologyandtheNextAssaultonBiodiversityandLivelihoods,ETCGroupCommuniqué104,Montreal,October,http://www.etcgroup.org/en/node/5232

[EuropeanCommission,2008]EuropeanCommission,CommissionRecommendationof7February2008onacodeofconductforresponsibleNanosciencesandnanotechnologiesresearch,OfficialJournaloftheEuropeanUnion,L116/46;April30,2008

[European Commission, 2009] European Commission, Ethics of Synthetic Biology, Opinion of the European GrouponEthics inScienceandNewTechnologies to theEuropeanCommission,No25,Nov17,2009;http://ec.europa.eu/european_group_ethics/docs/opinion25_en.pdf

[FAS,2010]FederationofAmericanScientists,BroadConsensusonGeneSynthesisGuidelines,http://www.fas.org/blog/ssp/2010/01/broad-consensus-on-gene-synthesis-guidelines.php

[Friendsof theEarth,2010]Friendsof theEarth,SyntheticSolutions to theClimateCrisis:TheDangersofSyntheticBiologyforBiofuelsProduction,September2010,http://www.foe.org/healthy-people/synthetic-biology

[Gaisser, et al., 2008]Gaisser, S., Reiss, T., Lunkes,A.,Müller, K., Bernauer, H., TESSYAchievements and FuturePerspectives inSynthetic Biology:TESSYFinalReport, http://www.tessy-europe.eu/public_docs/TESSY-Final-Report_D5-3.pdf

[Gardneretal.,2000]Gardner,T.S.,Cantor,C.R.andCollins,J.J.,ConstructionofagenetictoggleswitchinEscherichia coli’,Nature403,339-342

[Garfinkel,etal.,2007]Garfinkel,M.S.,Endy,D.,Epstein,G.L.andFriedman,R.M.,SyntheticGenomics:Options forGovernance,Rockville,MD, J.CraigVenter Institute,WashingtonDC,Center forStrategic and InternationalStudies;Cambridge,MA,MassachusettsInstituteofTechnology

http://openwetware.org/wiki/Adventures

http://ec.europa.eu/european_group_ethics/docs/opinion25_en.pdf

http://www.fas.org/blog/ssp/2010/01/broad-consensus-on-gene-synthesis-guidelines.php

http://www.tessy-europe.eu/public_docs/TESSY-Final-Report_D5-3.pdf


P 46

[Georgescuetal.,2008]Georgescu,C.,Longabaugh,W.J.R.,Scripture-AdamsD.D.,David-Fung,E-S.,Yui,M.A.,Zarnegar,M.A.,Bolouri,H.,andRothenberg,E.V.,AgeneregulatorynetworkarmatureforTlymphocytespecification,Proceedings of the National Academy of Sciences of the USA,105,20100-20105

[Gibsonetal.,2008]Gibson,D.G.etal.,Completechemicalsynthesis,assembly,andcloningofaMycoplasma genitalium genome, Science319,1215-1220

[Gibsonetal.,2010]Gibson,D.G.etal.,Creationofabacterialcellcontrolledbyachemicallysynthesizedgenome,Science329:52-56

[Glassetal.,2006]Glass,J.I.,Assad-Garcia,N.,Alperovich,N.,Yooseph,S.,Lewis,M.R.,Maruf,M.,Hutchison,C.A.,Smith,H.O.andVenter,J.C.,Essentialgenesofaminimalbacterium’,Proceedings of the National Academy of Sciences of the USA,103,425-430

[Glass,etal.,2007]Glass,J.I.,Smith,H.O.,HutchinsonIII,C.A.,Alperovich,N.Y.,Assad-Garcia,N.(Inventors);J.CraigVenterInstitute,Inc.(Assignee),Minimalbacterialgenome,USpatentapplication20070122826

[Hayden, 2009] Hayden, E.C., Keeping genes out of terrorists’ hands, Nature 461, 22 http://www.nature.com/news/2009/090831/full/461022a.html

[HellerandEisenberg,1998]Heller,M.andEisenberg,R.,CanPatentsDeterInnovation?Theanticommonsinbiomedicalresearch,Science280,698-701

[HenkelandMaurer,2009]Henkel,J.andMaurer,S.M.,Parts,property,andsharing,Nature Biotechnology 27,1095-1098

[Hessetal.,2001]Hess,H.,Clemmens,J.,Qin,D.,Howard,J.andVogel,V.,Light-controlledmolecularshuttlesmadefrommotorproteinscarryingcargoonengineeredsurfaces,Nano Letters1,235-239

[IASB,2009]InternationalAssociationforSyntheticBiology,IASBCodeofConductforBestPracticesinGeneSynthesis,Cambridge,MA.,Nov3,2009

[Ideker,2004]Ideker,T.,Systemsbiology101-whatyouneedtoknow, Nature Biotechnology22,473-475

[IRGC,2005]InternationalRiskGovernanceCouncil,WhitePaperofRiskGovernance–TowardsanIntegrativeApproach,http://www.irgc.org/IMG/pdf/IRGC_WP_No_1_Risk_Governance__reprinted_version_.pdf

[IRGC,2007]InternationalRiskGovernanceCouncil,NanotechnologyRiskGovernance:recommendationsforaglobal,coordinatedapproachtothegovernanceofpotentialrisks,http://www.irgc.org/IMG/pdf/PB_nanoFINAL2_2_.pdf

[IRGC,2008]InternationalRiskGovernanceCouncil,SyntheticBiology:RisksandOpportunitiesofanEmergingField,http://www.irgc.org/IMG/pdf/IRGC_ConceptNote_SyntheticBiology_Final_30April.pdf

[IRGC,2009a]InternationalRiskGovernanceCouncil,RiskGovernanceDeficits:Ananalysisandillustrationofthemostcommondeficitsinriskgovernance,http://www.irgc.org/IMG/pdf/IRGC_rgd_web_final.pdf

[IRGC,2009b]InternationalRiskGovernanceCouncil,RiskGovernanceofSyntheticBiology,http://www.irgc.org/IMG/pdf/IRGC_Concept_Note_Synthetic_Biology_191009_FINAL.pdf

[IRGC, 2009c] International Risk Governance Council, Appropriate Risk Governance Strategies for NanotechnologyApplicationsinFoodandCosmetics,http://www.irgc.org/IMG/pdf/IRGC_PBnanofood_WEB.pdf

[Kitano,2002]Kitano,H.,Systemsbiology:abriefoverview,Science295,1662-1664

http://www.nature.com/news/2009/090831/full/461022a.html

http://www.irgc.org/IMG/pdf/IRGC_Concept_Note_Synthetic_Biology_191009_FINAL.pdf


P 47

[Kool,2002]Kool,E.T.,ReplacingthenucleobasesinDNAwithdesignermolecules, Accounts of Chemical Research,35,936-943

[LaBeanetal.,1999]LaBean,T.H.,Winfree,E.andReif,J.H.,Experimentalprogressincomputationbyself-assemblyofDNAtilings,DNA Based Computers5,123-140

[Lartigueetal.,2007]Lartigue,C.etal.,Genometransplantationinbacteria:changingonespeciestoanother, Science 317,632-638

[Ledford,2010]Ledford,H.,Gene-synthesisrulesfavourconvenience, Nature467,898

[Lowrie,2010]Lowrie,H.,BalancingBenefitsandRisksofSyntheticBiology,Action Bioscience,Oct2010http://www.actionbioscience.org/newfrontiers/lowrie.html

[Luisi,2006]Luisi,P.L.,TheEmergenceofLife:FromChemicalOrigins toSyntheticBiology,Cambridge,CambridgeUniversityPress

[Luisietal,2006]Luisi,P.L.,Ferri,F.andStano,P.,Approachestosemi-syntheticminimalcells:areview,Naturwissenschaften 93,1–13

[Maoetal.,2003]Mao,C.,Flynn,C.E.,Hayhurst,A.,Sweeney,R.,Qi,J.,Georgiou,G.,Iverson,B.andBelcher,A.M.,Viralassemblyoforientedquantumdotnanowires, Proceedings of the National Academy of Sciences of the USA,100,6946-6951

[Martin et al., 2003]Martin, V. J. J., Pitera,D. J.,Withers, S.T., Newman, J. D. andKeasling, J. D., Engineering amevalonatepathwayinEscherichiacoliforproductionofterpenoids,Nature Biotechnology21,796-802

[MontclareandTirrell,2006]Montclare,J.K.andTirrell,D.A.,Evolvingproteinsofnovelcomposition,Angewandte Chemie International Edition,45,4518-4521

[Mukundaetal.,2009]Mukunda,G.,Oye,K.A.andMohr,S.C.,Whatroughbeast?Syntheticbiology,uncertainty,andthefutureofbiosecurity,Politics and the Life Sciences,28(2)

[NEST,2005]NESTExpertGroup report,SyntheticBiology:ApplyingEngineering toBiology, Luxembourg,Office forOfficialPublicationsoftheEuropeanCommunities

[NEST,2007]NEST,SyntheticBiology:ANESTPathfinderInitiative,Luxembourg,OfficeforOfficialPublicationsoftheEuropeanCommunities,ftp://ftp.cordis.europa.eu/pub/nest/docs/5-nest-synthetic-080507.pdf

[NIHGuidelines,2009]USNationalInstitutesforHealthGuidelinesforResearchinvolvingRecombinantDNAMolecules,http://oba.od.nih.gov/rdna/rdna.html

[NoireauxandLibchaber,2004]Noireaux,V.andLibchaber,A.,Avesiclebioreactorasastep towardanartificialcellassembly,Proceedings of the National Academy of Sciences of the USA,101,17669-17674

[NSABB,2006]NationalScienceAdvisoryBoardforNationalSecurity,AddressingBiosecurityConcernsRelatedtotheSynthesisofSelectAgents

[Nurton,2009]Nurton,J.,WhatRaisingtheBarMeansattheEPO,ManagingIntellectualProperty,http://www.managingip.com/Article/2309678/What-raising-the-bar-means-at-the-EPO.html

[OECD,2009a]OrganisationforEconomicCo-operationandDevelopment,TheBioeconomyto2030:designingapolicyagenda,http://www.oecd.org/futures/bioeconomy/2030

http://www.managingip.com/Article/2309678/What-raising-the-bar-means-at-the-EPO.html


P 48

[OECD,2009b]OrganisationforEconomicCo-operationandDevelopment,PolicyBrief:Improvingthequalityofregulations,http://www.oecd.org/dataoecd/5/0/44124554.pdf

[OyeandWellhausen,2009]Oye,K.A.andWellhausen,R.inM.Schmidt,A.Kelle,A.Ganguli-MitraandH.deVriend(eds),SyntheticBiology:TheTechnoscienceanditsSocialConsequences,Heidelberg,Springer

[Peters,2002]Peters,T.,PlayingGod?:GeneticDeterminismandHumanFreedom,NewYork,Routledge

[Pleiss,2006]Pleiss,J.,Thepromiseofsyntheticbiology,Applied Microbiology and Biotechnology,73,735-739

[Pollack,2001]Pollack,A,Scientistsarestartingtoaddletterstolife’salphabet, New York Times,July24,2001

[POST, 2008] POST, Postnote: Synthetic Biology (Number 298), London, The Parliamentary Office of Science andTechnology,http://www.parliament.uk/documents/upload/postpn298.pdf

[RaiandBoyle,2007]Rai,A.andBoyle,J.,Syntheticbiology:caughtbetweenpropertyrights,thepublicdomain,andthecommons,PLoS Biology5(3),e58

[Rodemeyer,2009]Rodemeyer,M.,NewLife,OldBottles:Regulatingfirst-generationproductsofsyntheticbiology,http://www.synbioproject.org/process/assets/files/6319/nano_synbio2_electronic_final.pdf

[Rothemund,2006]Rothemund,P.W.K.,FoldingDNAtocreatenanoscaleshapesandpatterns,Nature440,297-302

[Royal Academy of Engineering, 2009] Royal Academy of Engineering, Synthetic Biology: Scope, applications andimplications,http://www.raeng.org.uk/news/publications/list/reports/Synthetic_biology.pdf

[RoyalSociety,2008]RoyalSociety,Syntheticbiology:policyissues,http://royalsociety.org/News.aspx?id=5989

[RoyalSociety,2009]RoyalSociety,NewApproachestoBiologicalRiskAssessment,http://royalsociety.org/WorkArea/DownloadAsset.aspx?id=6457

[SantaCruzetal.,1996]SantaCruz,S.,Chapman,S.,RobertsA.G.,Roberts I.M.,PriorD.A.M.andOparkaK.J.,Assembly andmovement of a plant virus carrying a green fluorescent protein overcoat,Proceedings of the National Academy of Sciences of the USA,93,6286-6290

[Sarikayaet al., 2003]Sarikaya,M.,Tamerler,C., Jen,A.K.-Y.,Schulten,K. andBaneyx,F.,Molecular biomimetics:nanotechnologythroughbiology,Nature Materials,2,577-585

[ScientificAmerican,2009]Opinion:ASeedyPractice, Scientific American,301,28

[Schmidt,2009a]Schmidt,M.,DoIUnderstandWhatICanCreate?Safetyissuesinsyntheticbiology,inM.Schmidt,A.Kelle,A.GanguliandH.deVriend(eds),SyntheticBiology:TheTechnoScienceanditssocietalconsequences,Heidelberg,Springer,81-100

[Schmidt,2009b]Schmidt,M.(ed.)Systems and Synthetic Biology3,1-4,SpecialIssue:SocietalAspectsofSyntheticBiology

[Seeman,2003]Seeman,N.C.,DNAinamaterialworld,Nature,421,427-431

[Soongetal.,2000]Soong,R.K.,Bachand,G.D.,Neves,H.P.,Olkhovets,A.G.,Craighead,H.G.andMontemagno,C.D.,Poweringaninorganicnanodevicewithabiomolecularmotor,Science,290,1555-1558

[StojanovicandStefanovic,2003]Stojanovic,M.N.andStefanovic,D.,Adeoxyribozyme-basedmolecularautomation,Nature Biotechnology,21,1069-1074


P 49

[Stone,2006]Stone,M.,Liferedesignedtosuittheengineeringcrowd,Microbe,1,566-570http://forms.asm.org/ASM/files/ccLibraryFiles/Filename/000000002705/znw01206000566.pdf

[Sunstein,2009]Sunstein,C.R.,GoingtoExtremes:howlikemindsuniteanddivide,Oxford,OxfordUniversityPress

[Szostaketal,2001]Szostak,J.W.,Bartel,D.P.andLuisi,P.L.,Synthesizinglife,Nature,409,387-390

[Tait,2001]Tait,J.,MoreFaust thanFrankenstein: theEuropeandebateabout risk regulation forgeneticallymodifiedcrops,Journal of Risk Research,4(2),175-189

[Tait,2007]Tait,J.,SystemicInteractionsinLifeScienceInnovation,TechnologyAnalysisandStrategicManagement,19(3),257-277

[Tait,2009a]Tait,J.,Governingsyntheticbiology:Processesandoutcomes,inM.Schmidt,A.Kelle,A.GanguliandH.deVriend(eds),SyntheticBiology:TheTechnoScienceanditsSocietalConsequences,Heidelberg,Springer,141-154 [Tait,2009b],Tait,J.,UpstreamEngagementandtheGovernanceofScience:Theshadowof thegeneticallymodifiedcropsexperienceinEurope,EMBO Report,10,S18-S22

[Tirrelletal.,1991]Tirrell,D.A.,Fournier,M.J.andMason,T.L.,Geneticengineeringofpolymericmaterials,MRS Bulletin,July,23

[US National Security Council, 2009] National Security Council, National Strategy for Countering Biological Threats,November23,2009http://www.whitehouse.gov/sites/default/files/National_Strategy_for_Countering_BioThreats.pdf

[VandenBelt,2009]VandenBelt,H.,PlayingGodinFrankenstein’sfootsteps:syntheticbiologyandthemeaningoflife,Nanoethics,3,257-268

[WagnerandMcHughen,2010]Wagner,R.andMcHughen,A.,ZerosenseinEuropeanapproachtoGM,EMBO Reports,11,258-262

[Wangetal.,2001]Wang,L.,Brock,A.,Herberich,B.andSchultz,P.G.,ExpandingthegeneticcodeofEscherichiacoli,Science,292,498-500

[Whaleyetal.,2000]Whaley,S.R.,English,D.S.,Hu,E.L.,Barbara,P.F.andBelcher,A.M.,Selectionofpeptideswithsemiconductorbindingspecificityfordirectednanocrystalassembly,Nature,405,665-668

[Wield,2008]Wield,D.,TheESRCCentreforSocialandEconomicResearchonInnovationinGenomics(Innogen),5:3SCRIPTed589,http://www.law.ed.ac.uk/ahrc/script-ed/vol5-3/innogen.asp

[Withers and Keasling, 2007]Withers, S. T. and Keasling, J. D., Biosynthesis and engineering of isoprenoid smallmolecules,Applied Microbiology and Biotechnology,73,980-990

[Youetal.,2004]You,L.,Cox,R.S.,Weiss,R.andArnold,F.H.,Programmedpopulationcontrolbycell–cellcommunicationandregulatedkilling’,Nature,428,868-871

Note:Allwebsiteslastaccessed22December2010

http://forms.asm.org/ASM/files/ccLibraryFiles/Filename/000000002705/znw01206000566.pdf


P 50

Acknowledgements

ThispolicybriefhasbeenwrittenforIRGCbyHeatherLowrie,PhDcandidate,andJoyceTait,InnogenScientificAdvisor,bothat theESRCCentre forSocialandEconomicResearchon Innovation inGenomics,UniversityofEdinburgh,UK.

Theauthorshavebenefittedfromadviceandinputfromanumberofdedicatedindividualsinvolvedinthisprojectandparticipants inthetwoworkshopsinJune2008andOctober2009.IRGCisverygrateful toparticipantsforcontributingtheirtimeandsharingtheirexpertiseandthoughtsduringandaftertheworkshops.Theirfeedbackandothercommentsreceivedhavebeenofsignificantassistanceforwritingthispolicybrief.AdditionalcontributionstothispublicationandtotheprojectasawholehavebeenmadebymembersofIRGC’sScientificandTechnicalCouncil (S&TC)and theSecretariat.Furthermore, thepolicybriefwas further improved througha revisionandupdatingin2010bysciencewriterPhilipBall.

IRGC’spolicyrecommendationsarepublishedonlyafterarigorousexternalpeer-reviewprocess.KennethOye,AssociateProfessorofPoliticalScienceandEngineeringSystems,MassachusettsInstituteofTechnology(MIT),US,acted,onbehalfofIRGC’sS&TC,asreviewcoordinator.CommentsandcritiqueswerereceivedfromWarnerNorth, President, NorthWorks, andmember of IRGC’s S&TC; LawrenceMcCray, Researcher, Knowledge andDecisionMaking,MIT;andArthurPetersen,MethodologyandModellingProgramme,NetherlandsEnvironmentalAssessmentAgency.

Finally,thisIRGCprojectandPolicyBriefwouldnothavebeenpossiblewithoutthegeneroussupportofIRGC’sdonors,includingtheSwissStateSecretariatforEducationandResearch,theSwissAgencyforDevelopmentandCooperation,theGovernmentofQuebec,AlpiqGroup,SwissReinsuranceCompanyandOliverWymanInc.


P 51

The International Risk Governance Council (IRGC)isanindependentorganisationbasedinSwitzerlandwhosepurposeistohelpimprovetheunderstandingand governance of emerging, systemic global risks.It does this by identifying and drawing on scientificknowledge and the understanding of experts inthe public and private sectors to develop fact-based recommendations on risk governance forpolicymakers.

IRGCbelievesthatimprovementsinriskgovernanceareessentialifwearetodeveloppoliciesthatminimiserisksandmaximisepublic trustandeffectiveness intheprocessesandstructuresofrisk-relateddecision-making.AparticularconcernofIRGCisthatimportantsocietalopportunitiesresultingfromnewtechnologiesarenotlostthroughinadequateriskgovernance.

MembersoftheFoundationBoard

CharlesKleiber(Chairman),FormerStateSecretaryfor Education and Research, Swiss FederalDepartmentofHomeAffairs,Switzerland;JohnDrzik (Vice-Chairman),PresidentandCEO,OliverWyman,USA;Pierre Béroux, Electricité de France, France(until 31.12.2010); Walter Fust, Former Head ofSwissDevelopmentCooperation,Switzerland;JoséMarianoGago,MinisterforScience,TechnologyandHigher Education, Portugal; Philippe Gillet, Vice-PresidentandProvost,FederalInstituteofTechnology(EPFL)Lausanne,Switzerland(from01.01.2011);C. Boyden Gray, Gray & Schmitz LLP, USA;DonaldJ. Johnston, Former Secretary-General, OECD,1996-2006 (until 31.12.2010); Wolfgang Kröger (IRGC Founding Rector), Director, Laboratory forSafetyAnalysis,SwissFederalInstituteofTechnologyZurich (ETH), Switzerland (until 31.12.2010); Liu Yanhua,Counsellor,Counsellors’OfficeoftheStateCouncil, People’s Republic of China;MichelMaila,President,MIGEMConsulting Inc.,Toronto,Canada(from 01.01.2011); Christian Mumenthaler, ChiefMarketing Officer Reinsurance and Member of theExecutiveCommittee,SwissReinsuranceCompany,Switzerland; L. Manning Muntzing, EnergyStrategistsConsultancyLtd,USA(until31.12.2010);Michael Oborne, Director, International FuturesProgramme, OECD, France (from 01.01.2011);Rajendra Pachauri, Chairman, IntergovernmentalPanel on Climate Change (IPCC) and Director-General,TheEnergy andResources Institute, India(until 31.12.2010);MargaretaWahlström,Assistant

Secretary-General, Special Representative of theSecretary-General forDisasterRiskReduction (UN-ISDR),Switzerland(from01.01.2011).TheOECDhasobserverstatus.

MembersoftheScientificandTechnicalCouncil

Prof. M. Granger Morgan (Chairman), Head,Department of Engineering and Public Policy,Carnegie Mellon University, USA; Dr V. S.Arunachalam, Chairman and Founder, Center forStudy of Science, Technology and Policy, India; Prof. Fabiana Arzuaga, Professor of Regulationof Biotechnology and Patent Law, Faculty of Law,University of Buenos Aires, Argentina; Dr LutzCleemann, Senior Adviser, Sustainable BusinessInstitute,Germany;DrAnnaGergely,Director,EHSRegulatory,Steptoe&Johnson,Belgium;DrJohnD.Graham, Dean, IndianaUniversity School of PublicandEnvironmentalAffairs,USA;Prof.ManuelHeitor,Secretary of State for Science, Technology andHigher Education, Portugal;Prof. CarloC. Jaeger,Head,SocialSystemsDepartment,PotsdamInstituteforClimate ImpactResearch (PIK),Germany;Prof.WolfgangKröger(IRGCFoundingRector),Director,Laboratory for Safety Analysis, Swiss FederalInstitute of Technology (ETH) Zurich, Switzerland;Jeffrey McNeely, Senior ScientificAdvisor, IUCN -The InternationalUnion forConservation ofNature,Switzerland; Dr Stefan Michalowski, Head of theSecretariat, Global Science Forum, OECD, France;DrWarner North, President, NorthWorks Inc., andConsulting Professor, Department of ManagementScienceandEngineering,StanfordUniversity,USA;Prof. Norio Okada, Director, Disaster PreventionResearch Institute, Kyoto University, Japan; Prof.KennethOye,AssociateProfessor,PoliticalScienceandEngineeringSystems,MassachusettsInstituteofTechnology(MIT),USA;Prof.OrtwinRenn,Professorfor Environmental Sociology, University of Stuttgart,Germany; Prof. Úrsula Oswald Spring, ResearchProfessor, Regional Centre of MultidisciplinaryResearch,NationalUniversityofMexico,Mexico;Prof.JoyceTait,InnogenScientificAdvisor,ESRCCentreforSocial andEconomicResearchon Innovation inGenomics,UK;DrTimothyWalker,Chair,Accountingand Actuarial Discipline Board, Financial ReportingCouncil,UK;Prof.XueLan,Dean,SchoolofPublicPolicyandManagement,TsinghuaUniversity,People’sRepublicofChina.

About IRGC



Chemin de Balexert 91219 ChâtelaineGeneva Switzerland

tel +41 (0)22 795 17 30fax +41 (0)22 795 17 39

[email protected]

© International Risk Governance Council, Geneva, 2010

ISBN 978-2-9700672-6-9