Controlling Dangerous Pathogens: A Prototype Protective Oversight System

Elisa  Harris

Advancements in the field of biological research are moving faster now than ever before. At the same time, these biological innovations have a ‘dual use’ potential of which researchers may not be aware. While on the one hand they may provide solutions to many of the world’s problems, on the other hand they may potentially be abused, mishandled or used for hostile purposes. As a result of these possible ‘dark’ uses of biotechnology, it is imperative that a dynamic international regime be put in place to meet, in a comprehensive manner, the multi-layered aspects of the new security challenges that biological advances now pose. The current international regime, led by the Biological and Toxin Weapons Convention (BTWC), has succeeded in setting normative standards governing non use by states of biological weapons in warfare. However, these shall soon be insufficient to cope with the rapid and momentous changes expected in the field of biotechnology in this century. The new regime must bring together the fields of industry, science and various non-governmental organisations (NGOs) to build together an effective web of response to the dark potentialities of biotechnology advances. Such a web implies a network of different solutions and organisations to tackle the problem. Indeed, there is no one single ‘magic’ solution to combating the multi-faceted nature of biological research advances, and the coordinated international response must reflect this.

A major consideration in Bio security and Bio defence is whether fungi should be excluded from the US government select agents list and other similar documentation. The mortality of spontaneous fungal infection is indeed low, but it is not an important factor for weaponizing a pathogen. The disruptive effect may be the true aim. Low contagiousness of fungi is also desirable to restrict the infection to the intended targets, while simplifying recruitment and training, and the handling of the device. Spore-generating fungi are easier to weaponize than bacteria, the natural occurring forms of which are not readily suitable for weaponization. As technology progresses, the genetic manipulation is not just to augment a microbe’s pathogenicity. Once such procedures are established, the microbe is not the weapon, but the vector for a preferably allogenic toxin or bio regulator. Τhe suitability formula proposed for calculating the Weapon Potential of a microbe includes vital parameters such as inoculum size, contagiousness, stability of the agent, inoculation time but others, with operational significance, such as undetectability, availability of medical countermeasures and circumstantial suitability are not mentioned at all. Such pitfalls should be addressed if the formula is to assist decision-makers to focus their vigilance according to available intelligence.

In light of the quandaries presented by domestic law, has the Biological Weapons Convention of 1972 (“BWC”) also been so outpaced by the technologies that it is no longer effective and meaningful in international law? Part II will examine the continuum of official actions that have attempted to keep pace with the growing biotechnologies that may present threats to global biosecurity through interpreting the BWC. Part III looks at how these definitions may not be sufficient. Finally, Part IV looks at other mechanisms that may provide a better way of controlling biological weapons than redefining the technologies through the current processes.

Controlling Dangerous Pathogens A Prototype Protective Oversight System John Steinbruner Elisa D. Harris Nancy Gallagher Stacy M. Okutani Controlling Dangerous Pathogens A Prototype Protective Oversight System John Steinbruner Elisa D. Harris Nancy Gallagher Stacy M. Okutani The Center for International and Security Studies at Maryland Advanced Methods of Cooperative Security Program The University of Maryland College Park, Maryland March 2007 Acknowledgements This monograph is the product of an intensive effort by a diverse group of scientists, public policy experts, and lawyers to grapple with the many challengesposedbyadvancedbiotechnology. Weareparticularlygratefulto Ron Atlas, Rocco Casagrande, Nancy Connell, Malcolm Dando, Christopher Davis,NeilDavison,RichardEbright,GeraldFink,AlexGreninger,GigiKwik Gronvall,PeterJahrling,CarlKaysen,BarryKellman,ShanLu,AlanPearson, Jens Kuhn, Piers Millett, Kathryn Nixdorff, Janet Peterson, David Sabatini, RichardSpertzel,RobSprinkle,MarkWheelis,andSimonWhitbywhohave contributed enormously to our deliberations through their working papers or presentationsatprojectworkshopsintheUnitedStates.Theirparticipationand our acknowledgement does not imply that they endorse the arguments we advance.Somehavemajordisagreements. Similarly, wealsohavebenefited greatlyfrom thepresentations givenat our regionalworkshopsbyOttorinoCosivi,MariaEspona,RobertoFernandez,Jozef Furesz, Joxel Garcia, Walter Mendoza, Roque Monteleone-Neto, Kathryn Nixdorff,DavidSawaya,KarlSimpson,SimoneScholze,GeoffreySmith,Mario Soberon,andAnaMariaTapajos.Specialmentionshouldalsobemadeofthe in-countryassistanceprovdedbyLajosRozsaandJackWoodallinorganizing ourregionalworkshops. Wealsoappreciatethetimemanyotherindividuals havedevotedtoattendingprojectworkshopsorconsultingwithusonspecific aspectsoftheproject. AlistofindividualswhohaveparticipatedinoneormoreoftheU.S.-based workshops can be found at Appendix A. A list of individuals who have participated in our regional workshops can be found at Appendix B. Again, inclusionontheselistsshouldnotbetakenasanindicationthattheindividual endorses the ideas outlined herein. Special thanks are also owed to Tim Gulden,JasonHarenski,JessicaMannMcCormick,andGordonMcMillanfor theirworkonourprototypedatamanagementsystemandtoMarcCaplan,Paula Harrison, Andrea Hoshmand, Jennifer Lindsey, Robert Maly, Katie Swanson, andMargotSiemerforoutstandingresearchandadministrativesupport. Wewouldespeciallyliketoacknowledgethefinancialandintellectualsupport of the Alfred P. Sloan, Ford, and John D. and Catherine T. MacArthur Foundations without which this exploration of the problem of controlling dangerouspathogenswouldnothavebeenpossible. Table of Contents Acknowledgements...................................................................................................i TableofContents.................................................................................................. iii Introduction .............................................................................................................1 ContextoftheProblem...........................................................................................3 CurrentStateofOversight ......................................................................................9 InternationalControls .........................................................................................9 USControls ......................................................................................................11 UKControls......................................................................................................15 SmallpoxResearch............................................................................................18 ExistingArrangementsandtheBRSS..............................................................19 ElementsofaPrototypeOversightSystem..........................................................21 DefiningResearchofConcern..........................................................................21 SystemArchitecture..........................................................................................26 PrinciplesandElements................................................................................27 InformationDisclosure .................................................................................29 InstitutionalArrangements............................................................................32 ComplianceandVerification........................................................................35 TheSysteminPractice.....................................................................................37 InstitutionalReview–ActivitiesofPotentialConcern ...............................39 NationalReview–ActivitiesofModerateConcern....................................40 InternationalReview–ActivitiesofExtremeConcern...............................42 TheWayForward .................................................................................................45 ConcludingObservations ......................................................................................49 AppendixA:US-BasedProjectWorkshopParticipants ......................................51 AppendixB:RegionalWorkshopParticipants .....................................................57 AppendixC:PrototypeDataManagementSystem:Overview ............................61 AppendixD:PrototypeLicensingQuestionnaire .................................................67 AppendixE:PrototypeProjectQuestionnaires ....................................................71 EndNotes..............................................................................................................79 iv ControllingDangerousPathogensReport .......... Introduction ..... Ashasbecomeincreasinglyevidentinrecentyears,advancesinbiologyare posing an acute and arguably unprecedented dilemma. The same basic sciencethatcouldinprinciplebehighlybeneficialcouldalsobeenormously destructive,dependingonhowitisapplied.Althoughthescopeofactual consequenceremainsuncertain,thepotentialisclearlyextraordinarywiththe healthofindividuals,thestabilityofsocietiesandtheviabilityoftheglobal ecologyallapparentlyatstake. Since compelling good and appalling harm cannot be disentangled at the leveloffundamentalscience,aburdenofmanagementisbeingimposedthat humaninstitutionsarenotcurrentlypreparedtohandle.Thedilemmaitself hasbeenexemplifiedinseveralwidelynotedexperiments1andprofessionally acknowledgedinreportsissuedbytheUnitedStatesNationalAcademiesof Science (NAS) and by the British Royal Society.2 Not surprisingly, however,andperhapsinevitably,effortstodeviseaneffectiveresponseare stillatanembryonicstage. Theproposalsseparatelyadvancedbythetwo scientific societies are directed at their own communities and are largely voluntaryincharacter.Thosearenaturalinitialsteps butwouldnotaloneproviderobustglobalprotection. Inanefforttoencourageproductivediscussionofthe problem and its implications, this monograph discusses an oversight process designed to bring independent scrutiny to bear throughout the world withoutexceptiononfundamentalresearchactivities thatmightplausiblygeneratemassivelydestructiveor otherwise highly dangerous consequences. The suggestionisthatamandatory,globallyimplemented processofthatsortwouldprovidethemostobvious meansofprotectingagainstthedangersofadvances in biology while also pursuing the benefits. The underlying principle of independent scrutiny is the centralmeasureofprotectionusedinotherareasof majorconsequence,suchasthehandlingofmoney, anditisreasonabletoexpectthatprinciplewillhave tobeactivelyappliedtobiologyaswell. The monograph outlines an advanced oversight arrangement, provisionally labeled the Biological ResearchSecuritySystem(BRSS),whichisdesigned to help prevent destructive applications of biology, whetherinadvertentordeliberate. Thearrangement is put forward with full realization that meaningful The suggestion is that a mandatory, globally implemented process of this sort would provide the most obvious means of protecting against the dangers of advances in biology while also pursuing the benefits. ControllingDangerousPathogensReport 1 protectioncanonlybeachievedbyimposingsomeconstraintonfreedomof actionattheleveloffundamentalresearch,whereindividualautonomyhas traditionallybeenhighlyvaluedforthebestofreasons. Constraintsofany sort on research will not be intrinsically welcome and will have to demonstratethattheprotectionprovidedjustifiesthecostsentailed.Agreat deal of conceptual innovation, legal specification, institutional design and politicalaccommodationwouldadmittedlyberequiredtoestablishsuchan oversightprocess,andthereisverylittleprecedenttoworkwith. Because of the demands imposed and the inconvenience involved, the monograph concedes that human societies after due reflection might choose at least initiallytoacceptlesserstandardsofprotectionanditdiscussesmorelimited incremental measures that might be undertaken. The centralcontention, however,isthattheeventualoutcomeshouldbe afullyconsideredchoice andnotthedefaultresultofinertiaorneglect. 2 ControllingDangerousPathogensReport .......... Context of the Problem ..... Becausethepotentialconsequencesofadvancedbiologyaresoextraordinary, the problems of management posed are arguably becoming one of the most consequential problems of public policy ever encountered. Knowledge of fundamental life processes has progressed to the point that extensive human interventioninthecourseofnaturalevolutionhasapparentlybecomefeasible, notonlytodetermineparticularoutcomesbuttoredirecttheprocessitself.One cancrediblyimaginetheeradicationofanumberofknowninfectiousdiseases. One can also credibly imagine the deliberate or inadvertent creation of new pathogensdramaticallymoredangerousthanthosethathavenaturallyevolved. Onecansimilarlyimagineboththerapeuticanddestructiveapplicationsaffecting basicfeaturesofcognitive,emotional,andreproductiveactivity. Hundredsof millions of lives might be enhanced, salvaged, manipulated, degraded, or terminateddependingonhowthesamebasicknowledgeisapplied. Littleof thatpotential has yet been accomplished but none of it can be dismissed as fantasy. Unfortunately,thecapacitytoalterbasiclifeprocessesisnotremotelymatched bythecapacitytounderstandtheextendedimplications. Fortheforeseeable future, moreover, that imbalance is much more likely to accelerate than to diminish. Itisnotrealistictoexpectthatthecurrentmomentuminmolecular biology, in particular, will extend to the many other disciplines necessary to assesstheconsequencesfortheevolutionaryprocessasawhole. Asaresult, thehumanspeciesisrelentlesslyacquiringpowerfarin excess of its vision and this is thereby posing monumental problems of prudential judgment – problems that society is not yet conceptually or The human species institutionally equipped to handle. Those are the stark factsofthesituation. is relentlessly Admittedly,factsofthatcharacterandmagnitudearenot readily absorbed. They are being explored by some groups,buttheinstitutionsthatwouldberesponsiblefor managingtheproblemhavenotseriouslyacknowledged the situation nor fathomed the implications. They are understandablyreluctanttoadmitproblemstheydonot knowhowtosolve,particularlyiftherequirementsare asextensiveandasradicalastheyappeartobeinthis case. The dominant inclination is to reduce even the most monumental questions to terms that can be managed by gradual adjustment. It is reasonable to assumethatcurrentmanagementofadvancedbiologyis in the early stages of such a process. It is also reasonable to assume that the adjustment eventually required will be much more extensive than currently admittedandthescheduleonwhichitoccursmorerapid. acquiring power far in excess of its vision and this is thereby posing monumental problems of prudential judgment. ControllingDangerousPathogensReport 3 It is important that those who are willing to assume that much begin to anticipatetheinnovationslikelytobenecessary. In current public discussion of the subject, fear of terrorism has been a particularlyprominenttheme,especiallyintheUnitedStatesintheaftermathof the 2001 anthrax letters. That concern reflects a circumstance of obvious importance. Anyindividualororganizationdedicatedtodestructionbutonly capableofundertakingsmall-scaleoperationsmightplausiblychooseadvanced biologyastheinstrumentofchoice.Thereisnoindicationthatanyonehasever attemptedwantondestructionofthatsort,andtherewouldbeveryappreciable practical difficulties and risks involved. Nonetheless, an attack with an especially virulent pathogen might in principle induce a disease epidemic sufficient to disorganize an entire society or degrade an entire economy. Otherwise a clandestine operation could only accomplish genuinely massive social destruction by the use of nuclear explosives, and the fissile material required is currently much more elaborately protected than are pathogens. Biotechnology is one of only two technologies that truly deserve the label “agentofmassdestruction”anditisbyfarthemoreaccessibleofthetwo. For all its current prominence, the threat of bio-terrorism, including statesponsoredterrorism,isnottheexclusiveoreventheprimarysourceofdanger. Asapracticalmatter,terroristorganizationsbytheirnatureareforcedtoevade detection and thus cannot independently generate the fundamental science requiredtoperpetrateactsofmassdestruction–asdistinctfromactsofmass sensation. Thebasicknowledgerequiredwouldhavetobeextractedfromthe legitimate research community, and the people involved would have to have been trained within thatcommunity.Atthemomentthereisverylittle …protective standards organized protection against the diversion of legitimate science to malicious purpose; more robustprotectioncanbeandalmostcertainlywill will have to be be devised. In so doing, it will be necessary to addressthedeeperproblemofinadvertence. developed for their own sake within the legitimate research community. That is the first, most important and most promising line of defense against deliberate maliciousness. 4 ControllingDangerousPathogensReport Preciselybecausetherateofdiscoveryinbiology is far outrunning the more integrated science requiredtoassesstheextendedsocialeffects,there is considerable danger that legitimate scientists pursuing compelling research ideas will initiate chainsofconsequencetheycannotvisualizeanddo not intend. The extensive and necessarily open process of medical and agricultural research is regularly producing results that are compellingly beneficial but that also, as an unavoidable byproduct, could be exceedingly dangerous. Given thatsituation,protectivestandardswillhavetobe developedfortheirownsakewithinthelegitimate research community. That is the first, most important and most promising line of defense against deliberate maliciousness. If that line of defense is not constructed, nothing else will be effectiveandliterallyeveryoneincreasinglywillbe indanger. The relevant biomedical research community is very extensive and globally distributed.Morethanamillionscientificarticlesarepublishedeveryyearand seminal results are generated in all parts of the world. Information flows rapidly among leading-edge scientists and knowledge of fundamental developmentsalsotransfersrapidlytothoseintraining.Giventhatsituation,it seems obvious that adequate measures of protection against the misuse of biological research would have to be devised globally, not just for academic researchers but also for those working in commercial and government labs. However, current regulation of advanced biology is conducted primarily by national governments and is principally concerned with the localized containment of dangerous pathogens, the safety of research personnel, the treatmentofresearchanimals,andthepreparationofdistributedproductssuch as drugs and vaccines. As discussed below, there have been as yet only embryoniceffortstoorganizeprudentialjudgmentattheoutsetoffundamental researchregardingtheextendedimplicationsoftheknowledgetobegenerated. Thelegitimatefearofinterferingwiththeprocessofscientificdiscoveryhas minimizedoversightatthatstage.Moreover,inareasconsideredtoberelevant to weapons application, national governments have imposed security classificationandareactivelyexploringthedestructiveapplicationofbiology under the justification of “threat assessment.” That practice is intensifying suspicionamongthemanygovernmentsalreadyinclinedtobesuspiciousofone another. Particularly in the United States, reaction to the 2001 terrorist events has stronglyreinforcedtheinstincttofocusonnationalresponses. Newterrorism legislation adopted in May 2002 imposed registration requirements on individuals and institutions that possess selected pathogens declared to be dangerous,undertermsthathavemadenationalidentityamajorcriterionfor access. The fact that registration requirements would have to be globally enactedtobeeffectiveappearstohavereceivednoconsideration. Therehas alsobeenadramaticincreaseinUSgovernmentfundingforbio-terrorismand bio-defenseresearch,withlittlerecognitionoftheneedtoaccompanythateffort with a protective oversight process. Bioterrorism funding at the National InstitutesofHealth(NIH),forexample,hasgrownfromamodest$53million in fiscal year 2001 to $1.9 billion (requested) in fiscal year 2007.3 The Department of Homeland Security is also playing a leading role in this area, establishing,aspartofitsmulti-milliondollarNationalBiodefenseAnalysisand Countermeasures Center (NBACC), a new Biothreat Characterization Center (BTCC) to conduct studies and experiments to better understand current and futurebiological threats.4 The mission of NBACC is “to provide the nation with the scientific basis for awareness of biological threat and attribution of theiruseagainsttheAmericanpublic”by:   Understanding current and future biological threats, assessing vulnerabilities, and determining potential impacts to guide the developmentofbiodefensecountermeasures;and, Providing national capability to conduct forensic analysis of evidence from bio-crimes and terrorism to attain a “biological fingerprint” to identifyperpetratorsanddeterminetheoriginandmethodofattack.5 ControllingDangerousPathogensReport 5 ConstructionofanewfacilityforNBACCatFt.DetrickbeganinJune2006. The 160,000 square foot facility will house the Biological Threat CharacterizationCenterandtheNationalBioforensicAnalysisCenter(NBFAC). Itwillincludeover70,000squarefeetoflaboratoryspace,20%ofwhichwill bebuilttoBL-4standards. Thisrelianceonnationalmeasureswasalsoreflectedinthe2001USdecision, over broad international objection, to block efforts to develop a compliance protocol for the Biological Weapons Convention (BWC). Within the current administration especially, the largely implicit but powerfully entrenched assumptionsarethatthedangerderivesmainlyfromhostileforeignsourcesand thatitcanbemanagedprimarilybycontrollingaccesstodangerouspathogens themselves. Understandableandperhapsinevitableasthatreactionmaybein politicalandemotionalterms,itishighlydysfunctionalintermsofscientific realityandwillalmostcertainlyintensifytheunderlyingperil. Acollisionbetweenattitudeandcircumstanceisafamiliarhumandrama.Itis unusuallypronouncedinthiscasebutnotunique. Overthelongertermitis reasonable to expect that circumstances as compelling as those biology is creating will eventually conquer even the most recalcitrant attitudes, but obviouslytherearemajorquestionsastohowsoonthatmighthappenandin what manner. Although dysfunctional attitudes are often abandoned only in reaction to compellingly painful experience, one cannot responsibly wait for suchexperienceinthiscase. Thosewhoareabletounderstandthesituation clearlyhavesomeresponsibilitytovisualizeanappropriateresponse.Although theconsequencesofadvancesinbiologymightturnouttobelessdramaticthan theycurrentlyseem,itisnonethelessnecessarytoexploretheimplicationsof current projections. Since that exploration will require very extensive, very demanding, and doubtless time-consuming discussion, it is quite important to begin. The basic method of protective oversight will have to be based on systematic information disclosure and informed peer review. In broad outline the requirements of managing advanced biology are not difficult to discern. The hard part, actually, is taking the problem seriously enough to be willing to examine the fairly obvious answer. It can be presumed that inherently dangerous areas of biological research will have to be subjected to a much more systematic process of protective oversight than is yet practiced in any country. That will have to be done globallyandthereforewillhavetobegloballyformulated andgloballyimplemented.Thebasicmethodofprotective oversightwillhavetobebasedonsystematicinformation disclosureandinformedpeerreview.Inareasofresearch capableofhavingmassiveconsequence,itistrulyavital matter to bring independent, adequately informed, and broadlyrepresentativescrutinytobear. Noindividualor research team, however competent, honorable, and patriotic,shouldcarrytheburdenorbegiventheauthority tomakeresearchdecisionsthatmightputanappreciable fractionofthehumanspeciesasawholeatriskwithout subjectingthemselvestoindependentoversightinadvance andthroughoutthecourseoftheirwork. 6 ControllingDangerousPathogensReport Thejudgmentsrequiredinsuchanoversightprocesscannotbeentirelyderived from any set of general guidelines, although common risk-benefit assessment criteriawouldbeanessentialfeatureoftheprocess.Validjudgmentsaboutthe balanceofbenefitandriskinanyspecificinstancecanonlybemadeindetailed contextbypeoplecapableofunderstandingboththescientificissuesinquestion and the social consequences. That implies a broadly representative group, includingscientists,securityandpublichealthexpertsandpublicrepresentatives notdirectlyinvolvedintheresearchinquestion. Theywouldhavetooperate through oversight bodies of extraordinary, indeed unprecedented, credibility. That credibility would have to be established not only by the quality of the individuals but also by a highly refined specification and limitation of their powers. The oversight system would be tiered, matching the degree of risk with the information disclosure and review requirements. In the prototype Biological ResearchSecuritySystemoutlinedinthispaper,localoversightbodieswouldbe chargedwithreviewingresearchprojectsofpotentialconcernbeingproposedby licensedresearchersworkingatlicensedfacilities. Suchresearchencompasses thoseactivitiesthatmayincreasethedestructivepotentialofbiologicalagents that otherwise would not be considered a threat. National oversight bodies wouldberesponsibleforresearchactivityofmoderateconcern,suchaswork withanthraxandotheragentsalreadyidentifiedashavingbiologicalweapons potential. Boththelocalandnationaloversightbodieswouldoperateonthe basis of internationally agreed standards. An international body would be chargedwithapprovingandmonitoringallresearchprojectsofextremeconcern. Thatauthoritywouldbenarrowlyfocusedonlyonthoseresearchactivitiesthat couldputanappreciablefractionofthehumanspeciesatrisk,suchaswork with smallpox or a yet more lethal contagious pathogen. Ultimately, the oversight process would have to be extended beyond individual projects involving consequential work with pathogens to address broader advances in immunologyandneurobiology,forexample,whichmayhavelittletodowith pathogens. Biological Research Security System International Oversight Activities of Extreme Concern National Oversight Activities of Moderate Concern Local Oversight Activities of Potential Concern No Oversight All Other Research ControllingDangerousPathogensReport 7 Theseoversightprovisionshavesomeprecedentincurrentnationalregulatory practice. Theentirearrangementconstitutedonaninternationalbasishasno close precedent, however, and there are many people who would summarily declareittobeimpossible. Perhapsintheenditwillbe,butinthatcasethe consequencesarelikelytobeverydireindeed. Ifoneisdeterminedtobea hardheaded realist in this situation, it is prudent to anticipate some response commensuratewiththemagnitudeofwhatisatstake. Protectiveoversightis the prime candidate. Whatever the eventual outcome, it will have to be seriouslyexplored. 8 ControllingDangerousPathogensReport .......... CCurrent State of Oversight ..... Various treaties, laws, regulations, and other legal and political instruments governthehandlinganduseofpathogens. Fewofthesecontrolsaddressthe researchprocessitself,andfewerstillrequireanindependentevaluationofthe possiblesecurityandpublichealthconsequencesofagivenbiologicalresearch project beforetheworkisundertaken.Thissectionlooksatsomeofthemore important oversight arrangements –ontheinternationallevel,withintheUS, withintheUK,andasregardsthespecialcaseofsmallpoxresearch–interms of their scope, limitations, and potential relevance to a future Biological ResearchSecuritySystem. InternationalControls The most significant development in the history of international efforts to preventthemisuseofbiologyforhostilepurposeswastheconclusionofthe 1972 Biological Weapons Convention, which prohibits the development, production, and possession of biological agents or toxins for other than prophylactic, protective or other peaceful purposes. The BWC imposes no limits, however, on research involving biological agents and contains no provisionsforverifyingcompliancewithitsobligations.Inanefforttohelpfill these gaps, BWC States Parties agreed at past treaty review conferences that certainopen-airtestsfallwithinthescopeoftheBWC’sprohibitionsandthat basicresearchinthebiologicalsciencesshouldgenerallybeunclassified.They alsoadoptedaseriesofconfidence-buildingmeasuresrequiringtheexchangeof informationonspecifictypesofbiologicalresearchactivitiesandfacilities. Asnotedabove,effortstomovebeyondthesepoliticallybindingarrangements towardamorerobust,legallybindingBWCcomplianceprotocolcollapsedin 2001,withtheUScitingconcernsaboutthepotentialimpactoftheproposed declaration and inspection measures on confidential business and national security information. Although both the European Union (EU) and many moderate non-aligned (NAM) countries believed that the draft protocol contained adequate provisions for protecting such sensitive information, the Bushadministrationdisagreed,andscuttledtheprotocolbecauseofthisissue. TheothermajorstumblingblockwastheNAM’sinsistenceontechnicaland economicassistance,includingtheeffortsofsometotrytousetheprotocolto eliminateexistingcontrolsontheexportofbiological-relatedmaterials. Tohelpfillthevoidleftbythefailureoftheprotocolnegotiations,BWCStates Parties agreed in November 2002 to a new process, whereby one experts meeting and one political meeting would be held each year to discuss and promote common understandingand effective actiononcertainagreedissues. AttheinsistenceoftheUS,howevereachexpertsmeetingwasonlytwoweeks longandeachpoliticalmeetingaweek.Inaddition,participantswerelimitedto ControllingDangerousPathogensReport 9 exchanging information on the agreed topics and had no decisionmaking authority. In2003,StatesPartiesdiscussednationalimplementinglegislation and the security and oversight of pathogens. In 2004, they focused on the issues of disease surveillance and investigations of alleged use of biological weapons and suspicious outbreaks of disease. In 2005, scientific codes of conductwerediscussed.Thesemeetingshelpedkeeptheissueofstrengthening the BWC on the international agenda and encouraged States Parties to share informationabouttheirnationalactivitiesineachoftheseareas.Butbecauseof thelimitationsplacedontheprocessbytheUS,noguidelinesorbestpractices couldbeagreedandrecommendedforadoptionbyStatesParties. At the Sixth Review Conference in December 2006, States Parties agreed to holdanewroundofannualexpertsandpoliticalmeetingsbetween2007and 2010. Of particular importance are the topics to be considered in 2008: national, regional and international measures to improve biosafety and biosecurity;andoversight,education,andothermeasuresaimedatpreventing the misuse of advances in the biosciences and biotechnology research. Unfortunately,thetimefortheexpertsmeetingontheseissueswashalved,from twoweekstoone.Moreover,theUSagainrejectedeffortstogivetheseintersessionalmeetingsdecisionmakingauthority,thusraisingquestionsabouttheir ultimateimpact.6 Otherinternationalinstrumentsalsohavebeenadoptedtodealwithconcerns about the environmental and public health implications of advances in biotechnology,inparticular.7In1992,aCodeofConductfortheReleaseof OrganismsintotheEnvironmentwasdevelopedbytheUnitedNationsIndustrial DevelopmentOrganization(UNIDO).8TheUNIDOCode,whichisvoluntaryin nature, called for the establishment of national risk assessment and decisionmakingstructurestoprovidescientificjudgmentsconcerningtheuseandrelease of genetically modified organisms (GMOs). It also called for linking safety precautionsandmonitoringarrangementstothelevelofassessedrisk,basedon thebiologicalpropertiesoftheorganismandthereceivingenvironment.Under the1992BiodiversityConvention,countriesarelegallyrequiredtoregulatethe useandreleaseofgeneticallymodifiedorganismsthatcouldhaveanadverse impactonbiodiversityandtoprovideinformationontheirregulationstoother StatesPartiestowhomsuchorganismsarebeingtransferred.9TheInternational TechnicalGuidelinesforSafetyinBiotechnology,whichwereadoptedbythe United Nations Environment Programme (UNEP) in December 1995, also emphasizetheimportanceofeffectiveoversightofactivitiesinvolvingorganisms with novel traits. Under the UNEP Guidelines, such oversight is defined as includingriskassessment,disclosureofrelevantinformationandcarefulrecord keeping. It can also include prior notification of certain contained uses and releasesoforganismswithnoveltraitsandpriorapprovalbyrelevantnational authorities.10 Finally, the World Health Organization published the first edition of its Laboratorybiosafety manualin1983toprovideguidancetocountriesonthe safehandlingofpathogenicmicroorganisms. Athirdeditionwaspublishedin 2004thatincludednewsectionsonbiosecurity,riskassessments,andthesafe useofrecombinantDNAtechnology.11 10 ControllingDangerousPathogensReport USControls Asontheinternationallevel,bothsecurityconsiderationsandenvironmentaland public health concerns have shaped US policy on the handling and use of dangerouspathogens. PriortotheconclusionoftheBWC,PresidentRichard Nixondecided,in1969,thattheUSshouldunilaterallyrenouncethepossession of biological weapons and confine the US biological weapons program to researchanddevelopmentfordefensivepurposesonly. Butthispolicy,which is still in effect, permits research into those offensive aspects of biological agents necessary to determine defensive requirements, thus underscoring the difficultiesofdistinguishingbetweenlegitimateandillegitimateactivitiesinthis area.12 Over the past decade, a variety of measures have also been adopted to strengthencontrolsonaccesstodangerouspathogens.UndertheAntiterrorism andEffectiveDeathPenaltyActof1996,anyfacilityinvolvedinthetransferof a “selectagent”fromalistofhumanpathogensdevelopedbytheCentersfor DiseaseControlandPrevention(CDC)mustregisterwithCDCandnotifyitof allproposedtransfers.13Intheaftermathoftheanthraxletters,newlegislation was adopted in October 2001 prohibiting the knowing possession of any biological agent, toxin or delivery system that is not reasonably justified for prophylactic, protective, bona fide research, or other peaceful purposes. The law,knownastheUSAPatriotActalsomakesitacrimeforcertainrestricted persons,includingillegalaliensandindividualsfromterrorist-listcountries,to possess,transport,orreceiveselectagents.14 In May 2002, additional bio-terrorism legislation extended the registration requirement for facilities that transfer select agents to include facilities that possess select agents as well. Under the Public Health Security and BioterrorismPreparednessandResponseActof2002,governmentbackground checksarerequiredforanyonethatistobegivenaccesstoselectagents. In addition,theDepartmentofHealthandHumanServices(HHS)isrequiredto develop a national database of registered persons and the select agents they possess,includingstrainandothercharacterizinginformationifavailable,andto carryoutinspectionsofrelevantfacilities. TheUSDepartmentofAgriculture (USDA)isrequiredtodevelopparallelregistration,security,recordkeeping,and inspection measures for facilities that transfer or possess specific plant and animalpathogens.15Underthefinalregulationstoimplementthelegislation,all affectedfacilitiesarealsorequiredtodevelopabiosafetyplan,drawingonthe biosafety and biosecurity standards for work with pathogens outlined in the CDCmanual,BiosafetyinMicrobiologicalandBiomedicalLaboratories.16 Since 1976, guidelines have been issued by the NIH Recombinant DNA Advisory Committee (RAC) to ensure the safety of research involving recombinant DNA molecules and organisms and viruses containing such molecules. TheoriginalNIHGuidelinesprohibitedsixtypesofexperiments. Over time, however, these prohibitions were replaced by a system of tiered oversightandreview,inwhichInstitutionalBiosafetyCommittees(IBCs)and InstitutionalReviewBoards(IRBs)atindividualfacilitiesdisplacedtheRACas theprimaryoversightauthorityformostcategoriesofregulatedresearch.17 Although the NIH Guidelines formally apply only to research conducted at institutesintheUSandabroadthatreceiveNIHfundingforrecombinantDNA ControllingDangerousPathogensReport 11 research, it is widely believed that many private companies and foreign researchersfollowtheGuidelinesvoluntarily.18A2004studybytheSunshine ProjectofUS-basedIBCs,however,revealedthatscoresofUSbiotechnology companies, including some three dozen companies conducting biodefense researchfortheUSgovernment,hadnoIBCregisteredwithNIHandmanyof theuniversityandotherIBCsthatwereregisteredeitherdidnotmeetorissued blanket approvals ratherthan review each specificproject.19 Nocomparable studyhasbeendoneofUS-basedIRBsandnoneseemslikelygivenprivacy considerations. Nevertheless,federalregulationsgoverningIRBsarefarmore elaboratethanthosethatcurrentlyexistforIBCs,containingnotonlyspecific requirements for IRB approval of human subject research, including for assessingtherisksandbenefitsofsuchresearch,butalsofordocumentingthe resultsofIRBdeliberations. UnderthecurrentNIHGuidelines,onlytwocategoriesoflaboratoryresearch involving recombinant DNA technology require oversight by the NIH itself. The first, “Major Actions,” cannot be initiated without the submission of relevant information on the proposed experiment to the NIH Office of Biotechnology Activities (OBA) and require IBC approval, RAC review, and NIH Director approval prior to initiation. These include experiments that involvethe“deliberatetransferofadrugresistancetraittomicroorganismsthat are not known to acquire the trait naturally if such acquisition could compromisetheuseofthedrugtocontroldiseaseagentsinhumans,veterinary medicine, or agriculture.” The second class of experiments requiring IBC approvalandNIH/OBAreviewpriortoinitiationinvolvesthecloningoftoxin moleculeswithLD50oflessthan100nanogramsperkilogrambodyweight.20 Under the new regulations to implement the May 2002 bioterrorism bill, the SecretaryofHHSmustalsoapproveexperimentsthatfallunderthesecategories if they involve the use of agents or toxins on the select agent list, and the Administrator of USDA’s Animal and Plant Health Inspection Service must approvethemiftheyinvolveagentsortoxinsonUSDA’scontrollists.21Unlike theNIHGuidelines,however,theserequirementsarebothlegallybindingand applytoallentitiesconductingtherelevantresearch,notjusttothosereceiving fundingfromNIHforrecombinantDNAresearch. Other types of research may soon be added to the NIH Guidelines and thus subject to IBC and, in some cases, possibly national-level review. In its October 2003 report, “Biotechnology Research in an Age of Terrorism,”an expert panel convened by the US National Academy of Sciences, under the chairmanship of MIT professor Gerald Fink, recommended giving IBCs responsibility for considering the security implications of seven categories of dual-useresearch.22These“experimentsofconcern,”as theFinkCommittee calledthem,includedthosethatwould: • • • • • • • demonstratehowtorenderavaccineineffective; conferresistancetoantibioticsorantiviralagents; enhancethevirulenceofapathogenorrenderanonpathogenvirulent; increasethetransmissibilityofapathogen; alterthehostrangeofapathogen; enableevasionofdiagnosisordetectionmethods;or enableweaponizationofabiologicalagentortoxin. 12 ControllingDangerousPathogensReport TheFinkCommitteealsorecommendedthedevelopmentofeducationprograms for scientists on the dual-use issue; pre-publication review of manuscripts by scientistsandscientificjournals;enhancedcommunicationbetweenthenational security,lawenforcementandlifesciencescommunityonthreatassessmentand countermeasures development; and international harmonization of efforts to manage the risks from dual-use research. To help guide these efforts, the Committee also called for the establishment of a National Science Advisory BoardforBiodefensewithinHHS. In March 2004, the Bush administration responded to the Fink Committee report, announcing the creation of a new government body to advise US governmentagenciesonhowtoreducetheriskthatlegitimateresearchwillbe misusedforhostilepurposes.23Themainfunctionsofthisnewbody, knownas theNationalScienceAdvisoryBoardforBiosecurity(NSABB),include:         developingcriteriaforidentifyingdual-useresearchandresearchresults; developing guidelines for local (IBC) oversight of dual-use research, includingtherisk/benefitanalysisofsuchresearch; advisingoncriteriaandprocessesforreferringresearchtotheNSABB foradditionalguidance; respondingtorequestsfrominstitutionsforadviceonresearchthathas beendeniedbyanIBC; providingrecommendationsonthedevelopmentofacodeofconductfor scientistsandlaboratoryworkers; providing recommendations on the development of mandatory biosecurityeducationandtrainingprogramsforscientistsandlaboratory workersatfederallyfundedinstitutions; advising on national policies governing the dissemination of research results,includingpublication;and recommendingstrategiesforcoordinatedinternationaloversightofdualuseresearch. Atitsfirstmeeting,attheendofJune2005,theNSABBagreedtoestablish working groups in five initial areas: criteria for dual-use research; communicationofresearchresults;codesofconduct;internationalcollaboration; and synthetic genomics. A sixth working group, on the critical issue of oversightofdual-useresearch,wasnotaddeduntilayearlater.AttheBoard’s July 2006 meeting, the NSABB also approved the initial work done by its criteria, communications, and codes working groups. In all three areas, however,theresultswerelimitedatbest.24Thecriteriaforidentifyingdual-use research of concern, for example, were largely a reformulation of the Fink Committee’sexperimentsofconcern. LiketheFinkCommitteeapproach,the NSABB criteria are too broad, and thus likely to capture a wide swath of research.Thecriteriaalsofocusexclusivelyonresearchactivities,ratherthana combinationofagentsandactivities,andfailtodistinguishbetweenlevelsof risk. Finally,thedefinitionofdual-useresearchofconcernthataccompanies thecriteria–“researchthat,basedoncurrentunderstanding,canbereasonably anticipatedtoprovideknowledge,productsortechnologiesthatcouldbedirectly misapplied by others to pose a threat to public health, agriculture, plants, animals,theenvironment,ormaterial”–bothfailstoconsidertheproblemof inadvertence and requires a judgment about the likelihood that the research resultscouldbemisused. Inshort,theNSABBdraftcriteriaareunlikelyto ControllingDangerousPathogensReport 13 provideanadequatebasisforidentifyingwhetherspecificresearchprojectspose potentialdual-useconcernsandthusshouldbesubjecttoindependentoversight. AttheBoard’sOctober2006meeting,thenewlyestablishedoversightworking group outlineditsinitial ideas.25 Ofparticular interest were thekeyfeatures identified by the working group for the oversight system. They include the following: • • • • institutional review of the scientific, ethical, and possible social consequencesofdual-useresearchandresearchfindings; theuseofriskassessmentandriskmanagementprinciplesinthereview process,withthedegreeofinstitutionaloversightlinkedtotheassessed risk; aprocessforappealingthedecisionsoftheinstitutionalreviewbody; and, thetrainingofscientists,reviewersandotherswhoareinvolvedindualuseresearch. Unfortunately, at least in its initial formulation, the working group suggested that compliance with the oversight system should be mandatory for federally funded institutions but voluntary for others. Classified research already is exempt from the NSABB’s purview by its charter. If research at private companies and other institutions that do not receive federal funding is also exemptedfrommandatoryoversight,thesystembeingproposedbytheNSABB willhavelimitedeffect. Development of Oversight Arrangements in the US 1976 NIH guidelines establish institutional biosafety committees (IBCs) to provide local oversight for recombinant DNA work. The Recombinant DNA Advisory Committee (RAC) at NIH reviews “Major Actions,” including some transfers of drug resistance and the cloning of toxin molecules with an LD50 of less than 100 ng/kg body weight. 1996 Registration requirement and notification to the CDC for any transfer of a human pathogen on the select agent list 2001 Legal prohibition on knowing possession of any biological agent, toxin or delivery system not reasonably justified for prophylactic, protective, bona fide research, or other peaceful purposes. Criminalizes possession and transfer of select agents by restricted persons, including illegal aliens and individuals from terrorist-list countries. 2002 Extension of the registration requirements to facilities that possess select agents. Government background checks required for anyone having access to select agents. HHS required to develop a national database of registered persons and select agents they possess. USDA required to keep similar registration, security, record keeping, and inspection measures for facilities that transfer or possess specific plant and animal pathogens. The Secretary, HHS and Administrator of APHIS (USDA) must approve certain experiments with agents or toxins on the select agent or control list, respectively. 2004 National Science Advisory Board for Biosecurity established to advise US government agencies on how to reduce the risk that legitimate research will be misused for hostile purposes. 14 ControllingDangerousPathogensReport In addition to the NIH Guidelines, there are also a number of other US government regulations concerning the handling or use of pathogens. Even thosethatgovernresearchwithpathogens,however,focusontheirtransferor release rather than laboratory-based activities. For example, under USDA regulations, any person wishing to import, move, or release genetically engineered plant pests within the US must either submit a notification to or obtainapermitfromUSDAbeforeproceedingwiththeproposedactivity. A USDApermitalsoisrequiredfortheimportofmicroorganismsthatcancause infectious, contagious, or communicable diseases in poultry or livestock.26 UnderEnvironmentalProtectionAgency(EPA)regulations,small-scaletestsof certaingeneticallymodifiedmicrobialpesticidesmustbenotifiedto,andreceive approvalfrom,EPA. Anexperimental releaseapplication mustalsobefiled withEPAforcertainresearchanddevelopmentactivitieswithmicroorganisms forcommercialpurposes.27EPAalsoadministerstheNationalEnvironmental Policy Act, under which federal agencies are required to prepare detailed environmental impact statements assessing both the risks of their proposed activities and efforts to mitigate risk through facility design and laboratory practices.28 The US Army also regulates research and other activities with biologicalagentsundertheBiologicalDefenseProgram,requiringaudittrailsof all agent shipments and the use of simulants in all open-air tests unless the SecretaryofDefensedeterminesthattestingwithactualagentsisnecessaryfor nationalsecurityreasons.29 UKControls TheUnitedKingdomhaswhatmaybethemostrobustoversightarrangements inplaceforresearchandotheractivitiesinvolvingpathogens. UnliketheUS, theUKgovernmenthasdirectlegalauthorityoverrelevantresearchanywherein the country, and does not have to rely on funding mechanisms to help bring scientistsintotheiroversightsystems. Following the September 11 terrorist attacks, the UK enacted new antiterrorism-related controls on pathogens similar to those adopted in the US. Under the Anti-Terrorism, Crime and Security Act passed in October 2001, facilitiesthatpossessorplantopossessspecifiedhumanpathogensarerequired to notify the government and to comply with any reasonable security enhancementsthatmaybeimposedafteraninspectionofthesite.Thebillalso requiresfacilitypersonneltocomplywithofficialrequestsforinformationabout securitymeasuresattheirfacilityandaboutpersonswhohaveorareproposed to have access to controlled pathogens. It also contains provisions for backgroundchecksandgivesthegovernmenttheauthoritytodenyindividuals accesstocontrolledpathogensorthefacilitiesinwhichtheyareheld.Thebill allowsbutdoesnotrequirethesamenotificationandotherrequirementstobe extendedtoanimalandplantpathogensandplantpests.TheUKanti-terrorism legislationdoesnot,however,requirepriorreviewofresearchprojectsinvolving thesecontrolledpathogens.30 Since the 1970s, the UK has also established a variety of controls on the handling and use of genetically modified organisms. As with the NIH Guidelines, the UK system was initially voluntary, with the categorization of experimentscoveredbythenotificationguidelinesbroadlysimilartothatinthe ControllingDangerousPathogensReport 15 US.31In1992,anewGeneticallyModifiedOrganisms(ContainedUse)Regulation wasissuedtoimplementthetightercontrolsonGMOsbeingdevelopedinthe European Union (EU). This regulation, as revised in 2000, requires a risk assessmentpriortobeginninganyworkwithageneticallymodifiedorganism and prior notification to UK health authorities of plans to carry out genetic modification work in any facility for the first time.32 The regulation also requiresprior-notificationtolocalgeneticmodificationsafetycommitteesofall butthelowestriskgeneticmodificationwork,withhigherriskresearchrequiring government consent. Prior to the 2001 terrorist attacks, all notifications were maintained in a register open tothe public.33 A separate regulation onthe deliberatereleaseofGMOsissuedin1992andrevisedmostrecentlyin2002 requires government consent before marketing a GMO or releasing such an organism into the environment. The application for consent must include an assessmentoftheenvironmentalriskoftheproposedactivityaswellasdetailed information on the GMO itself, monitoring arrangements and, as appropriate, marketingorreleaseplans.34 Other regulations have been adopted in the UK to implement EU oversight requirementsforhuman,plantandanimalpathogensthatcouldhaveanadverse impact on public health or the environment.35 Under the 1994 Control of SubstancesHazardoustoHealthRegulation,asamendedmostrecentlyin2002, employersmustnotifyUKhealthauthorities30dayspriortostoringorusing certainhumanpathogensforresearchorotherpurposesforthefirsttime.The notificationmustincludeanassessmentoftheriskstoworkerhealthandsafety, informationonthepathogen,andproposedmeasurestoprotectworkerhealth andreducetheriskofexposure.36The1993PlantHealthOrderprohibitsthe import of infected plants or plant pests into the UK for research purposes without a license. The regulation also prohibits the import, movement, or keepingofgeneticallymodifiedplantpestsorgeneticmodificationworkwith plantpestswithoutalicense.37Underthe1980ImportationofAnimalPathogens Order,alicenseisrequiredtoimportananimalpathogenorcarrierintotheUK. The 1993 Specified Animal Pathogens Order, as amended in 1998, requires laboratories and scientific establishments that wish to hold or handle certain pathogensornucleicacidscapableofproducingsuchpathogenstobelicensed. Thepathogenscoveredbythisregulationarethosethatcouldpotentiallycause anepidemicamonglivestock.38 TheUKhasevenmoreextensiveoversightarrangementsforresearchactivities involvinganimals.Underthe1986Animals(ScientificProcedures)Act,acostbenefitanalysis,weighingthepotentialforanimalsufferingagainstthepossible medical benefits, must be done before undertaking any research project involving animals. The Act provides for a triple licensing system of places, projects,andpersonnel.Morespecifically,itrequiresthatanimalresearchtake placeonlyatestablishmentsthathaveappropriateanimalaccommodationand veterinaryfacilities,aspartofanapprovedresearchortestingprogram,andby individuals with sufficient training, experience, and skills. Inspectors visit licensedresearchestablishments,usuallywithoutwarning,anaverageofeleven timesayear. In1998,theexistingoversightarrangementswereexpandedto include a requirement for an ethical review process at all licensed establishments. This process, begun at the conceptual stage of new research projects,aimstoprovidesupportandindependentethicaladviceforlicenseeson potentialissuesconcerningethicsandanimalwelfare. Asof1999,therewere 13,700activepersonallicensesand296facilitylicenses.39 16 ControllingDangerousPathogensReport Development of Oversight Arrangements in the UK 1986 Triple licensing system established for places, projects, and personnel for animal research. Inspection of such licensed research establishments done an average of eleven times per year. 1993 Licensing requirement for the import of infected plants or plant pests into the UK for research purposes or for the import, movement, or keeping of genetically modified plant pests or genetic modification work with plant pests. 1998 Licensing requirement for laboratories and scientific establishments intending to hold or handle certain pathogens or nucleic acids capable of producing such pathogens. 2000 Requirement for a risk assessment prior to initiating work with a genetically modified organism and prior notification to UK health authorities of plans to carry out genetic modification work in any facility for the first time. Also a requirement for prior notification to local genetic modifications safety committees of all but the lowest risk genetic modification work, with higher risk requiring government consent. 2002 Requirement for employers to notify UK health authorities 30 days prior to storing or using certain human pathogens for research or other purposes for the first time. 2001 Notification and security enhancement requirements for facilities that possess or plan to possess specified human pathogens. TheUKGovernmenthasestablished severalbodiestoprovideadvicetoUK healthandsafetyagenciesontheseoversightarrangements.40GMOregulation andcontrolarethefocusoftheAdvisoryCommitteeonGeneticModification41 andtheAdvisoryCommitteeonReleasestotheEnvironment.42TheAdvisory CommitteeonDangerousPathogens43assiststheUKGovernmentinprotecting workersandothersagainsttherisksfromexposuretohuman,plantandanimal pathogens.Allthreeadvisorybodiesarecomposedofemployeeandemployer representatives,aswellasexpertsfromthescientificcommunity,thusallowing theUKGovernmenttoensurethatanynewcontrolsandregulationsarebased onfieldexperienceandareeffective. AsintheUnitedStates,theUK’sleadingscientificadvisorybody,theRoyal Societyhasalsoconsideredtherisksfromdual-useresearchandrecommended relyingpredominantlyonscientiststhemselvestopreventhostileapplicationsof theirwork. LiketheFinkCommittee,theRoyalSocietyhasproposedgreater oversightofdual-useresearchbyfundingbodiesandresearchinstitutesaspart of their general peer review process and by research institutions during execution of the work. They have given particular emphasis to the role of scientific codes of conduct, both as a means of raising consciousness among scientistsaboutthepotentialformisuseoftheirworkandasafocalpointfor education and training programs on both national laws and regulations and international treaty obligations. They have also called for the research communitytoretainresponsibilityforassessingpotentialrisksassociatedwith publication of their work and to help develop universal standards for the ControllingDangerousPathogensReport 17 conduct of dual-use research that could be incorporated into existing internationaltreaties.44 SmallpoxResearch TheWorldHealthOrganization(WHO)successfullyledtheglobalprogramto eradicatethesmallpoxvirusfromnature.45Asaresultofitsprominentrole,without whichtheviruscouldhavecontinuedkillingmillionsinthe25yearssinceits eradication,WHOacquiredthescientificandmoralauthoritytosetpoliciesfor thesafehandlingofthevariolavirusatthetwoauthorizeddepositories,inthe USandRussia.In1999,theWorldHealthAssembly(WHA)decidedtodelay destructionofallknownviralstocksinfavorofalimitedresearchprogramwith thevirusthatWHOwastooversee.46 Although the Committee onOrthopoxvirusInfectionssetguidelinesforwork withthevariolavirusin1994,47anewbody,theAdvisoryCommitteeonVariola Virus Research, was later formed to implement the WHA’s1999resolution. TheAdvisoryCommitteeconformstoWHOrulesregardingadequateregional representationwhilealsoincludingthenecessaryscientificexpertisetoensure thattheexperimentaldesignissafeandcommensuratewiththegoalssetbythe WHA.48 Underthisinternationalprocess,WHOhasapprovedresearchwiththelivevirus aimedat:determiningthefullorpartialDNAsequencesofisolatesintheUS andRussiancollections;validatingimproveddiagnostictests;screeningantiviral drugstoidentifythosesuitablefortreatingsmallpox;developingandproducing monoclonal antibodies to treat the disease; developing a safer vaccine; and creating a model of smallpox in a non-human primate to facilitate testing of antiviraldrugs,vaccines,anddiagnostics.49 InNovember2004,theAdvisoryCommitteerecommendedrevisionstothe1994 guidelines to allow newer techniques to be used for more efficient drug screening, among other purposes.50 While scientific consensus wasreached within the committee, its recommendations caused some controversy at the WHA’s annual meeting in May 2005, leading to a ban on proposed genetransferstudies,whileallowingothertypesofresearchtoproceedwithcloser scrutiny.51 As currently structured, WHO’s oversight process provides for international scientificreviewofallresearchwiththevariolavirus,whilealsoassuringstates thattheresearchwillbeperformedinasafemannerandinaccordancewith WHA’sagreedresearchagenda.ThatbalanceisnowbeingputatriskbyWHO memberstateswantingtohavemoredirectauthorityovertheresearchrather than allowing the scientific committee its own discretion to make those judgments. Research is now reviewed twice before commencing: by the AdvisoryCommitteeandbytheWHA,bothofwhichmeetonlyonceayear. Thisaddssignificantdelaysanduncertainties. Despite these many hurdles and restrictions, no US or Russian scientist is known to have violated the recommendations of the WHO committees on smallpoxresearchsincetheagreedresearchprogrambeganin1999. TheUS and Russian governments comply with the arrangement, including biosafety 18 ControllingDangerousPathogensReport inspectionsoftheirBL-4labs,eventhoughWHOresolutionsareonlypolitically binding. WHO’soversightprocessprovidesaccountabilityandlegitimacyto research with the variola virus and reassurance about the defensive intent of suchresearch.Thisprocessisapotentialprecedentforhowtoconducthighly consequentialresearchthroughascientificallyrigorousandpoliticallyinclusive system. ExistingArrangementsandtheBRSS Itisclearfromthisreviewthatavarietyofoversightarrangementshavebeen developedbothinternationallyandnationallyinresponsetoconcernsaboutthe possible misuse of biology. Most focus narrowly on limiting or controlling accesstopotentiallydangerouspathogensoronensuringthatsuchpathogensare handled safely, including minimizing any adverse impact from research involving their release into the environment. The few proposals aimed at addressingtherisksposedbydual-useresearchapplytoonlyaportionofthe life sciences research community and are generally based on voluntary adherencetomeasuresthatarenationalinscope. Despitetheselimitations,someofthekeyprinciplesofamoreadvancedsystem for oversight of dual-use research can be found within these existing arrangements.AswithWHOoversightofsmallpoxresearch,thesystemwould be based upon rules and procedures that have been developed and agreed internationally, with a presumption of equitable treatment of all legitimate participants. Itwouldestablishlegallybindingobligationsforthehandlingof dangerouspathogensastheBWCandtheBiodiversityConventiondo.Itwould applytoallrelevantbiotechnologyresearchactivities–academic,government andindustry–asisthecasewiththeUKregulationsonGMOs.Andlikethe NIH Guidelines, it would rely heavily on input from scientists themselves, whose judgments would be critical to any evaluation of the potential implicationsofagivenresearchproject. Manyofthespecificelementsthatmightbeincluded inanadvancedoversightsystemliketheBRSScan also be found within these existing oversight arrangements. Several of the provisions of the US and UK anti-terrorism legislation, for example, including those requiring facility registration, information disclosure (on both researchers and pathogens), data management, background checks, andinspections,aredirectlyrelevanttostrengthening oversight of biological research. The US NIH GuidelinesandtheUKregulationsonGMOstakethe oversight process one step further, requiring tiered oversightandpriorapprovalofcertaincategoriesof research involving the construction of genetically modified organisms. Both the UNEP Technical Guidelines and current US regulations governing human subject research require a risk-benefit assessment of all proposed research projects and careful record keeping throughout the oversight process.Evenmoreadvancedstillaretheoversight …some of the key principles of a more advanced system for oversight of dual-use research can be found within these existing arrangements. ControllingDangerousPathogensReport 19 arrangementsintheUKforanimalresearch,inwhichrisk-benefitassessmentis coupledwithatriplelicensingsystem—ofplaces,people,andprojects—in anefforttoguardagainstinappropriateordangerousexperiments.Allofthese elementshaveapotentialroletoplayinaBiologicalResearchSecuritySystem. 20 ControllingDangerousPathogensReport .......... ..... Elements of a Prototype Oversight System Individualscientists,institutions,andsecurityofficialsmustcurrentlyfindtheir ownbalancebetweenthenormagainstdestructiveapplicationsofbiologyand the equally strong but sometimes contradictory scientific drive to answer interesting questions and find useful applications of fundamental research.52 Theyhavelittleknowledgeofthedecisionrulesusedbyothers,andoftenno independentexternalreview. TheBiologicalResearchSecuritySystemwould reflectasharedrecognitionthat,forsometypesofresearch,eitherforegoingthe work or proceeding with inadequate protections could have damaging consequencesthatextendfarbeyondthelaboratory,firm,orcountrywherethe decisionwasmade.Fortheseconsequentiallinesofresearch,theBRSSwould provide common standards, peer review, and reassurance that the power of biologywasbeingusedappropriately. The right balance between freedom of scientific investigation and protective oversightdependsonthedegreeofriskinvolved.Therefore,thedesignofthe Biological Research Security System must start by attempting to define the differentlevelsofresearchactivityofconcernsothattheycanbematchedwith the appropriate oversight procedures. The next step is to address a set of architectural questions associated with the overall system design, such as principles and elements, information disclosure requirements, institutional structure,andverificationandcompliancemanagement. Thethirdrequirement istoexplainhowthesystemmightworkinpracticeateachlevelofoversight. Eachoftheseissuesisaddressedbelow. DefiningResearchofConcern Thefirstandarguablymostcriticalstepinestablishingaprotectiveoversight arrangement is that of determining a reasonably clear, globally credible and judiciouslylimitedscopeofapplication. Legalobligationscannotbeimposed unlesstheyarepreciselyandlegitimatelydefined.Obligationsformallyimposed willnotbeeffectivelyimplementedunlesstheburdenentailediscrediblyrelated toajustifyingpurpose.Thedeterminationofthatpurposemustbeunderstood andacceptedintheentirecommunityaffected. Inregulatorypracticetodate,thepurposeofoversighthasbeenmorerestricted butthescopeofapplicationoftenmoreexpansivethantheBiologicalResearch Security System would presumably require. For almost three decades, pathogens have been graded into four categories of danger in order to set biosafety standards for preventing laboratory accidents. The more recent US selectagentlistandUKpathogencontrollistswereconstructedbyresearchers andmedicalprofessionalstakingintoaccountthedemonstratedeffectsofthe ControllingDangerousPathogensReport 21 agentsinquestionaswellastheirsusceptibilitytopublichealthmeasuresand medicaltreatment.Thejudgmentsmadeareplausibleineachinstance,butthe securityrisksassociatedwiththevariouslistedagentsdifferconsiderably. Thethreatposedbyanthrax,forexample,isquitesevere–usuallylethal–to those who inhale the bacterial spores without realizing they have done so. Sincethereistypicallyatwo-dayincubationperiodbeforethediseaseproduces detectable symptoms, however, and since the toxin-producing spores are normally quite susceptible to antibiotic treatment, the severity of the threat dependsagreatdealonthestealthandefficiencyofitsoriginaldissemination. A person afflicted with anthrax generally will not infect another individual. Smallpox,bycomparison,islesslikelytobelethaltoagivenindividualbutis nonethelessmuchmoredangeroustosocietygenerallybecausethevirusspreads fromoneindividualtoanother.Insomehistoricaloutbreaksofsmallpoxeach infectedindividualhasinfectedonaveragesometwotothreeotherindividuals, amultiplicationfactorsufficienttogenerateadevastatingepidemic,absentrapid intervention. Thecasefatalityrateforsmallpoxepidemicshastypicallybeen around30%.Mostvariantsoftheinfluenzavirusareyetmorecontagiousthan smallpox but also much less lethal. Even so, the notorious 1918 H1N1 influenzastrainkilledsomewherebetween20and40millionpeopleworldwide inthecourseofayear,withacasefatalityrateestimatedtohavebeenabout 4%. Theanthraxbacteriumandthevariolavirusthatcausessmallpoxareon the select agent list. Until October 2005, when H1N1 was added, the only influenzastrainontheselectagentlistwasavianinfluenza. An IfoneoftheprimarygoalsoftheBRSSistopreventboththeinadvertentand thedeliberatecreationofbiologicalagentsthatareyetmorelethalorotherwise moredestructivelyconsequentialthanthosepresentlyknown,thenthecurrent controllistsareinherentlyinadequate.Theydonotincludepathogensthathave become conceivable but do not yet exist and are not officially named. Regarding those pathogens that do exist and provide the basis for the constructionofmoredestructivevariants,thelistsareatoncetooinclusiveand notinclusiveenough.Theydesignateagentssuchasanthraxthatarenotorious butdonotposeamassdanger.Butuntilrecently,theyomittedoneofthemost virulent strains of influenza, perhaps the most contagiousknownagent,despitethefactthatitcould be made more lethal. They do not address research techniques that might transform currently benign initial biologicalagentsintomassivelydestructiveones. approximation of the concept of intrinsic danger can be derived from basic epidemiology. Toaddressthepriorityconcerneffectively,anintrinsic definitionofdangerwillnotonlyhavetobedevised butalsotranslatedintoaformthatcanbeimplemented successfully.Admittedly,theserequirementsaremuch easier to state than to accomplish. But an initial approximationoftheconceptofintrinsicdangercanbe derived from basic epidemiology. It is generally understood that the course of an infectious disease depends on two basic characteristics of the pathogen thatcausesit:theabilitytotransferspontaneouslyfrom onehosttoanotherandtheconsequenceforthehostof theresultinginfection.Usingcommonsenseterms,one can label the first property transmissibility and the 22 ControllingDangerousPathogensReport second virulence. Although any disease outbreak is also affected by environmentalcircumstances,publichealthmeasures,individualimmunesystem reactionsandtherapeutictreatment,foragivensetofsuchconditionspathogens clearly vary in terms of transmissibility and virulence. None of the currently knownpathogenssetsthehigheststandardforbothproperties,andthereissome tradeoff between them. In particular a disease that is too rapidly lethal underminesitsabilitytopropagatebetweenhosts.Thereisnoreasontobelieve, however, that either the intrinsic limits of these properties or the most destructivecombinationhasyetbeendemonstratedinnature.Asthedynamics ofdiseaseareunderstoodinmoredetail,ithasbecomeevidentthatthenatural process of evolution has been moderating rather than maximizing the overall lethalityofhuman,plant,andanimalpathogens.Inprinciple,thismoderating effectmightbeoverturnedbydeliberateoraccidentalhumanintervention. Onecanimagineadefinitionofintrinsicdangerbasedonthecombinationof transmissibilityandvirulenceofknownpathogensassuggestedinFigure1.In principlethesetwopropertiesmightbemeasuredinsomestandardmannerand each known pathogen or agent located in the two dimensional space of the Figure. The space might then be segmented in terms of the degree of social dangerposedasindicatedbythebands.Researchtechniquescanbeconceived asvectorsoperatinginthisspace–thatis,asarrowsindicatingmagnitudeand direction. If a given technique is judged or shown to be capable of transformingagivenagentsoastomoveitintoahigherdangerzone,thenthe oversightproceduresassociatedwiththatzonewouldbeappliedassoonasthe potentialisrecognized. Thisapproachwouldconsiderthepathogensandthe researchtechniquesbeingappliedtothem,thuscombiningelementsoftheUS selectagentprogram,whichfocusessolelyonagents,andtheFinkCommittee andNSABBapproaches,whichfocussolelyonresearchactivities. Under this conception, the highest demonstrated values for each of the dimensions would delineate the threshold of maximum concern, and the oversight process would attempt to keep the area beyond those thresholds unoccupiedinnatureevenifitisexploredinscience. Workwitharestricted setofpathogenswhoseperformancedefinesthethresholdareawouldbegiven special designation and subjected to the most active form of international oversight. Successivelylessintrusiveandmorepermissiveformsofoversight wouldbeappliedtothelowerbandsofconcern. Admittedly,itwouldbeverydifficulttoestablishbroadlyagreedmeasuresof transmissibilityandvirulenceforallknownpathogens,letalonetopredicthow muchchangemightresultfromaproposedresearchactivity.Generallyagreed specificationsforeventhemostprominentpathogenscannotbeextractedfrom existing literature,53 and a systematic effort to undertake the measurements requiredcouldnotbeorganizeduntilthefeasibilityandimportanceofdoingso was broadly established.One can nonetheless attempt to connect the basic conceptualization of danger represented in Figure 1 to an operational specificationofdifferingrisklevelsthatpracticingscientistswouldrecognize. Anotionalcategorizationschemeisoutlined. ControllingDangerousPathogensReport 23 Figure 1: Conceptual Categorization of Danger Extreme Concern Work involving the most dangerous of currently known pathogens or possibly resulting in the creation of a significantly more dangerous pathogen. Moderate concern Work with listed agents, particularly activities that enhance weaponization. Potential concern Work that significantly increases the destructive potential of non-threat agents. The category of extreme concern is limited largely to the relatively few activitiesthatinvolveorcouldresultinpathogenssignificantlymoredangerous thanthosethatcurrentlyexist.Italsoincludessomeworkwithagentsclassified asBSL-4/ABSL-4intheUnitedStatesorequivalentlevelsinothercountries. The category of moderate concern encompasses a larger universe of activity involvingbiologicalagentsalreadyidentifiedasposingathreattopublichealth, particularlyactivitiesthatenhancethepotentialofsuchagentstobeusedasa weapon. The US select agent list is used for illustrative purposes, but it is recognized that an agreed list would have to be developed and maintained. Under an advanced oversight system, this would be done internationally, as discussedbelow.Thecategoryofpotentialconcernfocuseslargelyonactivities thatincreasethedestructivepotentialofbiologicalagentsthatotherwisewould notbeconsideredathreat.Theresearchactivitiescoveredbythesecategories areverysimilartotheexperimentsofconcernoutlinedintheFinkCommittee report, but have been calibrated to distinguish between different levels of concern. Inprinciple,theresearchactivitieslistedinTableIcouldbeusedtodetermine oversightjurisdictionwhiletheparametersoftransmissibilityandvirulencein FigureIcouldbeusedasgeneralguidelinesforjudgmentwithineachofthe oversightjurisdictions. Butasdiscussedbelow,morespecificcriteriaarealso neededtoassessthebenefitsandrisksofproposedresearchprojectsandthus whetherandunderwhatcircumstancestheyshouldproceed. 24 ControllingDangerousPathogensReport Table I: Illustrative Categories of Research Activities Activities of Extreme Concern (AEC) Work with eradicated agents*; work with an agent assigned as BL-4 / ABL-4; de novo synthesis of above; expanding the host range of an agent to a new host (in humans, other animals and plants) or changing the tissue range of a listed agent**; construction of antibiotic- or vaccine-resistant listed agent. Activities of Moderate Concern (AMC) Increasing virulence of listed agent or related agent; insertion of host genes into listed agent or related agent; increasing transmissibility or environmental stability of listed agent or related agent; powder or aerosol production of listed agent or related agent; powder or aerosol dispersal of listed agent or related agent; de novo synthesis of listed agent or related agent; construction of antibiotic- or vaccine-resistant related agent; genome transfer, genome replacement, or cellular reconstitution of listed agent or related agent. Activities of Potential Concern (APC) Work with listed agents – or exempt avirulent, attenuated, or vaccine strain of a listed agent –- not covered by AEC/AMC; Increasing virulence of non-listed agent; increasing transmissibility or environmental stability of non-listed agent; powder or aerosol production of non-listed agent; powder or aerosol dispersal of non-listed agent; de novo synthesis of non-listed agent; genome transfer, genome replacement, or cellular reconstitution of non-listed agent. * This would include, for example, activities with the 1918 influenza virus and chimeric influenzaviruseswithatleastonegenefromthe1918influenzavirus. **Thiswouldinclude,forexample,activitieswithchimericinfluenzaviruseswithatleastone genefromahumaninfluenzavirusandatleastonegenefromanavianinfluenzavirus. Table Definitions Agent: fungus, protozoan, bacterium or archaeon, virus, viroid, or prion; or genetic element, recombinant nucleic acid, or recombinant organism. Listed Agent: agent on CDC Select Agent list, USDA High-Consequence Livestock Pathogens list, or USDA/APHIS/PPQ Plant Pathogens list. Related agent: for fungi, protozoans, or bacteria or archaea, an agent that currently is, or in the last two years was, assigned to the same genus as a listed agent; for viruses, viroids, or prions, an agent that currently is, or in the last two years was, assigned to the same family as a listed agent; for genetic elements, recombinant nucleic acids, or recombinant organisms, an agent orthologous to a listed agent. (This includes any avirulent, attenuated, or vaccine strain of a listed agent, if said strain is exempt under the CDC Select Agent list, USDA HighConsequence Livestock Pathogens list, or USDA/APHIS/PPQ Plant Pathogens list.) Non-listed agent: agent other than a listed agent or related agent. Eradicated agent: agent previously in circulation in nature but not within the last decade, as determined by cases of or isolation from humans, animals, or plants, or by detection of antibodies to the agent from individuals younger than the time-span elapsed since the last recorded isolation. De novo synthesis: construction of agent using synthetic genomic nucleic acid (non-prion agents) or synthetic protein (prions), irrespective of whether said construction require additional reagents, extracts, cells, or ‘helper’ entitites. For purposes of this definition, ‘synthetic genomic nucleic acid’ refers to nucleic acid that corresponds to an agent genome and that is prepared using, in any step or set of steps, chemically synthesized oligonucleotides, corresponding to at least 5% of said agent genome. Powder: powder other than lyophilized reference specimen (<10 mg). Antibiotic: antibiotic of therapeutic utility against listed agent. Vaccine: vaccine of therapeutic utility against listed agent. ControllingDangerousPathogensReport 25 This approach, which focuses on the impact of certain research activities on pathogens,willbecriticizedbythoseconcernedwithconsequentialapplications of biotechnology that do not involve pathogens. The manipulation of the immune system, for example, using bioregulatorsdeliveredbynon-microbial mechanismssuchasimmunotoxinsorfusionproteinsisacaseinpoint.54But the most likely means of delivery for bioregulators, the ones that have been developedfarthestuptonow,areeitheraerosolsormodifiedvirusesorbacteria, bothofwhicharecoveredbyouroversightsystem. Moreover,ifverylarge numbersofpeople—inthehundredsofmillionsormore—aretobeexposed toalethalorotherwisenefariouseffectinashortperiodoftime,atthemoment thatcouldonlybeaccomplishedbyahighlytransmissibleandhighlyvirulent pathogen. That fact provides an obvious rationale for devising an oversight arrangementwhoseinitialscopeofapplicationislimitedtotheeffectsofcertain researchtechniquesontheinherentpropertiesofpathogens. The Fink Committee clearly believed that the experiments of concern that it proposedforoversightwereastartingpointforwhatultimatelywouldbean evolvingsystemofreview.“TheCommitteehasinitiallylimiteditsconcernsto coverthosepossibilitiesthatrepresentaplausibledanger,”thereportdeclared. “Overtime,however,theCommitteebelievesitwillbenecessarytoexpand the experiments of concern to cover a significantly wider range of potential threats.”55Sotooisitwithourapproach.Extensiveadditionaldiscussionswithin themanyrelevantprofessionalcommunitieswillberequiredtoworkoutwhich researchactivitiesshouldfallunderthedifferentoversightlevelsinoursystem and,ultimately,toextendtheoversightprocesstoincludeother,non-pathogenrelatedconcerns.Onecannotbeconfidentinadvancethatworkableconsensus couldbeachieved. Itseemsevident,however,thatanorganizedeffortofthis sort should be attempted. If it did succeed, it would provide the clarity of definitionthatisessentialforaprotectiveoversightarrangement. Ifitdidnot succeed,presumablytheeffortwouldbeinstructive. SystemArchitecture Since there appears to be no valid categorical distinction that can be made betweenpotentiallybeneficialandpotentiallydestructivelinesoffundamental research, there is a natural presumption that protective oversight must be performedbyscientificpeersabletounderstandthetechnicaldetailsofeach individualprojectandtodiscerntheprobableimplications.Butthereisalsoa presumption that protective oversight would have to include people whose experience and training would prepare them to judge social consequence –a significant extension of the established practice of scientific peer review. Because both the scientific and the social judgments made would have very broadconsequenceandwouldbepotentiallycontroversial,onewouldwantthem to emerge from a collaborative effort involving the relevant professional communitiesandgovernmentauthorities,ratherthansimplybeingimposedbya governmentbureaucracyalone.Atthesametime,oneneedsthelegalauthority, financial resources, and the clarity of obligations that come from formal intergovernmentalagreementonoversightstandardsandpractices. 26 ControllingDangerousPathogensReport Formaximumeffectiveness,anoversightsystemwouldhavetobe:       globallyimplemented; appliedwithoutexceptiontoallscientistsengagedinrelevantresearch; adequatelyfinanced; efficientlyorganized; backedbyappropriatelegalauthority;and accompaniedbycredibleprovisionstopreventmisuseofitsauthority. Inmeetingthoserequirementstheoversightprocesswouldhavetoestablishand preservesomeimportantbalances.Comprehensivejurisdictionoverallrelevant research would have to be qualified by judicious limitation of the oversight mandate to those areas of research that validly pose the possibility of broad socialdanger–hencetheimportanceofidentifyingthedeterminantsofsocialas distinct from individual danger. Within that limited mandate, oversight judgmentswouldhavetoassessthebalanceofbenefitandriskandrecommend, wheneverpossible,waystoachievethebeneficialobjectiveswhileminimizing potentialdanger. Full realization of all of those provisions would clearly be a major feat of institutionalinnovation.Manywouldargueitisanimprobableaccomplishment and some would consider it intrinsically undesirable because of its inherent intrusiveness. The underlying problem is certainly serious enough to induce innovationofsomesort,however,andthosewhoposecategoricalobjectionsare obliged to offer an equally effective scheme. Meanwhile the idea of an advancedoversightarrangementisausefulreferencebothforassessingpotential alternativesandforconsideringothermeasuresthatcouldlaythefoundationfor amoreadvancedoversightsystemandthatcouldmorereadilybeachieved. PrinciplesandElements Thebasicstandardonwhichanyoversightarrangementwouldbebasedisthe principle that biology should not be used to do deliberate harm under any circumstanceforanyreason.ThatisthecoreprincipleoftheHippocraticOath thathasbeenrecognizedsinceancienttimes. Itisalsothecoreprinciplethat underliestheprohibitionontheuseofbiologicalweaponspromulgatedinthe 1925GenevaProtocolandonthepossessionofbiologicalweaponsembodiedin theBiologicalWeaponsConvention.Althoughneitherofthoseaccordsenjoys universal legal adherence, no country currently proclaims the right or the intention to deploy biological weapons. The basic standard is already in practice a universal norm, and it could be substantially strengthened with a dedicated effort to do so. Indeed, a central purpose of an oversight process would be to assure consciousness of the basic standard by those undertaking work that could pose a meaningful violation and to provide reasonable reassuranceoftheircompliancecalibratedtothedegreeofdangerentailedinthe worktheyaredoing. The oversight process would include two key elements. The first, national licensing,wouldbeusedtoidentifyrelevantindividualsandresearchfacilities andformalizetheiradherencetothebasicnorm.Similarprocessesarealready beingusedinadvancedbiologytoensurethatcertainindividualsandfacilities meetspecifiedsecurityandsafetyrequirements. Forexample,boththeMay 2002 bioterrorism bill and the select agent regulations in the US require ControllingDangerousPathogensReport 27 background checks on any individual having access to select agents and registration of relevant facilities. Various regulations in the US and other countries also require licensing of facilities that produce drugs and other products derived from biotechnology to ensure their safety and efficacy. Outside of biology, there are other examples of licensing requirements for individuals and facilities engaged in activities that could affect substantial numbers of people — doctors, for example, and laboratories that work with radioactivematerials. Thepersonnellicensingrequirementwouldextendtoallscientists,studentsand technicalstaffproposingtoconductresearchcoveredbytheoversightsystem. Thepurposeofthelicensingwouldbetoensurethattheaffectedindividualsare technically qualified (either by virtue of an academic degree or on the job experience),haveundertakenbiosecuritytraining(andthushavebeensensitized to the dual-use potential of their work and educated about both national and internationaloversightrules),andhavenothingintheirbackground(suchasa pastbiosafetyviolation)thatwouldmakeitinappropriateforthemtoconduct consequentialresearch. Receiptofapersonnellicensewouldbeviewedasan acknowledgment of the individual’s special status within his or her broader professionalcommunity.Thefacilitylicensingrequirementwouldextendtoall facilitieswhererelevantresearchtakesplace,andwouldbedesignedtoensure thatsuchfacilitiesmeetexistingsafetyandsecuritystandards. In addition to personnel and facility licensing, there would also be a vetting requirementforotherstudents,secretaries,janitorsandindividualsworkingin licensedfacilitiesbutwhoarenotthemselvesconductingresearchthatissubject tooversightunderthesystem.Thepurposeofthisvettingprocesswouldbeto ensurethatthereisnothingintheindividual’sbackgroundthatwouldmakeit inappropriateforthemtohaveaccesstoareaswherecontrolledpathogensare stored. In implementing both this vetting requirement and the personnel licensing system, it will be important to ensure that individuals are not arbitrarily disapproved for political or other reasons unrelated to their qualificationstocarryouttherelevantwork. The second element is independent peer review of relevant projects prior to theirinitiation.Anyindividualinterestedinconductingresearchcoveredbythe oversightsystemwouldberequiredtoprovideinformationabouttheirproposed projecttotheappropriateoversightbodyforreviewandapproval. Toensure equitabletreatmentofallproposedresearchprojectsbothwithinandbetween thedifferentoversightlevels,commoncriteriawouldbeneededbytherelevant reviewbodiesforuseinassessingthepotentialbenefitsoftheworkaswellas thepossiblerisks. Sucharisk-benefitassessmentprocesswouldbesimilarto thatwhichiscurrentlyrequiredintheUSforIRBapprovalofhumansubject research.LiketheIRBreviewprocess,therisk-benefitassessmentofdual-use biologicalresearchwouldapplytoallrelevantresearch,irrespectiveofwhether it is to be carried out in a government, industry or academic laboratory. In addition, the relevant review body would be required to consider certain specifiedissueareasaspartofitsdeliberationsandtodocumentthediscussion of these issues as well as its overall risk-benefit assessment in its meeting minutes.Arecordofthereviewjudgmentswouldbepreservedatalllevelsand under the most advanced arrangement the international review body would periodically organize efforts to harmonize the judgments made by separate 28 ControllingDangerousPathogensReport national and local review bodies using project case histories as the basis for discussion. TenissueareasandnearlytwodozensuggestedquestionsarelistedontheIRB reviewprotocol.56Basedonapeerreviewsimulationexerciseoffivehypothetical projects,57wehavedevelopedacomparablesetofissuesandquestionsthat could be used to assess the risks and benefits of proposed dual-use research projects.Thefirsttwoissueareas,whichfocusonbiosafetyandthedetailsof theproposedresearchplan,concerntheconductofthework. Theremaining fourissueareasrelatetothejustificationforthework,andcoverpublichealth, biodefense, current necessity and potential impact. Similar issue areas and questionshavebeensuggestedbytheBritishRoyalSocietyforassessingdualuse research.58 Our notional risk-benefit assessment criteria are listed in TableII. InformationDisclosure As the criteria outlined above show, meaningful peer review would require disclosuretotheappropriatereviewbodyofdetailedinformationnecessaryto weigh the risks and benefits of a proposed experiment. In an advanced arrangement,theinternationalreviewbodywouldhaveprimaryrighttoinformationdirectlyrelevanttoprojectsfallingunderitsjurisdiction. Inparticular, informationdemonstratingextremerisktothehumanspeciesasawholewould havetobedisclosed,aswouldinformationrelatingtothedefiningdeterminants ofrisk.Withinastrictdefinitionofdirectrelevance,theserequirementswould override considerations based on proprietary interest or national security. Nationalandlocalreviewbodieswouldalsoneedsufficientinformationtobe abletoassessprojectsand,assumingthattheoveralljudgmentwaspositive,to makerecommendationsaboutwaystomaximizebenefitwhileminimizingrisk. In rare cases, the relevant review body might decide to approve a proposed projectbuttorestrictthedisseminationofinformationabouttheprojectorits results. That would require agreed guidelines for determining whether and underwhatcircumstancesinformationmighthavetoberestrictedorclassified. It would also require an agreed process for determining who could be given access to controlled information, based on professional qualification and documented responsibility rather than on national identity or organizational affiliation. At the moment there are no such provisions, and practical discussions generally debate the merits of open publication as compared to proprietyornationalsecurityclassification. Onepossibleapproachwouldbetobuildupontheideasoutlinedin1982bya NationalAcademyofSciencespanelonscientificcommunicationandnational security chaired by former Cornell University President Dale Corson. The CorsonReport,asitisknown,concludedthatthenationalwelfare,including nationalsecurity,isbestservedbyallowingthefreeflowofallscientificand technicalinformation“notdirectlyandsignificantlyconnectedwithtechnology critical to national security.”The report recommended that most fundamental research at universities should be unclassified; that a limited amount might require classification; and that a small grey area could require limited restrictions short of classification. Criteria for making these classification decisionswerealsoincluded,which,withsomemodification,couldserveasa modelforsimilardecisionsconcerningsensitivelifesciencesresearchtoday.59 ControllingDangerousPathogensReport 29 Table II: Notional Criteria for Risk-Benefit Assessment of Dual-Use Research Biosafety Issues (1) Does the proposed research plan contain appropriate protections to minimize risk to the public or environment? • Proposals receiving a “no” answer would have a low biosafety rating Evaluation of Research Plan (1) Are the proposed research plan and stated rationale for the work consistent with one another? (2) Are the risks posed by the agent (either from the perspective of public health or bioterrorism) and the stated rationale for the work consistent with one another? (3) Is the proposed research plan logically sequenced? (4) Are there scientific reasons why the same outcome cannot be pursued through alternate means? For example, could other methods or materials be used? • Proposals receiving two or more “no” answers would have a low research plan evaluation rating Public Health Considerations (1) Do agents to be constructed currently exist in nature? (2) If not, are said agents expected to be generated by natural processes? (3) Will the research advance our understanding of disease-causing properties of currently existing agents? • Proposals receiving “no” answers either to questions (1) and (2) or to question (3) would have low public health rationale Biodefense Considerations (1) Do agents to be constructed currently exist in nature? (2) If not, is the work being done in response to a “validated threat” (i.e. one for which there is credible information) or “theoretical threat” (i.e. one that is possible but for which there is no credible information)? (3) Will the countermeasures that are expected to result from the work significantly reduce the threat posed by the agent? • Proposals receiving two or more “no” answers would have low biodefense rationale Current Necessity (1) Are countermeasures against agents to be constructed currently unavailable? (2) Are there scientific reasons why countermeasures cannot be developed without access to such agents? • Proposals receiving one or more “no” answers would be of limited current necessity Potential Impact (1) Will the proposed research contribute to new knowledge (e.g., by furthering our understanding of basic life processes or pathogenesis) rather than primarily confirm work already done? (2) Are the research results likely to be definitive enough to inform policy decisions (e.g., vaccination strategies)? (3) Are there significant obstacles to using the research results to develop a more dangerous pathogen or to overcome current countermeasures? • Proposals with two or more “no” answers would have limited positive impact 30 ControllingDangerousPathogensReport Admittedly, the context in which the Corson panel put forward its recommendationsisverydifferentthantheonetheworldcurrentlyfaces.The 1982ReportwasaresponsetoconcernsthattheSovietUnionwasbenefiting militarilyfromaccesstoUSscientificandtechnicalinformation,especiallyin computerscienceandotherareasofthephysicalsciences.Today,thedominant concernisaboutamuchmorediffusesetofnationalandpossiblysubnational actorsmisusingadvancesinthelifesciencesforhostilepurposes.Butnorogue nationmuchlessanyterroristgroupthatcurrentlyexistsisbettercapablethan theSovietUnionwasofadaptingfundamentalresearchresultsfordestructive purposes. If these criteria were deemed appropriate to deal with the Soviet military threat, they should be at least as effective against the much less sophisticatedthreatstheworldnowfaces. DrawingontheCorsonReport,onecouldrequirethatnorestrictionsshouldbe placedonbasicorappliedresearchorresearchresultsatuniversity,industryor governmentlaboratoriesunlessthefollowingcriteriaaremet:      the technology is developing rapidly and time from basic science to applicationisshort; thetechnologyhasidentifiabledirectmilitaryapplicationsorisisdualuseandinvolvesprocessorproduction-relatedtechnologies; thetransferoftechnologywouldgiveaBWproliferator(e.g.,national levelorsubnational)asignificantnear-termcapability; therearenoothersourcesofinformationaboutthetechnology,orall thosethatcouldalsobethesourcehaveeffectivesystemsforsecuring theinformation;and, thedurationandnatureoftheproposedrestrictionswouldnotseriously compromisetheworkofthosedirectlyresponsibleforpublichealth. The requirement to take account of the public health implications of any proposed restrictions was not, of course, part of the original Corson panel approach.Butpreciselybecauselegitimateapplicationsoflifesciencesresearch canhaveaprofoundlypositiveimpactonpublichealth,consideringonlythe securityimplicationsofsuchresearchisnotsufficient. Insituationswherecertainresearchresultsmightneedtoberestricted,itwould be important to ensure that anyone with a legitimate need to know for the purposesofresearch,publichealthormedicalpracticewouldhaveaccesstothe relevantinformation,andthatsuchaccessisdocumentedandtheindividualis held accountable to rules about the use and further dissemination of the information. A relevant process was used by the US NAS to handle the disseminationofsensitiveportionsofits2002studyonagriculturalbioterrorism. InresponsetosecurityconcernsfromtheUSDepartmentofAgriculture,which funded the study, NAS officials developed guidelines for the types of individualswhocouldbegivenaccesstothecontrolledinformation. Anyone interested had to submit a written request and be interviewed by NAS staff beforebeingprovidedacopyofthecontrolledinformation.60 Arguably, arrangements such as this for the disclosure and use of scientific informationmightbemorereadilyacceptedinthepublichealthcommunityand academiathaninindustryorinthemanynationalsecurityestablishmentsthat conductbiologicalresearchprograms. Theoperatingprinciplesofmostpublic ControllingDangerousPathogensReport 31 health practitioners and academics are generally aligned with the rules of transparencyandindependentpeerrevieweveniftheydonotasyetimplement themtotheextentthatanadvancedoversightarrangementwouldrequire. In contrast, proprietary and national security organizations generally reserve the right to restrict outside access to their research activities and consider that practice to be justified by their respective missions. At the present time, prevailingdefinitionsoflegitimateinterestarenotrefinedorrobustenoughto provide a widely agreed basis for subordinating these organizations to an advancedoversightprocess.Theauthoritativedelineationoflegitimateinterest therefore would be one of the first and fundamental requirements for implementingsuchanoversightarrangement. Advancedinformationtechnologywouldbeusedateachleveloftheoversight systemtohelpprotectagainsttheunauthorizedreleaseofsensitiveinformation andtofacilitatereportingbyaffectedresearchersandtospeedthepeerreview process. To illustrate how this might be done, we built a prototype data management system using open source software and financial-grade security standards. Thesystemwehavedevelopedhasatree-likestructure,witheach oversightnode(i.e.localinstitutions,nationalauthorities,andtheinternational body) operating its own secure server for storing information under its jurisdiction. Information required for licensing and peer review would be collectedusingquestionnairesthatmeetBRSSreportingrequirementsaswellas other national or local reporting requirements. Information would be sent securelyfromonenodetoanother–suchaswhenaproposedprojectmeetsthe requirementsforhigher-levelreview–buthigher-levelnodeswouldnotbeable toaccessinformationfromlowernodeswithoutthelowernode’s permission. Thedatamanagementsystemmakesiteasytoaddnewquestionnairesorrevise existingonesandautomaticallypropagatethesechangesthroughoutthesystem tokeeppacewithadvancesinscienceandtechnology.Theuseofopen-source softwaredecreasesexpenseandallaysconcernsabouthiddenfeatureswhilestill including multiple levels of security. Details about the prototype data managementsystemareinAppendixC. InstitutionalArrangements Decisions concerning the institutional entities necessary to implement the oversightsystemwouldnaturallybeaproductoftheprocessthatcreatedthem. For purposes of immediate discussion, we use the term Biological Research Security System to describe the overall arrangement. The term International PathogensResearchAuthority(IPRA)referstothebodythatwouldfulfillthe international functions of the BRSS. National Pathogens Research Authority (NPRA)referstothegovernmentalbodiesexercisingnationaloversight,while LocalPathogensResearchCommittee(LPRC)referstothereviewbodiesthat wouldexerciseoversightwithinindividualinstitutionsorregionally. WHOhassomeoftherelevantexpertiseandmissionthatwouldberelevantto afullydevelopedIPRA,givenitsworkinrecentyearshelpingdevelopnational preparedness and response capabilities, international disease surveillance systems, and laboratory biosafety and biosecurity guidelines for handling pathogens. But neither it nor any other existing international organization currentlyhaseitherthespecificmandateorthefullrangeofscientific,security, legal, and other expertise necessary to implement an advanced oversight arrangement.Moreover,sinceplantandanimalpathogenswouldalsobewithin 32 ControllingDangerousPathogensReport its scope of concern, the IPRA would have to have a close functional relationshipwiththeFoodandAgriculturalOrganization(FAO)andtheWorld OrganizationforAnimalHealth,knownastheOIE. Thus,althoughitmight ultimatelybedesirabletobringsomeoralloftheglobal-levelfunctionsofthe IPRAintoaWHOwithmorereliablefinancesandmoreauthority,fornowit makessensetoconceptualizetheinternationalpartofthesystemwithoutbeing constrainedbythelimitationsofanyexistinginternationalorganization. The International Pathogens Research Authority need not be a large organization,butitwillrequireanadministrativestructurethatreflectsitsmixed character as a security, scientific, and public health organization. The IPRA shouldbeestablishedwiththelegalauthoritytoperformsomefunctionsitself(a directsystemofregulation)andtosetrequirementsfortheperformanceofother functions by its States Parties (an indirect system of regulation). Like most internationalorganizations,itshouldincludeagoverningbodycomprisedofall memberstatesthatwouldmeetannuallytosetguidingprinciplesandpriorities, approvebudgets,andmakeotherauthoritativepolicydecisions. Itwouldalso need a smaller executive body to oversee implementation of the system, the seatsonwhichwouldbeallocatedbothtoensuregeographicrepresentationand toreflecttheglobaldistributionofrelevantindustriesandscientificexpertise. TheIPRAwouldalsoneedatechnicalsecretariat,aswellasseveralstanding committees that include policy representatives from national delegations, specialists from the technical secretariat, and non-governmental experts as needed. It would also have special committees of internationally respected scientists and security experts who would be responsible for peer reviewing researchofextremeconcernandforhelpingdefinetheresearchactivitiesthat wouldbesubjecttooversightateachlevelofthesystem.61 Toachievetherequirementsofanadvancedoversightarrangement,theBRSS wouldhavetobeestablishedbytreatyoranequivalentlegalinstrumentand adherencetotheinstrumentwouldhavetobemadesuchaninsistentobligation that all countries would be under enormous pressure to ratify it. The IPRA wouldhavetobeprovidedwithanassuredbudgettailoredtoitsresponsibilities. Underanadvancedconception,theIPRAwouldhavethefollowingfunctions: 1. Itwoulddefinethecategoriesofresearchactivitiessubjecttooversightand establishstandardsforreview,withupdatesasrequiredtokeeppacewith scientificadvancement. 2. Itwouldconducttheoversightprocessforallprojectsinvolvingactivitiesof extreme concern, including initial approval of the individuals, research facilitiesandprojects;implementationoftheapprovedresearchplan;and disseminationoftheresults. 3. It would determine the criteria for identifying research that is of unusual importanceforreasonsofglobalprotectionandwouldactivelyencourage andfundhighpriorityprojectsmeetingthosecriteria,whetheridentifiedby theorganizationoroutsideresearchers. 4. It would establish reporting requirements, rules for access to sensitive information,andprotectionsagainstthemisuseofdisclosedinformation. ControllingDangerousPathogensReport 33 5. It would provide software and technical support for a secure data managementsystemtobeusedateachoversightlevelandwouldmaintaina databaseofinformation,includingstrainvariations,onallprojectsreviewed underinternationalauthority. 6. Itwouldprovidescientific,legal,andtechnicalassistanceuponrequestto helpmemberstates,localreviewcommittees,andindividualscientistsmeet theirnational-andlocal-leveloversightobligations. 7. It would assess the case judgments being made on a national basis for researchmeetingthecriteriaforactivitiesofmoderateconcernandpotential concern. 8. Itwouldconductperiodicconferencesdesignedtoencourageharmonization of national standards and case judgments, and identify any major discrepanciesthatappeartobeoflegitimateinternationalconcern. Inordertoperformthesefunctionsinaworldofirretrievablydividedlegaland politicaljurisdiction,theIPRAwouldhavetobeconstitutedinamannerthatis globally representative and explicitly dedicated to providing an equitable distributionofburdenandbenefit.Itwouldalsohavetospecifyproceduresthat assurecompliancewithitsrequirementsbutalsoprotectagainstmisuseofits authority. In general, it must be given the mandate to be equitable and sufficientcapacitytobeeffectivebutnottheabilitytobeabusive. Oftheseunderlyingrequirements,theincentivetobeequitableshouldbethe least controversial. Concern about the misuse of advances in biology is currentlyhighestinmoreeconomicallyadvancedcounties,withpoorercountries focused on infectious diseases such as malaria, tuberculosis and HIV/AIDS, which kill millions of people each year. The poor provide a reservoir for emergentdiseasesthatalsoposeanincipientthreattomoreaffluentpopulations, butlackthemoneyandexpertisetohandletheproblemontheirown.Although participationintheBRSSislikelytoimposefewburdensonsuchcountries, governmentsalreadystretchedthinmightbemorewillingtoparticipateifthe oversightsystemalsofundedresearchonsomeofthehuman,plantoranimal pathogens that pose a clear threat to their own country’s security and wellbeing.Scientistsandpublichealthofficialsinthedevelopedworldmightalso have a stronger incentive to participate in the oversight system if it also included a positive mission aimed at contributing to the global fight against infectious disease. Recent international cooperation on SARs and on avian influenza demonstrates the importance both of international scientific collaboration and of ensuring that those who conduct consequential research adheretocommonproceduresandrules. Ofcourse,thefinancialcostsoftheIPRAwouldneedtobesharedequitablyas well.IftheIPRA’sresponsibilitieswerenarrowlyrestrictedtothemissionof researchoversight,anappropriatelevelofoperationsmightfallintherangeof hundredsofmillionsofdollarsperyear. Amoreadvancedarrangementthat includedthemandatetoaddressthemostdestructiveofthecurrentinfectious diseasesmightwellrequirebillionsofdollarsperyearormore. Thosewould be large increments to current international public health expenditures but comparable to the additional amounts the US has explicitly directed to bioterrorismresearchintheaftermathofthe2001anthraxletters. 34 ControllingDangerousPathogensReport ComplianceandVerification The question of compliance, a term that involves the perennially contentious issueofverification,islikelytobeacontroversialissueinthedevelopmentof any oversight system. Some will argue that the threat of malicious intent is virtuallytheentireproblemandthatthosededicatedtodestructiveapplications ofbiologywillreadilyevadeanyoversightarrangementsacceptabletoeveryone else.Whenappliedinextremeformagainstnationstates,thatargumentmakes anypreventiveeffortintractableinprincipleandleavesmilitaryforceagainst those with evil intent as the only supposedly realistic option. Even in more moderateform,theargumentseekstoimposeaheavyburdenofproofonthe expectationofcomplianceandthefeasibilityofverification.Althoughtolerably robustcomplianceprovisionshavebeendemonstratedinwhatwouldappearto be roughly comparable situations –financialaccounting,forexample–inits formative stages an advanced oversight arrangement for biotechnology would undoubtedly have to labor against categorical doubts about compliance that wouldbeveryassertivelyexpressed. The constructive case for the feasibility of compliance rests on a number of arguments. The first holds that there is a problem of innocent misjudgment serious enough to justify the establishment of a system of independent peer reviewofrelevantresearch.Mostpracticingscientistsstronglybelieveintheir own good intentions, but most can also be readily induced to recognize the possibility of unpleasant surprise. Many also are distinctly less confident of their colleagues collectively than they are of themselves. If misjudgment is accepted as the occupational hazard it certainly appears to be and not as a characterflaw,thenitisreasonabletoexpectthatcompliancewithacarefully designed oversight process can be established as a professional standard endorsed, practiced and enforced by virtually all practicing researchers as protectionagainstsocialbacklashtriggeredbyinadvertenterror. Thatcanin principlebemadeanintegralpartofthesocialcontractandaroutinefeatureof professionalpractice. Thatwouldnotprecludewillfulviolationbutitwould makeitunambiguouslyillegitimateandmuchriskierasapracticalmatterthanit currentlyis.Detectionofviolationismorelikelytooccuragainstabackground ofroutinedisclosureandpeerreview,anddetectedviolationsaremorelikelyto beprosecutedifclearstandardsofcomplianceareset. Ingeneral,consensual information disclosure ubiquitously practiced offers far more consequential protection than adversarial forms of verification evoked only in instances of allegedviolation. Officials at all levels of the oversight system are likely to rely heavily on information gathering and analysis mechanisms to assist them in assessing compliance.62Thisincludesreviewingprojectreportsforinternalconsistency, cross-checkinginformationprovidedbyonelabwithsubmissionsfromothers with which it interacted, or comparing research project records with findings publishedinacademicjournalsandpatentapplicationsforbio-medicalproducts. Tosupplementthedatareportedformallyunderthesystem,informationcould also be obtained from unofficial sources such as non-governmental organizations. Additional information could come from periodic visits or inspections,whichmanylaboratoriesalreadyaresubjecttoonanationalbasis forreasonsotherthansuspicionofwrongdoing. ControllingDangerousPathogensReport 35 BRSS member states can also enhance confidence in compliance by being responsivetoquestionsfromothercountriesabouttheirimplementationoftheir oversightobligations. ThiscouldbedoneattheannualmeetingsoftheIPRA where, in addition to approving budgets and making other policy decisions, governmentscouldanswerquestionsfromotherparticipatingstates.Theycould alsoconsultdirectlywithothermemberstatesiftheyhadaquestionorconcern, followingestablishedconsultationandclarificationprocedures. TheIPRAcouldalsorequireadditionalprotectivemeasuresthatarefeasibleand prudent for projects undertaken at its level. This includes, for example, allowing activities of extreme concern only to be carried out at a limited numberofdesignatedsitesthatwouldhaveaccesscontrolstolaboratorywork areas as well as to the containers in which dangerous pathogens are stored. That would create a detailed record of access and enable the imposition of multiple person rules analogous to those applied to nuclear weapons-related work.Therealsocouldbecontinuousvideomonitoringoftheworkareasand electronicmonitoringoftheequipmenttoassureadetailedrecordofresearch activity as well as basic access. Rules and procedures of this sort are provisionally being developed in some places but not yet comprehensively appliedandmanaged.Iftheywere,thestandardofprotectionwouldclearlybe muchhigherthanitcurrentlyis. Despitethesemechanisms,onecanstillimaginethataroguestatemightevade theoversightsystembyexemptingitsnationalandlocalreviewbodiesfromthe agreedrequirementsorbyrefusingtoestablishanationaloversightsystemat all. Ifallmajorcountriesendorsedandimplementedthesystem,however,it wouldbemuchharderforaroguestatetodefyit. Withvirtuallytheentire internationalcommunityadheringtothesystem,theUNSecurityCouncilmight morereadilydevelopasupplementaryverificationprocesscapableofimposing adversarialinspectionsonsuspectfacilitiesbelievedtobeengagedinactivities that threaten international peace and security, including international public health. Sustained and unresolved issues of compliance arising within the oversight system’s more cooperative processes could be made the trigger of assertive verification. Many of the standard enforcement provisions, ranging fromsanctionsto,inextremecases,theuseofmilitaryforce,couldbecredibly broughttobearifbasicrulesofbehaviorweresetandbroadlypracticed.Itcan reasonably be argued that an advanced oversight system would substantially enhancetheprospectsofdiscipliningatemptedrogue. Thatsuppositionisat least as plausible as the contrary assertion that rogues are inevitable and unpreventable. Infact,despitepredictabledisputesoverprobablelevelsofcompliance,assuring appropriate restraint in an advanced oversight process is probably the more demandingproblemoverthelongerterm.Asdiscussionproceedsandthebasic featuresofthesituationareabsorbed,mostpeoplearelikelytorecognizethe potentialpowerofsystematicinformationdisclosureandmandatorypeerreview andarelikelytobeinsistentlyinterestedineffectiveprotectionagainstmisuse of that power both as a basic legal right and as a matter of administrative procedure. SincethefunctionsoftheIPRA,inparticular,areessentiallyunprecedented,it seems evident that substantial legal innovation is likely to be required to establish appropriate safeguards. Rules regulating access to information 36 ControllingDangerousPathogensReport disclosed under the oversight system, specifying both legitimate uses and prohibitedapplication,wouldbeneeded. Civilremediesandpossiblycriminal sanctionswouldhavetobeallowedinnationaljurisdictionsforunauthorized disclosures.WithintheUnitedStates,andprobablywithinmanyothercountries as well, a decision by the international review body to deny approval of a proposedprojectinthecategoryofextremeconcernwouldhavetobesubjectto appealinthecourtsasamatterofconstitutionalright.Aninternationalruling thatwascontestedandnotupheldinanationalcourtsystemcouldcreatean operationalproblemfortheoversightsystemasawhole. Sowouldcivilsuits againsttheinternationalbodyforanyinadvertentorwillfulmismanagementof the information it gathers. Presumably national courts would be reluctant to contestinternationalrulingsonscientificgrounds,buttheywouldappropriately demand procedural safeguards protecting the rights and interests of those subjectedtooversight.Concernsaboutdueprocesswouldbeminimizedtothe extentthatoversightproceduresandruleshavebeenharmonizedbothamong countries and between the national and the international level, and involve similarlicensingandpeerreviewrequirements. TheSysteminPractice Inenvisaginghowtheoversightprocessmightworkinpractice,itishelpfulto begin with the licensing provisions for scientists and facilities. We then consider the project peer review process starting from the lowest level, both becausethisisthepartofthesystem,ifany,thatwoulddirectlyaffectmost scientists,andbecausethisisthepointatwhichallprojectssubjecttooversight wouldinitiallyenterthesystem.Adiagramofthekeystepsinthepeerreview processisinFigureIIbelow. Anyscientistwishingtocarryoutaresearchprojectsubjecttooversightunder theBRSSwouldhavetobelicensedaswouldthefacilitywheretheproposed workwouldtakeplace. Inordertoobtainapersonnellicense,theresearcher wouldcompleteanewuserquestionnaire.Thisformwouldrequireinformation on the individual’s academic credentials and employment history, including currentemployer. Inordertoobtainafacilitylicense,theinstitutionhousing thelaboratorywhereBRSS-coveredresearchistotakeplacewouldcomplete bothanewinstitutionquestionnaireandanewlaboratoryquestionnaire. The formerwouldrequiregeneralinformationabouttheinstitution(name,address), theactivitiesofitsbiosafetyandotherreviewbodies(e.g.,IBC,IRB)andits laboratory inspection and hazardous materials handling procedures. The new laboratory questionnaire would require information specific to the laboratory wheretheBRSSresearchwouldtakeplace,includingtheagentswhichareused inthelaboratoryandtheindividualresponsibleforcoordinatingagentresearch. Completionofthenewlaboratoryquestionnairewouldalsotriggeraseparate questionnaireonsecuritymeasures,whichwouldrequiredetailedinformationon measuresinplaceatthelabforpreventingunauthorizedaccesstodangerous pathogens.OnceaprojectthatwassubjecttoBRSSoversightwasproposed,all relevantlicensingformswouldbeprovidedtotheappropriatepeerreviewbody for use in its risk-benefit assessment. A complete set of prototype licensing questionnairesisatAppendixD. ControllingDangerousPathogensReport 37 Figure II: Peer Review Process Step 1 Licensed researcher completes relevant questionnaires for proposed project at a licensed facility. Step 2 Research project is assigned to appropriate review body. Local (LPRC): Activities of Potential Concern National (NPRC): Activities of Moderate Concern International (IPRC): Activities of Extreme Concern Step 3 Review body decides whether the project should be approved and under what conditions based on Criteria for Risk-Benefit Assessment: Biosafety Issues; Evaluation of Research Plan; Public Health Considerations; Biodefense Considerations; Current Necessity, Potential Impact Step 4 Approved project assessed for possible restrictions on dissemination based on adaptation of Corson Panel conditions: 1. 2. 3. 4. Technology developing rapidly? Time between research result and application is short? Technology has direct, identifiable military applications? Technology transfer would give a BW proliferators a significant near-term capability? 5. No other sources of information about the technology, or do all potential sources have effective systems for securing the information? 6. The duration and nature of proposed restrictions would not seriously compromise the work of those directly responsible for public health? Step 5 Periodic and final reports by researcher to relevant review body. 38 ControllingDangerousPathogensReport InstitutionalReview–ActivitiesofPotentialConcern Proposed research activity in this category would be subject to institutional review and approval bya Local PathogensResearchCommittee. The LPRC wouldbesimilarinsomewaystotheInstitutionalBiosafetyCommitteesthat currently exercise local oversight of much recombinant DNA research, but would need to meet more frequently and be provided with more resources, including compensation for the committee members’ time and administrative support.Itwouldalsoneedtohavemoreformalizedproceduresforconducting risk-benefit assessments and for documenting its deliberations and resulting decisions.TheLPRCwouldconsistofnofewerthanfivevotingmemberswho collectivelyhaveexpertisebothintheresearchareassubjecttooversightatthis level and if possible on security matters. At least one member would be required to be a public representative. Advisors to the committee could be appointedonanadhocbasisifadditionalexpertisewasrequiredtoreviewa particularproject. A licensed scientist who wanted to initiate a project involving activities of potential concern at a licensed facility would start by logging into the data management system and completing a new project questionnaire. The questionnairewouldrequireadescriptionoftheproposedproject(bothgeneral andtechnical)anditspurpose,aswellasinformationontheagentorsequence involved,priorrelevantwork,techniquestobeemployed(includinghumanor animal experiments, recombinant DNA work or aerosol studies), expected benefits,potentialrisks(includingimpactonvirulence,environmentalstability or host-range), biosafety level, and whether there are alternative means of obtainingthesameinformation. Itwouldalsorequireacertificationfromthe researcherthattheproposedprojectdoesnotraiseBWCcomplianceconcerns. Completionofthenewprojectquestionnairewouldtriggeraseparatepersonnel security questionnaire identifying the scientists participating in the project as well as other laboratory personnel and a laboratory biosafetyquestionnaire containingquestionsonbiosafety-relatedequipmentandproceduresinthelab. Otherquestionnaireswouldhavetobecompletediftheworkinvolvedtheuse of recombinant materials or pathogenic microorganisms. If the data managementsystemwasbeingusedtomeetotherregulatoryrequirements,such asthoserelatedtohumansubjectoranimalresearch,questionnairespertaining to those issues would be completed as well. A complete set of prototype projectquestionnairesisatAppendixE. The institutional biosafety officer would be responsible for ensuring that the proposalreceivedallappropriatereviewsbeforeworkbegan.Heorshewould confirmthatthenecessaryquestionnaireshadbeencompletedbytheresearcher and,togetherwiththechairpersonoftheLocalPathogensResearchCommittee, thatthenecessaryexpertisewasavailableontheCommitteetopeerreviewthe proposedprojectforitsdual-useimplications.Thebiosafetyofficeralsowould actasaliaisonwiththeotherlocalreviewcommittees,suchasthosegoverning human subject or animal research, in an attempt to promote expeditious and efficientconsiderationoftheproposedprojectbythosebodies.Thiswouldbe facilitatedbythedatamanagementsystem,whichinourprototypeincludesnot ControllingDangerousPathogensReport 39 onlythequestionsrequiredtomeetBRSSobligationsbutalsosomeofthose necessarytomeetotherregulatoryrequirements. When deciding whether to approve a project, the LPRC would consider the experienceoftheprincipalinvestigatorbutthemostimportantfactorwouldbe theresultsofitsrisk-benefitassessmentoftheproposedwork.Astandardized protocol,alongthelinesoftheonedescribedearlier,wouldbeusedtoguidethe Committee’sdeliberationsandinformitsdecision.TheLPRCcouldapprovea proposal as submitted, require that the research activities be redesigned to reduce risks, recommend that the research be reviewed and conducted at a differentfacilitywithadditionalbiosafetyandsecurityfeatures,orelevatethe proposaltotheNationalPathogensResearchAuthorityforreview. Aspartof itspeerreviewoftheproject,theCommitteewouldalsoconsiderthepossible needforrestrictionsonthedisseminationofinformationabouttheresearchor research results, based on standardized criteria like those discussed above, although such restrictions generally would not be expected at this level. If, however,aprojectproducedunexpectedresultsthatmetthecriteriaforresearch activitiesofmoderateorextremeconcern,thenthescientistwouldberequired toworkwiththenationalorinternationaloversightbodyasappropriateona plan for handling any sensitive materials or information that had been developed. The LPRC would be required to reach a decision on the project within45daysofreceivingacompletedapplicationpackage. Researchers would not be required to be present at the LPRC meeting when theirprojectisdiscussedalthoughtheywouldbeencouragedtodosoinorder to answer any questions the Committee might have. Minutes of the LPRC meetingswouldbekeptconfidentialbutwouldbemadeavailabletotheNPRA uponrequest. Theseminuteswouldneedtoincludethemeetingparticipants, decisionsreached(includingthenumbervotingfor,againstorabstaining),the basisforanyrequiredchangesinordisapprovaloftheresearch,andasummary ofthediscussion. AtthediscretionofthechairpersonoftheLPRC,anexpeditedreviewprocess couldbefollowed,inwhichthechairperson,asubsetoftheCommitteeorthe entireCommitteewouldreviewtheproposedprojectelectronicallyratherthan duringaformalmeeting.Suchaprocesswouldonlybeusedincasesinvolving new proposals believed to pose minimal risk or minor changes to previously approved proposals. A written record of the risk-benefit assessment and the decision would be prepared and circulated to other LPRC members for any projectgivenexpeditedreview. Uponcompletionoftheproject,theprincipalinvestigatorwouldberequiredto submitabriefreportontheresearchresults.Thisreportwouldbeincludedin theinstitution’sdatabasealongwithotherinformationsubmittedaspartofthe projectapplication.Selectinformationfromthelocallevelwouldbesenttothe national review body, which in turn would forward information of broader internationalrelevanceinanannualreporttotheinternationalorganization. NationalReview–ActivitiesofModerateConcern Researchactivitiesinthiscategorywouldrequireoversightandapprovalbythe National Pathogens Research Authority. The NPRA would also periodically 40 ControllingDangerousPathogensReport review the work of the Local Pathogen Research Committees and provide guidance on how to handle research of potential concern that produced unexpected results that, if misapplied, could have serious public health consequences. TheNationalPathogensResearchAuthoritywouldbeagovernmentbodywith direct authority to regulate scientists and facilities within its jurisdiction. It couldbeestablishedwithinanexistingagencysuchastheNationalInstitutesof Health in the US, or it could be a separate government agency, perhaps includingpersonneldrawnfromdifferentgovernmentdepartments.TheNPRA would include one or more review committees of up to 20 members with expertiseonboththescientificissuessubjecttooversightatthislevelandon securityissues.Reviewcommitteememberswouldbehighlyrespectedleaders intheirrespectiveprofessionalcommunitieswillingtodevoteaportionoftheir time to reviewing proposals and making policy recommendations. Review committees would also include individuals who are neither scientists nor securityexpertsbutwhohaveotherrelevantformsofexpertise(e.g.ethics)or whoseinterestswouldbeaffectedbytheirrecommendations.Thespecificform ofthisinputcouldvarybycountry. OneofthetoughestchallengesfortheNPRAwillbetomaintaindomesticand international confidence in its oversight without compromising confidential business or national security information. To this end, the NPRA should be transparentaboutitsprocesses,shouldconductpublicforumstopromotebroad debate on contentious policy questions, and should publish an annual report summarizing the significance of research proposals approved, modified, or rejected.Ifnecessarytoprotectsensitiveinformation,thereportshouldinclude aspecialannexthatwasonlyavailabletoclearedindividualswitha“needto know.”AllNPRAstaffandreviewcommitteemembersandanyoneelsewho hadaccesstosensitivecommercialandnationalsecurityinformationthroughthe NPRAwouldbevettedandrequiredtosignstrictconfidentialityagreements. Review committee meetings would not be conducted publicly nor would meeting minutes be available to the public. As with the LPRC, however, detailedmeetingrecordswouldbekept. The National Pathogens Research Authority would maintain a comprehensive picture of high-consequence research within its jurisdiction by licensing all scientists,technicalsupportstaff,andfacilitiesengagedinresearchcoveredby theBiologicalResearchSecuritySystem. TheNPRAwouldworkwithother appropriategovernmentagenciestoconductbackgroundchecksonresearchers andotherpersonnelwhoworkwithorhaveaccesstodangerouspathogensand toconductinspectionsofrelevantfacilities.Onceapproved,apersonnellicense wouldremainvalidforuptofiveyears,aslongasannualactivityreportswere submittedandtherewasnoevidenceofviolationsofotherrelevantregulations. Facility licenses would be valid for up to 10 years but would have to be renewedinthecaseofanymajorstructuralchanges. Scientistswhowishedtopursueresearchactivitiesofmoderateconcernwould berequiredtosubmitaprojectapplicationthroughtheirlocalreviewbodyto the NPRA for consideration. Applications for research at this level would requireasignaturefromaseniorofficialattheinstitutionwheretheresearch was to take place indicating institutional support for the proposed project. ResearcherswouldberequiredtopresenttheirproposedprojecttotheNPRA ControllingDangerousPathogensReport 41 review committee. The committee would have to reach a decision on the projectwithinsixtydaysofreceivingacompleteapplicationpackage. Ifthe resultsoftheresearchmightbesubjecttodisseminationrestrictions,theNPRA wouldadvisetheprincipalinvestigatoratthetimetheprojectisapproved.The NPRA could also determine that the proposed work meets the definition of researchofextremeconcernandthereforeshouldbesubmittedforinternational reviewbytheIPRA. Once the project was approved, the principal investigator would receive a project permit to conduct only the activities authorized. Although minor modifications to the project could be handled through an expedited process, significant changes would have to be considered under the regular review procedures. Upon completion of the project, a detailed report would be submittedtotheNPRA.Thisreportwouldbeincludedinthenationaldatabase alongwithotherinformationsubmittedaspartoftheprojectapplication. Asdiscussedabove,theNPRAcoulduseawiderangeofinformationgathering andanalysistechniquestoensuretheaccuracyandcompletenessofinformation thathasbeendisclosedandtoconfirmcompliancewithotherBRSSobligations. TheNPRAcouldalsorequesthelpfromothernationalregulatorybodiesand lawenforcementagenciesaswellasfromtheIPRAtoassistitinmeetingits oversightrequirements. The NPRA would report annually to the IPRA about its implementation of BRSSobligations.Thiswouldincludeabasicdescriptionofcompletedresearch projectsandanyresultswithprotectiveimplicationsforthebroaderinternational community. This would facilitate IPRA efforts to promote international harmonization of national implementation activities. The NPRA would also reportonnationalcomplianceissuesandstepstakentoredressthem. InternationalReview–ActivitiesofExtremeConcern The IPRA would perform many of the same functions that the National PathogensResearchAuthorityperformsforresearchactivitiesunderitscontrol. Thus,itwouldhaveoneormorereviewcommitteesofupto15scientistsand security experts who would be responsible for conducting risk-benefit assessments of projects under the IPRA’sjurisdiction. OtherIPRAadvisory committees would provide advice on the types of high priority research the IPRA should support and help define and update the categories of research activities subject to oversight at each level of the system. The IPRA would have the discretion to select additional members on an ad hoc basis to complementtheexpertiseonthesestandingpanels. Scientists from member states who wished to pursue research activities of extreme concern would submit a project application through their local and national review bodies to the IPRA for consideration. In addition to the relevantquestionnaires,proposalsforresearchatthislevelwouldalsorequirea statement of support from the relevant national review body. All senior scientistsinvolvedintheproposedprojectwouldhavetobepresentduringthe IPRA review committee’s consideration of the proposal. As the volume of researchproposalswouldbemuchlowerthanattheotherlevelsoftheBRSS, the review committee would be expected to reach a decision on the project within 45 days of receiving a complete application package. If a proposed 42 ControllingDangerousPathogensReport project raised important new policy questions, however, the committee’s recommendationontheconductoftheresearchandthehandlingoftheresults would have to be approved by the executive body of the international organization. Because research projects at this level generally would be expected to be importanttoglobalhealth,allprojectdecisionsbytheInternationalPathogens Research Authority would be reported to member states. The results of all research approved by the IPRA also generally would be disseminated to all members. Wheneverpossible,theIPRAwouldfollowthemodelofopenness setbyWHOinreviewingproposedresearchprojectswithsmallpox,themost dangerousexistingpathogen. WHOmeetingstoreviewproposedprojectsare open to observers from WHO member states, with detailed meeting notes availableontheWHOwebsite.TheresultsofallWHO-approvedprojectsare also publicly available, although there can be a delay between submission to WHO and publication. As noted above, however, in rare circumstances the IPRAmightconclude,onthebasisofstandardizedcriterialikethoseusedat otherlevelsofthesystem,thattheglobalinterestwasbestservedbyrestricting accesstothedetailsofaresearchprojectunderitsjurisdictionorthesubsequent results. Researchers carrying out projects involving activities of extreme concern would be requiredtosubmitbiannualreportstoIPRA, outlining proposed changes in personnel; detailed experimental results and plans for further research; proposed changes in protocols; the status of agent stocks; safety violationsorsecuritybreaches;andlicensing changes. Asatotherlevelsoftheoversight system,minorchangescouldbeapprovedby anexpeditedprocessbutsignificantchanges wouldhavetogothroughtheregularreview procedures. Uponcompletionoftheproject, theprincipalinvestigatorwouldsubmitafinal reporttotheIPRAontheresearchresults,the disposition of any recombinant materials (accountingbothfortheagentsconsumedin experiments and destruction of excess materials),andpublicationplans. IPRA-approved research facilities would be monitoredtoensurethattheworkwasdone in accordance with protocols authorized by theIPRA. Thiscouldincludethereviewof laboratory notebooks, interviews, and sampling. Any irregularities would be promptlyreportedandscientistswhostrayed substantiallyfromtheirproposedworkwould be subject to penalties and possibly suspensionorlossoftheirrighttoparticipate inIPRA-levelprojects. In rare circumstances the IPRA might conclude, on the basis of standardized criteria like those used at other levels of the system, that the global interest was best served by restricting access to the details of a research project under its jurisdiction or the subsequent results. ControllingDangerousPathogensReport 43 In addition to its work directly overseeing projects involving activities of extreme concern, the International Pathogens Research Authority would also establish and maintain a database of information on such projects, the researchers involved, and all relevant pathogen strains. The database would include strong firewalls to prevent unauthorized access and a sophisticated system for storing, retrieving, translating and cross-referencing data. Access would be limited to specified employees of the IPRA. Confidentiality agreementswouldbeinplaceandinformationthatwasaccessedcouldonlybe usedforapprovedpurposes. The IPRA would also engage in a variety of activities aimed at assisting participatingcountriesindevelopingthecapacitytomeetthepeerreviewand oversight requirements at the heart of the system. Such capacity building measurescouldincludethedevelopmentofdetailedguidelinesoutliningbestpractices;programstotrainnationalofficialsonwhatisrequiredtocomplywith the oversight system; formal processes for sharing information, including lessonslearned;andspecificassistanceonnationalimplementation,including regulatoryrequirements. Itwouldalsoassessthejudgmentsbeingmadeona nationalbasisonresearchofpotentialandmoderateconcernandholdperiodic conferences aimed at promoting harmonization of national implementation activities. 44 ControllingDangerousPathogensReport .......... ..... The Way Forward The advanced oversight system that has been outlined would involve three major innovations over existing oversight arrangements: it would subject the mostconsequentialareasofresearchtointernationaljurisdiction;itwouldapply oversight comprehensively within all jurisdictions; and it would make the oversightprocessalegalobligation.Thoseprovisionsaresuggestedinorderto assureeffectiveprotection.Itisdoubtfulthatexclusivenationaljurisdictioncan achieve a globally harmonized system. It is similarly doubtful that adequate protection could be achieved in any jurisdiction if oversight is partial and optional.Itisuncomfortablyprobablethatsecretivenationalthreatassessment programsexemptedfromindependentoversightwillultimatelygeneratehostile emulation. Those are serious considerations that can be said to reflect the imperatives of emerging circumstance. They do clearly defy, however, the dominantinclinationofinstitutionaltraditionandpoliticalsentiment. Legal authority and political affiliation are both vested primarily in national governments throughouttheworld,andthosegovernmentswill predictably be the preferred venue for exploiting thebenefitsandmanagingthedangersofadvances inbiology.Moreover,themomentumofscientific discoverythatisthesourceofbenefitanddangeris basedonfreedomofinquiry,andtheautonomyof the fundamental research process will predictably be defended against fears of perverse regulatory intrusion. The practical question is whether acceptable incremental measures can be devised that would mitigate these objections and provide meaningful benefit without compromising the ultimate achievement of an advanced oversight system. In principle that is clearly possible. The BRSS wouldbebasedonnationalandlocaloversightand would subject only a limited set of especially dangerousactivitiestodirectglobaljurisdiction.A surveyofjournalarticlespublishedintheUSfrom 2000 to mid-2005 indicates that some 310 US facilities and 2,574 US researchers would have been subject to the suggested BRSS oversight procedureshadtheybeenineffect.63Lessthan1% of US research publications involving bacteria, virusesorprionswouldhavebeenaffectedinany way.Amongthosethatwouldhavebeenaffected, only12ofthefacilitiesand185oftheindividuals A survey of journal articles published in the US from 2000 to mid2005 indicated that some 310 US facilities and 2,574 US researchers would have been subject to the suggested BRSS oversight procedures had they been in effect. ControllingDangerousPathogensReport 45 wouldhavebeenassignedtointernationaljurisdiction—atinyfractionofthe American biomedical research community. Fourteen facilities and 133 individualswouldhavebeenassignedtonationaljurisdiction;and231facilities involving 2119 individuals would have fallen under local jurisdiction. Fiftythree facilities and 137 individuals would have encountered multiple jurisdictions.Thosenumberssuggestthatindependentdevelopmentofnational andlocaloversightprovisionswouldcovermostofwhatanadvancedsystem wouldeventuallyinvolveandwouldlaythefoundationforsuchasystemas long as the national and local provisions are based on globally compatible principles. In practice, relevant initiatives already are being undertaken. With encouragement from the US National Academy of Sciences and the British Royal Society, for example, individual scientists and professional scientific organizations are discussing applicable scientific codes.64 Much of this discussionisfocusedonethicalcodes,whichdescribepersonalandprofessional standards or codes of conduct, which provide guidelines on appropriate behavior. Virtually no attention is being given to codes of practice, which outlineenforceableproceduresandrules.Thus,inSeptember2001,theWorld MedicalAssociationissuedadeclarationonbiologicalweaponswhich,among otherthings,calledon“allwhoparticipateinbiomedicalresearchtoconsider theimplicationsandpossibleapplicationsoftheirworkandtoweighcarefully in the balance the pursuit of scientific knowledge with their ethical responsibilitiestosociety.”65InJune2004,guidelinestopreventthemalevolent useofbiomedicalresearchwereadoptedbytheAmericanMedicalAssociation and incorporatedin theAMA’s Codeof MedicalEthics.66 Other codesof conduct related to life sciences research have been put forward by the International Committee of the Red Cross67 and by Canadian bioethicist Margaret SomervilleandformerASMpresidentRonaldAtlas.68InDecember2005,the Inter-AcademyPanel,anassociationofover80nationalacademiesofscience, released a set of general principles to guide the development of codes of conductbyindividualscientistsandlocalscientificcommunities.69Asnoted earlier,workalsoisbeingdonebytheNSABBintheUnitedStatesontheissue ofcodesofconductforscientistsandlaboratoryworkers. Itisnotenough,ofcourse,tosimplyhavescientificcodes,whateverthetype. Scientistsmustbeeducatedaboutthedetailsofsuchcodesandthepotentialfor misuse of their work. They also must be informed about relevant laws and regulationsgoverningtheconductofdual-useresearchandprovidedtrainingto enable them to meet the oversight requirements that are in place. Such educationandtrainingprogramswillbeimportantnotonlyforstudentsatthe beginning of their academic studies but also for established researchers who beforenowhaveconsideredthepotentialbenefitsbutnotthepotentialrisksof theirwork.Aprototypebiosecuritycourseforstudentshasbeenpostedonthe website of the US journal, Politics and the Life Sciences. Additional biosecurity educational modules are being developed by the Federation of AmericanScientistsandotherorganizations.70 Theseinitiativescouldbesignificantlyreinforcedbyscientificfundingagencies, research institutions and journals if they required all those with whom they interactonaprofessionalbasistoadheretorelevantscientificcodes,lawsand regulations. In September 2005, the UK’s three leading bioresearch funding agencies, the Medical Research Council, the Wellcome Trust, and the 46 ControllingDangerousPathogensReport BiotechnologyandBiologicalSciencesResearchCouncil,announcedthatthey would now require grant applicants, reviewers and funding agency board memberstoallconsiderwhethertheproposedresearchcouldbemisusedfor harmful purposes.71 Research institutions, especially those in industry or government that might initially be outside the scope of a formal oversight arrangement,couldimposeasimilarrequirementforindividualresearchersand theheadsofthelaboratoriesinwhichtheyworktoexplicitlyconsiderthedualuseimplicationsofresearchtheyconductasaconditionofemployment. For theirpart,scientificjournalscouldrefusetopublishmanuscriptssubmittedby researcherswhodidnotfollowsuchrules. Inadditiontothesemeasures,otherinterimstepscouldbetakenbynational governmentsthatcouldmoredirectlystrengthenoversightofdual-useresearch. In the United States, this would include adding the categories of dual-use researchandtherisk-benefitassessmentcriteriadevelopedbytheNSABBtothe NIH Guidelines, consistent with the Fink Committee recommendation. It wouldalsoincludeextendingthescopeofthe NIH Guidelinestoapplytoall relevant research facilities, irrespective of whether they are receiving recombinantDNAfundingfromNIH,72andconvertingtheGuidelinesfroma voluntarycommitmenttoalegallybindingrequirement. Asdiscussedabove, the US has already taken a step in this direction by requiring government approval of two particular classes of recombinant DNA experiments if they involveworkwithpathogensontheselectagentlist. Newlegalauthorityas wellasadditionalfundingwouldberequiredtorevamptheIBCsystemtotake ontheseaddedresponsibilitiesandtogiveNIHthecapacitytomoreeffectively monitor, through IBC reporting and periodic inspections, compliance with its rules. IBCaswellasNIHoversightwouldalsobeenhancedbytheadoption ofanelectronicdatamanagementsystemliketheprototypewehavedeveloped, whichnotonlyconsolidatesvariousbiosecurity,biosafetyandotherreporting requirements but also facilitates the transfer of relevant information to the necessaryoversightbody.73 OutsideoftheUS,othercountriesthatfollowthe NIHGuidelinesorthathave similar oversight processes for recombinant DNA research could also be encouraged to include specified dual-use research activities in their national regulationsandtorequireadherencebyallfacilitiesundertakingsuchwork,on a mandatory basis. These national standards and regulations could then be harmonizedamonglike-mindedcountries,perhapsbeginningwiththe30nations (plus the European Union) that comprise the Organization for Economic Cooperation and Development (OECD). This would be consistent with the O E C D ’s efforts since 2001 to develop a harmonized approach to the managementandsecurityofculturecollectionsandotherbiologicalresources74 aswellasitsmorerecentinterest,comingoutoftheSeptember2004Frascati conference,inpromotingresponsiblestewardshipinthebiologicalsciencesand preventingabuseofresearch.75TheOECDcoulddevelopauniformlistofdualuseresearchactivitiestobesubjecttooversightaswellasstandardizedcriteria forassessingtherisksandbenefitsofsuchresearch. Itcouldalsoestablisha processforperiodicreportingonnationalimplementationofthesemeasuresby OECDmemberstates. Efforts such as this by the OECD or other like-minded countries could be facilitated by WHO, which has a long history of providing technical information,guidanceandassistancetothepublic,healthcareprofessionalsand ControllingDangerousPathogensReport 47 policymakers on the control of dangerous pathogens.76 WHO’s Laboratory BiosafetyManual,firstpublishedin1983,hasprovidedpracticalguidanceon biosafetytechniquesforuseinlaboratoriesaroundtheworld. Sincethe2001 anthraxletterincidentsintheUS,WHOhasalsobeendevelopingguidelinesfor enhancingthesecurityofdangerouspathogensinlaboratoryenvironments.And ithasbeenhelpingtostrengthenglobalpublichealthpreparednessandresponse capabilitiesfornatural,accidentalordeliberatereleasesofbiologicalandother agents that affect public health by developing networks of laboratories and experts on biological agents, providing guidelines for assessing national capabilities,anddisseminatingtechnicalinformationonspecificagentsthatpose athreattopublichealth.Inmid-2004WHOinitiatedanexploratoryprojecton thegovernanceoflifesciencesresearchanditsimplicationsforpublichealth.77 Manyoftheissuesthatwerehighlightedinthisexploratoryworkarenowbeing consideredinanewWHOprojectaimedatexaminingtheimplicationsoflife sciencesresearchforglobalhealthsecurity. Inadditiontoraisingawareness abouttheopportunitiesandrisksoflifesciencesresearch,thisprojectcouldalso laythefoundationforthedevelopmentbyWHO,inpartnershipwithFAOand OIE,oftechnicalguidelinesforoverseeingdual-useresearch.78 There are thus a variety of incremental measures that can be pursued by scientists, national governments and international organizations that can help prevent life sciences research from being used, either deliberately or inadvertently, for destructive purposes. Some of these measures, such as ethical codes and codes of conduct, are likely to have a very limited impact unlessscientistsareeducatedaboutthepotentialrisksoftheirworkandtheir responsibilities to society and funders, employers and publishers formally requirethemtocomplywithexistingrules,whatevertheirform. Others,such asnationaloversightsystemsandinternationallydevelopedtechnicalguidelines, canclearlyhaveamoredirectandpositiveimpactoneffortstomanagedualuseresearch.Noneissufficientbutallofthemcanhelplaythefoundationfor themoreadvancedoversightsystemoutlinedabove. 48 ControllingDangerousPathogensReport .......... Concluding Observations ..... Boththeargumentsunderlyingourapproachtothedual-useproblemandthe specific proposals we have put forward in this monograph and in other publications seem distinctly less radical today than when we first began this projectin2001. ThisisespeciallytrueintheUnitedStates,whereattitudes amongthescientificeliteandamongpolicyexpertshaveundergoneasignificant change.ThisisperhapsbestexemplifiedbytheworkoftheFinkCommittee, which in its initial meetings appeared confident that the existing process for overseeingrecombinantDNAresearchwasmorethancapableofhandlingany residual concerns about biotechnology. In its final report, however, the Committeepaintedamuchstarkerpictureofthepotentialthreatposedbydualuseresearchandunderscoredtheabsenceofnationalandinternationaloversight mechanisms to address the problem. It also challenged the conventional wisdomthatdangerousresearchcouldnotbedefinedandexplicitlyendorsedthe adoptionofatieredpeerreviewprocesstoassesssuchresearch.Anditmade clearthatanyseriousattempttoreducetherisksassociatedwithbiotechnology mustultimatelybeinternationalinscope. Since the Fink Committee report in 2003, other leading scientists have acknowledgedtheweaknessesoftheexistingIBCsystem,79asdocumentedby the Sunshine Project, with some recommending that the NIH Guidelines on which it is based be replaced by a more comprehensive, legally binding requirement.80Supporthasalsocomefromanumberofdifferentquartersfor licensing not only facilities doing work with dangerous pathogens81 but also biologiststhemselves.82AndformerseniorofficialsfrombothUSpolitical partieshaverecentlycalledforthedevelopmentofinternationalguidelinesfor reviewing, approving and monitoring dual-use research, and urged that WHO andotherinternationalscientificorganizationsplayaroleinthiseffort.83 Atthemomentweknowthatthepaceofscientificdiscoveryisrapidandthat theaccomplishmentsaretrulyextraordinary.Wedonotknowwhattheultimate consequenceswillbeortheamountoftimeoverwhichtheywillemerge.We alsodonotknowhowmuchofamanagerialburdenwillbeimposed,butthere isgoodreasontoassumethatitwilleventuallybesubstantialenoughtochange evendeeplyentrenchedhabitsandpractices.Asweevolvecarefully,therefore, anddowhatisimmediatelyacceptable,weshouldstraintothinkbroadlyand boldly. And the appropriate we in this situation is the human species as a whole.Ifoursurvivalisnotliterallyatstake,thenourprosperityverylikelyis andourcommoninterestmuchstrongerthanwehaveyetappreciated. Ifso, thenwewilleventuallyneedmoreadvancedformsofprotectiveorganization, andwehadbeststartdiscussingthedetailedimplications. ControllingDangerousPathogensReport 49 50 ControllingDangerousPathogensReport Appendix A US-Based Project Workshop Participants Affiliationsarecurrentforthetimetheindividualparticipatedintheprojectand areforinformationpurposesonly. Norma Allewell Dean,CollegeofLifeSciences UniversityofMaryland Jeffrey Almond SeniorVPforExternalR&Dand DiscoverySciences AventisPasteur Ron Atlas Dean,GraduateSchool UniversityofLouisville Joseph R. Barnes BrigadierGeneral(Retired) USArmy Natalie Barnett BiosecuritySystemsAnalyst SandiaNationalLaboratories Kennette Benedict Director,InternationalPeaceand SecurityProgram TheJohnD.andCatherineT. MacArthurFoundation Leslie Berlowitz ExecutiveOfficer AmericanAcademyofArtsand Sciences Gregg Bloche ProfessorofLaw GeorgetownUniversity Orley Bourland FormerOfficial FortDetrick Allan Cameron ProgramManager,NationalSecurity Program ComputerSciencesCorporation Rocco Casagrande PrivateConsultant Shubha Chakravarty SoftwareEngineer BrookingsInstitution Allison Chamberlain ProgramAssistant,NationalScience AdvisoryBoardforBiosecurity NationalInstitutesofHealth Marie Chevrier Professor UniversityofTexasatDallas Eileen Choffnes Director,ForumonMicrobialThreats NationalAcademyofSciences Rashid Chotani AssistantProfessor JohnsHopkinsUniversity George Church ProfessorofGenetics HarvardMedicalSchool Nancy Connell Professor UniversityofMedicineandDentistry ofNewJersey Derek Cummings ResearchAssociate,Departmentof InternationalHealth BloombergSchoolofPublicHealth JohnHopkinsUniverstiy Malcolm Dando Professor,DepartmentofPeace Studies UniversityofBradford ControllingDangerousPathogensReport 51 Christopher Davis ChiefScientist&Directorof BiomedicalResearch CUBRC Neil Davison DepartmentofPeaceStudies UniversityofBradford Paul Doty MallinckrodtProfessorof Biochemistry,EmeritusDirector HarvardUniversity Gregory Douglass SystemsAnalyst,Environmental Safety UniversityofMaryland Richard Ebright Investigator,HowardHughesMedical Institute RutgersUniversity Chris Eldridge ProgramOfficer,Committeeon InternationalSecurityandArms Control NationalAcademyofSciences Gerald Epstein SeniorFellowforScienceand Security,HomelandSecurityProgram CenterforStrategicandInternational Studies Joshua Epstein SeniorFellow BrookingsInstitution David Fidler ProfessorofLaw IndianaUniversity Gerald Fink ProfessorofGenetics MassachusettsInstituteofTechnology Joe Fitzgerald SeniorAssociate,Centerfor Biosecurity UniversityofPittsburghMedical Center 52 ControllingDangerousPathogensReport David Franz ChiefBiologicalScientist MidwestResearchInstitute Arthur Friedlander SeniorScientist U.S.ArmyMedicalResearchInstitute ofInfectiousDiseases(USAMRIID) Claire Fraser President TheInstituteforGenomicResearch Jennifer Gaudioso InternationalBiosecurityAnalyst SandiaNationalLaboratories Alex Greninger MedicalStudent UniversityofCalifornia,San Francisco MaryE.Groesch SeniorAdvisorforSciencePolicy, OfficeofBiotechnologyActivities NationalInstitutesofHealth Gigi Kwik Gronvall Fellow,CenterforBiosecurity UniversityofPittsburghMedical Center Tim Gulden ResearchFellow,SchoolofPublic Policy UniversityofMaryland Harlyn Halvorson Director,PolicyCenterforMarine Bio-SciencesandTechnology UniversityofMassachusetts,Boston Peggy Hamburg VicePresidentforBiological Programs NuclearThreatInitiative Peter Hammond HeadofCorporateAffairs,Centrefor EmergencyPreparednessand Response,PortonDown UKHealthProtectionAgency Jason Harenski Architect InsubstantialArts Alastair Hay Professor,EnvironmentalToxicology, SchoolofMedicine UniversityofLeeds Lucas Haynes ProgramOfficer,InternationalPeace andSecurityProgram TheJohnD.andCatherineT. MacArthurFoundation Lisa Hensley ResearchMicrobiologist U.S.ArmyMedicalResearchInstitute ofInfectiousDiseases(USAMRIID) Thomas Holohan ExecutiveDirector,NationalScience AdvisoryBoardforBiosecurity NationalInstitutesofHealth James Holt SeniorAttorneyforOfficeofthe GeneralCounsel CentersforDiseaseControl Jo Husbands SeniorProjectDirector,Policyand GlobalAffairsDivision NationalAcademyofSciences Peter Jahrling ChiefScientist NationalInstituteofAllergiesand InfectiousDiseases Joseph Jemski FormerOfficial FortDetrick Anna Johnson-Winegar Consultant Rebecca Katz DoctoralCandidate WoodrowWilsonSchoolofPublic andInternationalAffairs PrincetonUniversity Carl Kaysen SkinnerProfessorofPolitical Economy,Emeritus MassachusettsInstituteofTechnology Barry Kellman Professor,CollegeofLaw DePaulUniversity Gregory Koblentz Post-DoctoralFellow,SecurityStudies Program MassachusettsInstituteofTechnology David Koplow Director,CenterforAppliedLegal Studies GeorgetownUniversity Jens Kuhn ResearchFellow BrighamandWomen’sHospital Edgar Larson FormerOfficial FortDetrick James LeDuc DirectorofBiologicalandRickettsial Diseases CentersforDiseaseControl Milton Leitenberg SeniorResearchScholar,CISSM UniversityofMaryland ShanLu AssociateProfessor UniversityofMassachusettsMedical School Martin Malin ProgramDirector CommitteeonInternationalSecurity Studies AmericanAcademyofArtsand Sciences Richard Manchee Director ArjempturTechnologyLimited ControllingDangerousPathogensReport 53 Jessica Mann ResearchTeachingSpecialist& LaboratoryManager CenterforEmergingPathogens UniversityofMedicineandDentistry ofNewJersey Gene Matthews LegalAdvisor CentersforDiseaseControl Alan Pearson ProgramDirector,Biologicaland ChemicalWeaponsProgram CenterforArmsControlandNonProliferation C.J. Peters Director,CenterforBiodefense UniversityofTexasMedicalBranch Caitronia McLeish ResearchFellow UniversityofSussex Janet Peterson AssistantDirectorandBiological SafetyOfficer UniversityofMaryland Jack Melling SeniorScienceFellow CenterforArmsControlandNonProliferation JamesB.Petro Chief,KnowledgeIntegrationProgram Office DepartmentofHomelandSecurity Peter Merkle ProjectManager,GroupCollaboration TechnologyDevelopment SandiaNationalLaboratories John Polanyi DepartmentofChemistry UniversityofToronto Matthew Meselson ThomasDudleyCabotProfessorof theNaturalSciences HarvardUniversity Piers Millet OrchardCollege Thomas Monath ChiefScientificOfficer Acambis Timothy Ng AssociateVicePresidentforResearch UniversityofMaryland Patricia Nicholas ProgramAssociate,International PeaceandSecurity CarnegieCorporationofNewYork Kathryn Nixdorff Professor,Departmentof MicrobiologyandGenetics DarmstadtUniversityofTechnology Paula Olsiewski ProgramDirector SloanFoundation 54 ControllingDangerousPathogensReport Alexander Rabodzey DoctoralCandidate,Divisionof MicrobiologyEngineering MassachusettsInstituteofTechnology Bryan Roberts President ParallelSolutions,Inc. Christopher Royse DeputyTaskLeader,Biological WeaponsProliferationSupportTeam ScienceApplicationsInternational Corporation Jennifer Runyon ResearchAssociate ChemicalandBiologicalArms ControlInstitute Ben Rusek ResearchAssociate,Committeeon InternationalSecurityandArmsControl NationalAcademyofSciences David Sabatini FrederickL.EhrmanProfessorand Chairman,DepartmentofCell Biology NYUSchoolofMedicine Reynolds Salerno Director,BiosecurityProgram SandiaNationalLaboratories Alan Schmaljohn Virologist Suzanne E. Spaulding Chair,StandingCommitteeonLaw andNationalSecurity Richard Spertzel FormerHeadofBiological Inspections, UnitedNationsSpecial Commission(UNSCOM) Robert Sprinkle AssociateProfessor,SchoolofPublic Affairs,UniversityofMaryland Dan Stein Professor,CellBiology UniversityofMaryland Eric Stephen Chemical&BiologicalMedical Countermeasures,R&DCoordination DefenseResearchandDevelopment Canada Emmanuelle Tuerlings TechnicalOfficer,Preparednessfor DeliberateEpidemics WorldHealthOrganization Sanford Weiner ResearchAssociate CenterforInternationalStudies MassachusettsInstituteofTechnology Mark Wheelis SeniorLecturer,Microbiology Department UniversityofCaliforniaatDavis Simon Whitby DepartmentofPeaceStudies UniversityofBradford Patricia Wrightson StaffDirector RoundtableonScientific CommunicationandNationalSecurity NationalAcademyofSciences Jenna Young ResearchAssistant FederationofAmericanScientist ControllingDangerousPathogensReport 55 56 ControllingDangerousPathogensReport Appendix B Regional Workshop Participants Affiliationsarecurrentforthetimetheindividualparticipatedintheprojectand areforinformationpurposesonly. Lucia Aleixo Researcher,FederalUniversityof MinasGerais,FaculdadedeMedicina, BRAZIL Philip van Dalen SeniorPolicyOfficer,Communicable Diseases/Bioterrorism,Ministryof PublicHealth,NETHERLANDS Jorge Arevalo HeadoftheMolecularEpidemiology ResearchUnit,InstituodeMedicina Tropical“AlexandervonHumboldt,” PERU Maria Espona ScienceandTechnologyProfessor NationalDefenseSchool ARGENTINA AntoniodePaduaRisoliaBarbosa DeputyDirectorofProduction,BioManguinhosOswaldoCruz Foundation,BRAZIL Borut Bohanec HeadoftheCenterforPlant Biotechnology,Universityof Ljubljana,SLOVENIA B.P. Berdal Head,InstituteofMicrobiology ArmedForcesMedicalServices NORWAY Edmundo Calva ProfessorofMolecularMicrobiology InstitutodeBiotecnologiaUNAM, MEXICO Filippa Corneliussen ResearchFellow,BIOSCentre LondonSchoolofEconomics UNITEDKINGDOM Ottorino Cosivi ProjectLeader,Preparednessfor DeliberateEpidemics,Deptof EpidemicandPandemicAlertand Response,WHO Emoke Ferenczi DepartmentofVirology,“BelaJohan NationalCentreforEpidemiology,” HUNGARY Roberto Fernandez ChiefofBiosafety,InstitutoPedro Kouri,CUBA Ake Forsberg ResearchDirector,FOI-NBCDefense, SWEDEN Jozsef Furesz ScientificDirector,InstituteofHealth Protection,HealthServicesof HungarianDefenceForces, HUNGARY Joxel Garcia SeniorVPandSeniorMedical Advisor,Maximus,Inc. FormerDeputyDirector,PAHO Natalia Kostereva StateFederalEnterpriseforScience ResearchCentreforToxicology& HygienicRegulationof BiopreparationsatFederalMedicoBiologicalAgency,RUSSIA ControllingDangerousPathogensReport 57 Vidal Rodriguez Lemoine ProfessorinGeneticsand Microbiology,FacultyofSciences, UniversidadCentraldeVenezuela VENEZUELA Marcin Niemcewicz SeniorResearchFellow,Military InstituteofHygiene&Epidemiology BiologicalThreatIdentificationand CountermeasuresCenter,POLAND Alemka Markotic AssociateProfessor,Headof ScientificUnit,UniversityHospital forInfectiousDiseases,CROATIA Pericles Palha de Oliveira DeputyDirector,BrazilianArmy InstituteofBiology,BRAZIL Leonardo Mateu President,InstitutodeEstudios Avanzados,VENEZUELA Caitriona McLeish ResearchFellow,SciencePolicy ResearchUnit,UniversityofSussex UNITEDKINGDOM Leda C.S. Mendonca-Hagler ProfessorofMicrobiology UniversidadeFederaldoRiode Janeiro,BRAZIL Carlos Alberto Mendoza Ticona InfectiousDiseasesandTropical Medicine,InstitutoNacionaldeSalud, PERU Gloria Palma Professor,Departmentof Microbiology,SchoolofHealth Sciences,UniversidaddelValle, CampusSanFernando,COLOMBIA Georg Pauli HeadoftheDepartmentofBiosafety RobertKochInstitute,GERMANY Bogdan Petrunov Director,NationalCenterofInfectious andParasiticDiseases,BULGARIA Gerard Pouw SeniorPolicyOfficer,Communicable Diseases/Bioterrorism,Ministryof PublicHealth,NETHERLANDS Walter Mendoza Consultant,UnitedNationsPopulation Fund,PERU Julius Rajcani AssistantProfessor,Instituteof Virology,AcademyofSciences SLOVAKIA Roque Monteleone-Neto UnitedNationsSecretariat 1540CommitteeExpertsOffice UNITEDNATIONS Lajos Rozsa AnimalEcologyResearchGroup HungarianAcademyofSciences HUNGARY Vivienne Nathanson DirectorofProfessionalActivities BritishMedicalAssociatioin UNITEDKINGDOM Guilherme Santana SuperiintendentedePlanejamentoe Pesquisa,AgênciaNacionaldo Petróleo,GásNaturale Biocombustiveis,BRAZIL Kathryn Nixdorff InstitutfürMikrobiologieundGenetik Technische,UniversityofDarmstadt, GERMANY 58 ControllingDangerousPathogensReport David Sawaya Bioeconomy/Biosecurity InternationalFuturesProgramme OECD Simone Scholze ProgrammeSpecialist,Ethicsof ScienceandTechnology,UNESCO Vladimir Sigaev StateFederalEnterpriseforScience, ResearchCentreforToxicologyand HygienicRegulationof BiopreparationsatFederalMedicoBiologicalAgency,RUSSIA N.J. Silman GroupLeader,CentreforEmergency PreparenessandResponse,Health ProtectionAgency,PortonDown UNITEDKINGDOM Karl Simpson President,Benezech–Simpson FRANCE Geoffrey Smith DepartmentofVirology,Facultyof Medicine,ImperialCollegeLondon UNITEDKINGDOM Mario Soberon HeadofDepartmentofMolecular Microbiology,Institutode Biotecnologia,UniversidadNacional AutonomadeMexico,MEXICO Ana Tapajos HeadofProjectsDivision,Officeof InternationalAffairs(Minister’s Cabinet),BRAZIL Judit Vegh NationalCommunicationsAuthority HUNGARY Rafael Vicuna FullProfessor,FacultyofBiological Sciences,PontificaUniversidad CatolicadeChile,CHILE Dominique Werner Head,ArmsControlUnit SPIEZLaboratory,SWITZERLAND Guillermo Whittembury SeniorInvestigatorEmeritus,Instituto VenezolanodeInvestigaciones Cientificas,VENEZUELA ControllingDangerousPathogensReport 59 60 ControllingDangerousPathogensReport Appendix C Prototype Data Management System: Overview TheproposedBiologicalResearchSecuritySystemforprotectiveoversightof researchwithdangerouspathogensrestsontwoinformation-intensiveelements: personnel and facility licensing and independent peer review. Individual researchers and academic, corporate, or government administrators will only makesensitiveinformationavailabletooutsidescrutinyiftheybelievethatthe benefitsofdisclosurewilloutweightheinconvenience,expense,andpotential formisuse.TheBRSShasbeendesignedtomatchthedisclosurerequirements with the degree of risk involved in a particular line of research. Thus, one necessary component for the success of the overall BRSS is a multi-level, access-controlled data management system that is easy to use, relatively inexpensive,highlyreliable,andextremelysecure. Nosuchdatasystemfortrackingresearchwithdangerouspathogenscurrently exists,andthemorelimitedsystemsthatareavailablehavebeencriticizedon groundsofusability,security,andprivacy.Forexample,U.S.legislationpassed inMay2002requiresallfacilitiesthatpossesscertainhuman,plantoranimal pathogenstoregisterwiththeCentersforDiseaseControlandPreventionorthe AnimalandPlantHealthInspectionService.ItalsodirectstheDepartmentsof HealthandHumanServicesandAgriculturetodevelopanationaldatabaseof registeredpersonsandthecontrolledagentstheypossess,includingstrainand othercharacterizinginformationifavailable.Scientistsandadministratorshave reacted to this limited data collection effort with complaints about the cumbersome reporting process, questions about the security value of some required information, and uncertainty about who could access the reported informationandhowitmightbeused. Clearly,boththecurrentlymandated data collection effort and our more ambitious proposal to collect information about research activities as well as pathogen holdings would benefit from a moresystematicefforttothinkthroughthedatamanagementquestionsfromthe perspectivesofthescientists,administrators,andtechnicalsupportstaffwhose cooperationisessential. PrototypeDataManagementSystem1 TheBRSSisessentiallyasetofrulesaboutwhattypesofinformationmustbe disclosed by whom, to whom, when, for what purposes, and with what protections. Accordingly, we have approached the BRSS’s prototype data 1 JasonHarenskidevelopedthefunctionalspecificationandGordonMcMillanbuiltthe prototypesystem,withassistancefromTimGulden.Thequestionnairesweredevelopedby JessicaMannMcCormick. ControllingDangerousPathogensReport 61 management software as a workflow system A workflow system passes information and tasks from user to user according to clearly defined internal rules. Suchasystemmustbedynamic,withdefinedproceduresforupdating and disseminating its internal rule sets when, for example, a BRSS policy decisionismadetoaddnewresearchactivitiestoexistingoversightprocedures or to require additional information about research activities at an existing oversightlevel. Ourprototypedatamanagementsystemisdistributedinatree-shapedstructure, witheachlocusofoversighthavingtheabilitytooperateitsownserversothat itcanaddcustomizedquestionsandretaindirectcontroloveritsdata. While wehaveconceptualizedthisasathreelevelstructurewithlocal,national,and international level nodes, the software is capable of supporting an arbitrary number of levels. Every end user (researcher, administrator, or technical support staff) is a “client” who communicates exclusively with a server that contains the relevant rule sets and retains physical control over records associated with its clients. The data management system could operate with only one functioning server (the root node at the international level), but typically the servers associated with the broader oversight bodies will act as parent nodes for child nodes that possess more detailed information about a geographicallysmallersetoflessdangerousactivities. Thisstructureprovides tremendousflexibilityandscalability.Forexample,itmeansthatifadecision wasmadetostarttheBRSSwithasmallnumberoflike-mindedcountriesand thentoexpanditovertime,thedatasystemcouldbefullyfunctionalatthe outset and grow with the oversight system. It also means that different countriescanorganizethenodesundertheirjurisdictionintodifferentpatterns depending on their own national regulatory structure, economic and technologicalcircumstances,andamountofresearchwithdangerouspathogens. We have built the prototype data management system using open-source software,includingsomepre-existingpackagesthathavebeenintegratedwith custom-writtencode. Thisdesignstrategyhasmadeitpossibletosatisfyour stringentrequirementswithoutpayingforunnecessaryandexpensivefeatures. Thedatamanagementsystemhasbeendesignedsothatnolicensefeeneedsto bepaidbyindividualusersorservernodes.Thus,decisionsaboutparticipation and node operation can be made on the merits alone. Using open-source softwareisalsoconsistentwiththeBRSSphilosophyoftransparency,reliability, and integrity. Before entrusting sensitive information to the system, any potentialusercancheckthecompletecodetomakesurethatthesoftwarewill dowhatitissupposedtodoandnothingmore. System Description TheprototypeBRSSdatamanagementsystemisdesignedtodemonstratethe keyfeaturesofsuchasystemandtoprovideaconcreteexampleonwhicha discussion of a full-blown system can be based. These features include the abilityto: • • • establishclient/serverandparent-node/child-noderelationships; presentuserswithuser-friendlyquestionnairesatappropriatetimes; collect, store, manage, and transmit information between databases accordingtoexistinginternalrules; 62 ControllingDangerousPathogensReport • • • changeinternalrulesanddisseminatemodifiedquestionnairestoreflect new BRSS policy decisions or additional requirements established by nationalorlocaloversightofficials; flagsituationsinwhichexistingrulesarenotfollowedornewrulesare rejected,sothatthesituationcanreceiveappropriatefollow-upatthe appropriateoversightlevel;and, providefinancial-industry-gradeaccesscontrolsandinformationsecurity atalltimes. Intheinterestofsecurityanddeploymentsimplicity,wehavechosena“thin client” framework where all processing and storage is conducted on server nodes that users access via a web browser client. This avoids the need for individual users to install custom software and allows client-server security protocolstobehandledinanindustrystandardway. TheprototypesystemusesquestionnairesreflectingBRSSpoliciesasabasisfor the oversight of institutions, laboratories, users, and projects. When a new institution, laboratory, user, or project is created in the system, the user associatedwiththisnewlycreatedentityisprompted(viaemail)tologintothe system and respond to a set of questions regarding the new entity (a new project, for example). This opening questionnaire gathers basic information aboutthenewprojectandthenasksaseriesofquestionsdesignedtodetermine theneedforfurtherquestions.If,forexample,theprojectinvolvestheuseof recombinant DNA technology, the user is queued a follow-up questionnaire abouthowthetechnologywillbeused,whattheresearcherhopestoaccomplish throughitsuse,etc.Answerstothesequestionsmay,inturn,triggeradditional questionnaires. Workinginconjunctionwithbiosafetyofficersandbenchscientistsinthearea ofpathogenresearch,wehavedevelopedelevenprototypequestionnaireswitha cascading design to minimize irrelevant questions. Although the system containsmanyquestionsoverall,mostuserswillneedtoaddressrelativelyfew ofthemforanygivenproject. Assigning administrative responsibilities by institution, laboratory, user, and projectalsoallowsustoavoidredundantquestions.Questionspertainingtoan institution (e.g. whether it has an institutional biosafety committee) need be answeredonlyonce,bytheadministrator(mostlikely,thebiosafetyofficer)of that institution. The system will prompt this administrator to update these answersperiodically,soindividualresearchersneednotbeburdenedwiththem for each new project they undertake. Similarly, a laboratory administrator (which may or may not be the same person as the principle investigator on projectsinthatlaboratory)willanswerandupdatequestionspertainingtohisor herlaboratory,butwillnotneedtoanswerthemagainforeachnewproject. Each user will answer and update questions about their own training, status, activities, etc. This means that a project administrator (usually the principle investigatorforthatproject)neednottrackdownalloftherelevantinformation foreachresearcheronaproject. Instead,thesystemwillmakeitcleartothe project administrator whether the researchers involved with the project meet existingBRSSrequirements. Questionnairespropagateautomaticallydownthetreehierarchysothatquestions whichareapprovedbytheinternationalgoverningbodycanbeenteredintothe ControllingDangerousPathogensReport 63 data system at the international node and automatically copied to all of the nationalandlocalnodes. Thisallowsthesystemtoensurethatthequestions required for international review are asked in a uniform manner. This also provides a mechanism for harmonizing review guidelines among nations for projects that will not be subject to international review. Where there is international agreement on questions that should be asked of all projects undergoing national- or local-level review, they can be asked in a uniform fashion.Itisalsopossiblefornational(orlower)levelnodestoaddquestions of their own that would apply only to nodes under their supervision. One objectiveoftheprototypeistodemonstratethatasinglesoftwareapproachcan supportarangeofdecisionsinthisarea. Answerstoquestionsaboutaproposedprojectaresenttoareviewcommittee comprisedofscientists,securityandpublichealthexperts.Thesereviewersare initiallyanonymousrelativetotheinvestigatorbutareknowntooneanother. Asthequestionnairesarecompleted,thereviewersareprompted(byemail)to logintothesystemandreviewthem. Iftheproposalhasbeendeterminedby therelevantreviewcommitteechairpersontoposeminimalriskortoinvolve minorchangestoapreviouslyapprovedprojectthereviewerscanapprovethe projectelectronically. Otherwisetheproposalwouldbereviewedinaformal meeting, which the senior scientists involved in the project generally would attend.Thereviewerscanapprove,disapprove,orelevatetheprojecttoahigher oversight level. Decision making in this prototype is by consensus, with approvalrequiredfromallreviewersbeforeaprojectcanproceed.Aprocedure roughly analogous to this project review procedure is used for licensing institutions,laboratories,andusers. If the reviewers choose to elevate the project, the questionnaires and related documents pertaining to the project are shared with the parent node. For example, if reviewers at a university determine that a project falls into the categoryof“moderateconcern”andthusrequiresnationaloversight,theycan elevatetheprojectforreviewbythenationalnode.Reviewatthenationalnode proceedsasitdidatthelocallevel. If,inturn,thesereviewersfindthatthe project fits the criteria for activities of “extreme concern,” they can further elevateitforreviewattheinternationallevel. Ifatanypointintheprocessanodewouldlikeoutsideinput–eitherfroman expert at a peer institution or from someone at one of the higher (or lower) levelnodes,thesystemallowsanoutsideexpertwhomeetsBRSSobligationsto “visit” another node at the invitation of the host node. This provides a mechanismbywhichinstitutionscansupplementtheirinternalexpertisewhile retainingcontroloverprojectswhichdonotrequireelevationtoahigherreview level. Thismechanismalsoprovideslimitedsupportforcollaborativeprojects whichinvolveresearchersfromseveralinstitutions,thoughafull-scalesystem mightneedmoreelaboratemechanismsinthisarea. Thesystemusesmultiplelevelsofencryptiontoensuresecurehandlingofdata. AlluserinteractionswiththesystemareconductedusingtheHTTPSprotocol, which is the industry standard means of transmitting sensitive financial informationtoandfromwebbrowsers. Theservernodesusestateoftheart, open-sourcesecuritystandardswhichprovideauniquebalanceofsecurityon theonehand,andtransparencyinthemeansofachievingthatsecurityonthe 64 ControllingDangerousPathogensReport other. Finally,storeddataisencrypted,ensuringthatevenifanintruderwere tobreachthesystemsecurity,hecouldnotretrieveanymeaningfulinformation. Byprovidingasecureandsystematicframeworktofacilitatethedevelopment, distribution, and review of questionnaires relating to the institutions, laboratories, persons and projects involved with high consequence pathogens research, this prototype provides a concrete example of how the information flowassociatedwithafull-scaleBRSSmightwork.Whiletheprototypedoes notaddresseveryconcernthatafull-blownsystemmightraise,webelievethat it is a valuable platform for demonstrating the information management techniquesthatwouldbeneededforarealsystemandforadvancingdiscussion fromabstractissuestowardconcretepolicies. ControllingDangerousPathogensReport 65 66 ControllingDangerousPathogensReport Appendix D Prototype Licensing Questionnaire New User 1. What is your name? Text 6. What is your current address? Long Text 2. Please enter your Social Security Number. If you do not have one, list your visa information. Text 7. What is your current phone number? Text 3. What is the highest academic degree you have obtained? 8. Please enter your work contact information. Long Text Bachelors degree (BA,BS, etc.) | Masters degree (MA, MS, etc.) | PhD | MD | No post secondary school 9. Please upload the most recent copy of your Curriculum Vitae. 4. From what institution did you obtain this degree? Text 5. What is the name of your current employer? Text Upload Document 10. For which role are you applying? Investigator| Reviewer| Compliance Officer| Site Administrator| Lab Manager| Technician | Other New Institution 1. Is this application: A new institution | A renewal of an existing license | An amendment to an existing license 8. Current CDC registration number, issue date, and expiration date (if applicable): Text 2. Institution name: Text 3. Address of institution: Text 9. Current APHIS registration number, issue date, and expiration date (if applicable): Text 4. City: Text 10. Responsible Official: 5. State: Text 6. Zip code: Text 11. Name of Alternate Responsible Official: Text 7. Type of Institution: Academic | Government | Commercial | Private | Other Text 12. Does your institution have an Institutional Biosafety Committee? Yes No ControllingDangerousPathogensReport 67 13. Please list the name and title of the Chairperson of the IBC: Text 22. Are routine lab inspections performed? Yes No 14. How often does your IBC meet? 23. How are records of these inspections maintained? How frequent are the inspections? Long Text Text 15. How is the procedure conducted for the review of protocols? Long Text 16. Pease upload all approved and pending IBC applications for infectious materials and rDNA for the past 12 months: Upload Document 17. Does your institution have an Institutional Animal Care and Use Committee (IACUC)? Yes No 18. Please list the name and title of the Chairperson of the IACUC: Text 19. How often does the IACUC meet? Text 20. Please attach all approved and pending applications pertaining to animal research for the past 12 months: Upload Document 21. Which department in your institution is responsible for biosafety and chemical hygiene? Text 24. Attach a copy of the inspection checklist: Upload Document 25. Does your institution have a chemical hygiene plan? Yes No 26. Does your institution have a standard procedure for handling hazardous materials? Yes No 27. Does your institution have an Institutional Review Board (IRB)? Yes No 28. Please list the name and title of the Chairperson of the IRB: Text 29. How often does your IRB meet? Text 30. Please attach the applications and consent form templates used by your IRB: Upload Document New Laboratory 7. Type of laboratory: 1. Is this application: A new laboratory | A renewal of an existing license | An amendment to an existing license 2. Laboratory Name: Text 3. Address of laboratory: Text 4. City: Text 5. State: Text 6. Zip code: Text 68 ControllingDangerousPathogensReport Academic | Government | Commercial | Private | Other 8. If "other" please explain: Long Text 9. Which listed agents are used in your laboratory? Dropdown list of listed agents (see attached) 10. Is there a coordinator of all listed agent related research in your laboratory? Yes No 11. If yes to question 10, please list the name and title of the person coordinating this research. Dropdown list of individuals at this institution 12. Upload a copy of the laboratory floorplan. Upload Document 13. Please choose all from the following list that describe your HVAC system. Single-pass | Re-circulated | Dedicated exhaust | Shared exhaust | Constant air volume | Variable air volume| Redundant exhaust fans | Emergency Power Backup 14. Which class of Bio-Safety Cabinet is being used in this laboratory? I | II, Type A1 | II, Type A2 | II, Type B1 | II, Type B2 | III 15. How is the Bio-Safety Cabinet connected to the HVAC System? Duct |Thimble | Re-circulating | none of the above 16. How often is the Bio-Safety Cabinet Certified? Six months | one year 17. Upload a description of the alarms and other monitors in your laboratory that are connected to the HVAC system. Explain each alarm and what it signals, as well as the repair efforts for each alarm type. Upload Document 18. Does laboratory have eyewash? Yes No 19. How often is the eyewash tested? Weekly | every two weeks | every three weeks | once per month 20. Does this laboratory have a biosafety manual? Yes No 21. MSDS workers? forms available for Yes No 22. Upload a copy of your Emergency Response Plans. Upload Document 23 Please upload a copy of all first responder assurance forms. Upload Document 24 Please summarize training methods for the Emergency Response Plan. Long Text 25 Have employees been provided with Bloodborne Pathogens Training in the past year? Yes No Security Measures 1. Which of the following barriers are present at your laboratory? Card Swipe | Pin Numbers | Locks on doors | Locks on incubators, refrigerators, etc. | Video cameras/Motion sensors | Other 2. Are security guards present at the entrance to the building in which your laboratory is located? Yes No 3. Is there a sign in/out book? Yes No 4. Explain how stored pathogens are coded (if at all): Long Text 5. Do you maintain inventories on all agents contained in your laboratory? Yes No ControllingDangerousPathogensReport 69 6. How are the inventory records for listed agents maintained? Long Text 10 Upload the current security plan for your laboratory: Upload Document 7. How is loss/theft of agents detected? Long Text 11 Summarize training plans for your security plan: Long Text 8 How many people have access to the agents? Text 12 Has your laboratory undergone a threat/vulnerability assessment? Yes No 9 Please explain the steps that persons wanting access to select agents must complete as well as measures in place to protect the select agents from theft. Long Text 70 ControllingDangerousPathogensReport 13 Which agencies have performed threat/vulnerability assessments for your laboratory? Long Text Appendix E PROTOTYPE PROJECT QUESTIONNAIRES New Project 1. Please describe the purpose and provide background information as to the reason for this project. Long Text 2. Explain your project in lay terms. Long Text 3. Please explain your project in detail in scientific terms. Long Text 4. What is your hypothesis? Long Text 5. Where will this project be conducted? Dropdown list of laboratories at the institution 12. If yes to question 11, please list the agent name (genus, species). Text 13. Does the agent(s) used in this project have any recognized or anticipated pathogenic, toxigenic or virulence potential for humans, plants or animals? Yes No 14. If yes to question 13, please explain in detail. Long Text 15. What Bio-Safety Level will be used? BSL1 | BSL2 | BSL3 | BSL4 16. Could these experiments increase virulence or environmental stability? Yes No 6. Please explain why you are qualified to perform this research. Long Text 7. Will research on listed agents be included in this project? Yes No 8. Select organism(s) you will be working with: 17. Could the host range be expanded as a result of these experiments? Yes No 18. Could the host range of the agents used in this project be expanded due to natural processes? Yes No Dropdown list of select organisms (see attached) 19. Will these experiments be performed in animal models? Yes No 9. Will you be working with an agent related to a listed agent? Yes No 20. Will you be utilizing human subjects? Yes No 10. If yes to question 9, please list the agent name (genus and species). Text 21. Will conducted? 11 Will you be working with a nonlisted agent? Yes No 22 Will work on recombinant materials (prions, DNA, replicating RNA, etc) be conducted? Yes No aerosol studies be Yes No ControllingDangerousPathogensReport 71 23 Will genome transfer, genome replacement, de novo synthesis, or cellular reconstitution of an agent be performed? Yes No multiple institutions? Yes No 27. If yes to question 26, please list the other participating institutions. Long Text 24. Please upload a detailed description as to the possible risks of this research as well as the possible benefits. In the discussion include a risk versus benefit comparison. Upload Document 25. Is an alternative method for conducting this experiment available that would achieve the same results? If so, would the alternative approach be safer? Long Text 26. Will this project be conducted at 28. Are projects similar to the one proposed being conducted at other institutions? Yes No 29. The Biological Weapons Convention (BWC) prohibits developing, producing, stockpiling of biological agents and toxins of types and in quantities that have no justification for prophylactic, protective or other peaceful purposes. I certify that I am in compliance with this international treaty. Yes No Pathogenic Organisms 1. What is the name and strain designation of the pathogenic organism to be used in this project? If it is not the wildtype strain, please explain how it differs from the wild type. Long Text use? Yes No 9. If yes to question 8, by what method? Text 10. Do you concentrate the organism in your protocol? Yes No 2. Does this pathogen infect: Humans | Animals | Plants 3. Is the organism attenuated? Yes No 11. If yes to question 10, what concentration will be used (in cfu/ml or pfu/ml) in experiment. Text 4. If the organism is not attenuated and is a listed agent, why must it used in the virulent form? Long Text 12. Method of concentration: 5. Is a toxin produced? 13. Source of organism: Yes No 6. If a toxin will be produced, will the project work with the toxin? Yes No centrifugation | precipitation | filtration | other | not applicable 14. Amount of acquisition: Long Text Text 15. CDC permit # for acquisition, if applicable. Text 7. Is drug resistance expressed? 8. Is the organism inactivated prior to 72 ControllingDangerousPathogensReport 16. APHIS permit # for acquisition, if applicable. Text 17. Will this organism require human blood, human or primate cells for growth? Yes No 30. Please list the antibiotics that are able to be used to treat possible infections with this pathogenic organism. Long Text 18. If yes to question 17, list the cell line used in this project, when pertaining to this organism. Long Text 31. Is there a vaccine available against this agent? Yes No 19. Are cultures, stocks, and items decontaminated prior to disposal? 32. If yes to question 31, please list recommended vaccines. Long Text Yes No 20. If yes to question 19, by what method? autoclave | chemical disinfectant | other | not applicable 21. If other, specify method: Text 22. Will the organism be aerosolized? 33. If no to question 31, is a vaccine currently being developed? Yes No 34. Will the strains be vaccine resistant? Yes No 35. Is medical surveillance necessary when working with this organism? Yes No Yes No 23. If the organism will be aerosolized, please upload detailed protocols to ensure personnel safety as well as experimental protocols for the production of aerosolized particles. Upload Document 36. Have all potentially exposed employees received the Hepatitis B vaccine or proven immunity? Yes No 24. Will these experiments increase the environmental stability or virulence of the organism? Yes No 25. If yes to question 24, please explain how. Long Text 26. Is this strain resistant to any antibiotics? Yes No 27. If yes to question 26, list.Long Text 28. Will strains be constructed to be antibiotic resistant? Yes No 29. If yes to question 28, please explain which antibiotic resistance gene(s) will be added. Long Text 37. Is there an additional recommended vaccination for workers when handling this organism? Yes No 38. What other means will be taken to monitor workers health when handling this organism? (i.e. serum banking, tuberculin skin testing, temperature taking) Long Text 39. If an accidental release of this organism were to occur, either from a theft or a breach in engineering controls, please explain possible consequences to public health. Please also describe possible economic impacts including those on agriculture and livestock. Long Text ControllingDangerousPathogensReport 73 Recombinant Materials 1. Provide a brief description of the proposed recombinant research. This should include any parts of the project in which recombinant materials enable the propagation of phenotypes as well as parts involving DNA, replicating RNA, and prions. 10. Does the insert contain more than 2/3 of a eukaryotic viral genome? YES NO 11. Is a helper virus used? Yes No 12. If yes to question 11, please specify its type: Text Long Text 13. Is it a retrovirus? 2. Specify the source and nature of the DNA sequence(s) to be inserted (genus, species, gene name): Long Text 3. Will the expressed? inserted gene be Yes No 4. If yes to question 3, what are the gene product effects? (specifically, its toxicity, physiological activity, allergenicity, oncogenic potential or ability to alter cell cycle.) Long Text 5. Describe the virus, phage and/or plasmid used for constructing your recombinants(prokaryotic, eukaryotic) Long Text 6. Identify host cell(s) or packaging cell line in which recombinant vector will be amplified: Long Text 7. Is the competent? vector 8. Are any viral sequences present? replication Yes No components/ Yes No 9. Specify the function and nature of any viral components specified in question 8: Long Text 74 ControllingDangerousPathogensReport Yes No 14. Describe the cell line or species that will be exposed to the recombinant? Long Text 15. Will animals be exposed to rDNA? Yes No 16. If yes to question 15, please specify animal: Text 17. Will the work involve transgenic animals? Yes No 18. Will human subjects be exposed to rDNA? Yes No 19. Does the donor rDNA, RNA, cDNA source or its vector have any recognized or anticipated pathogenic, toxigenic or virulence potential for animals, plants, or humans? Yes No 20. If yes to question 19, please explain: Long Text 21. What quantity of material will be used? < 1 Liter | 1-10 Liters | > 10 Liters Human Subjects 1. Select all categories of subjects you will be using for this research. Minors | Non-English Speaking | Minorities | Females | Genetic Materials | Pregnant Females | Fetuses | Abortuses | Healthy Volunteers | Students or Employees | Psychiatrially impaired | Cognitively impaired | Prisoners | Other 2. Number of subjects to be enrolled at this site Text 3. Is this a multicenter study? Yes No 4. If this is a multicenter study, please enter the names of all sites. Long Text 5. If this is a multi-center study, please list the total number of human subjects for the project, encompassing all sites. Text 10. Please give an outline of the proposed study, including plans for analysis and inclusion/exclusion criteria. Long Text 11. What are the potential benefits to subjects or others? Long Text 12. What are the potential risks to subjects and the incidence of these risks? Long Text 13. What treatments? are the alternative Long Text 14. Will you recruit your own patients for this study? Yes No 15. Please outline the recruitment process. Long Text 6. Is there a Clinical Trial Agreement or Letter of Indemnification? Yes No 16. If using a flier or email text to recruit subjects, please upload a copy here. Upload Document 7. If yes to question 6, upload a copy of the Clinical Trial Agreement or Letter of Indemnification and a budget. Upload Document 17. If non-English speaking subjects are being recruited, has the consent form been translated? Yes No 8. Please upload a copy of the Human Subjects Protection Training and Examination certificate for all those listed as PIs, co-Investigators, study coordinators or other personnel on this project Upload Document 9. What procedures and/or processes will be used during this project that affect the subject? Examples: phletbotomy, amount of blood drawn, bone marrow aspiration, exact procedure used and how much sample is taken. Long Text 18. If the consent form was not translated please provide the rationale. Long Text 19. During the consent process, at what times will the subjects be asked if they have questions? before |during | after signing | before procedure 20. Will subjects receive a copy of the signed consent form? Yes No 21. How will the consent process be documented? Long Text ControllingDangerousPathogensReport 75 22. Upload a copy of the current consent form. Upload Document 31. Will specimens be stored for future use? Yes No 23. Please explain where the signed consent forms will be kept as well as efforts to maintain subject confidentiality. Long Text 32. If yes to question 31, please list the specimens stored, and how confidentiality will be protected. 24. Who will obtain consent? 33. Will the storage of specimens serve as a database or repository? Yes No PI | co-PI | Co-Inv | Study Coordinator | Other 25. Please list the names of all those who will be charged with obtaining consent. Long Text 26. Is there a data safety monitoring board for this project? Yes No Long Text 34. Will an investigational drug be administered? Yes No 35. If yes to question 34, please list the IND# for the drug being administered. Text 27. Describe what educational activities or scientific knowledge, if any, will be furthered by this study. 36. Will an investigational device be used in this study? Yes No Long Text 37. If yes to question 36, please supply the IDE# for the device. Text 28 Will patient charts or medical records be reviewed? Yes No 29. If personal medical history will be obtained from the subjects, please upload the blank medical history sheet. Upload Document 38. Is this a clinical trial? If yes, please choose the type of trial: Phase 1| Phase 2| Phase 3| Phase 4 Post Marketing 39. What is the status of this project with your institution's IRB: Denied | Submitted via this form 30. If questionnaires will be used, please upload them. Upload Document Animal Use 1. Will materials be administered to animals? Yes No 4. Is the pathogen? 2. If yes to question 1, please list the animal species: Text 5. Is the material a human pathogen? 3. What kind of material will be administered to the animal? Text 6. Is it possible for the agent to be transmitted from animals to humans in the laboratory environment?Yes No 76 ControllingDangerousPathogensReport material an animal Yes No Yes No 7. Will the material or organism be inactivated prior to use in animals? 16. What disinfectant will be used? Text Yes No 8. By what route will the material be administered? Text 17. Describe your procedure for changing bedding and papers. How will these be disposed? Long Text 9. In what volume will it be administered? Text 18. Describe disposal method for animal carcasses: Long Text 10. At what administered? 19. Describe routine cleaning/ decontamination of animal cages: titer will it be Text Long Text 11. Please explain this choice of route, volume and titer: Long Text 20. What Animal Biosafety level has been requested? Text 12. Will microisolator cages be used? Yes No 13. Will barrier housing be used? Yes No 14. What special procedures will be used for containment? Long Text 15. Will work be done in a biosafety cabinet? Yes No 21. What is the status of this project with your institution's IACUC: Approved | Pending Approval | Denied | Submitted via this form 22. Please provide IACUC number, IACUC approval date, and IACUC approval expiration date. (specify if pending) Long Text Laboratory Biosafety & Engineering Controls 1. Please list the building/room in which experiments will be performed. Text 2. Please list the building/room location in which the bacteria/virses will be stored. Text 3. At what biosafety level will the work be done? (Reference CDC/NIH BMBL4th Edition. www.cdc.gov 1|2|3|4 4. What engineering controls are available to control significant aerosol generating steps for work requiring BL-2 containment or higher (e.g. centrifugation, vortexing, sonification, egg harvesting): Class I Biological Safety Cabinet (BSC) | Class II BSC | Centrifuge safety cups | Containment Suite | Other 5. If other, please describe: Long Text 6. Will sharps (syringes, scalpels, glass) be used? Yes No 7. Has the research protocol been reviewed to minimize the use of sharps where possible? Yes No 8. Will sharps with integrated safety devices be used? Yes No ControllingDangerousPathogensReport 77 9. If yes to question 8, please describe these devices (type, model, brand): Long Text 10. What personal protective equipment is recommended and available for this work (select all that apply): Lab Coat | Nitrile Gloves | Non-powdered Latex Gloves | Vinyl Gloves | Safety Glasses w/side shields | Respiratory Protection | Other 11. What disinfectant(s) will be used to for routine cleanup? 1/10 bleach | 70% ethanol | povidone-iodine | phenolic product| chlorine dioxide product | quaternary ammonium product | other 12. What disinfection method(s) will be used for solid waste? 1/10 bleach | 70% ethanol | povidone-iodine | phenolic product| chlorine dioxide product| quaternary ammonium product | other 13. What disinfection method will be used for liquid waste? 1/10 bleach | 70% ethanol | povidone-iodine | phenolic product| chlorine dioxide product| quaternary ammonium product | other Personnel Security 1. Please select the approved individuals who will be involved with this project. 4. Has anyone in your laboratory been denied approval? Yes No Dropdown list of licensed individuals at this institution 5. If yes to question 4, please list the name, social security number and/or DOJ number, and the reason given for denial for each person who has been denied approval. Long Text 2. Are there any individuals in your laboratory currently awaiting approval? Yes No 3. If yes to question 2, please list the name and social security and/or DOJ number for each person awaiting approval. Long Text 6. Is anyone awaiting approval or who has been denied approval currently working on a different aspect of this project? Yes No 7. If yes to question 6, please explain. Long Text 78 ControllingDangerousPathogensReport End Notes 1 See,forexample,RonaldJ.Jacksonetal.,“ExpressionofMouseInterleukin-4byaRecombinant EctromeliaVirusSuppressesCytolyticLymphocyteResponsesandOvercomesGeneticResistanceto Mousepox,”JournalofVirology(February2001):1205-1210andJeronimoCelloetal.,“Chemical SynthesisofPolioviruscDNA:GenerationofInfectiousVirusintheAbsenceofNaturalTemplate,” Sciencexpress(July11,2002),availableatwww.sciencemag.org/cgi/content/abstract/1072266v1. 2 NationalResearchCouncil,“BiotechnologyResearchinanAgeofTerrorism,”(Washington,DC: NationalAcademiesPress,2003),availableathttp://www.nap.edu/books/0309089778/html/;and,Royal Society,“Donoharm:reducingthepotentialforthemisuseoflifesciencesresearch,”RSpolicydocument 29/04,October2004. 3 Inadditiontobasicresearch,thesefiguresalsocoverconstructionofnewbiosafetylaboratoriesand developmentofmedicalcountermeasures.DepartmentofHealthandHumanServices,“BudgetinBrief, FiscalYear2007,”availableatwww.hhs.gov/budget/07budget/2007/BudgetInBrief.pdf. 4 USDepartmentofHomelandSecurityandUSArmyGarrison,“FinalEnvironmentalImpactStatement: ConstructionandOperationoftheNationalBiodefenseAnalysisandCountermeasuresCenter(NBACC) FacilitybytheDepartmentofHomelandSecurityatFortDetrick,MD,”December23,2004.Foracritical analysisoftheBTCC’spotentialrole,seeMiltonLeitenberg,JamesLeonard,RichardSpertzel, “Biodefensecrossingtheline,”PoliticsandtheLifeSciences22,no.2(May17,2004). 5 USDepartmentofHomelandSecurityandUSArmyGarrison,“FinalEnvironmentalImpactStatements” (23December2004). 6 ThefinaldocumentfromtheSixthReviewConferenceisavailableat www.unog.ch/80256EDD006B8954/(httpAssets)/ICEE7A27069559C5C125723E00647FBF/$file/BWC+CON F.VI+CRP.4-altered+as+ammended.pdf. 7 ThisdiscussiondrawsonGrahamS.PearsonandMalcolmR.Dando,“StrengtheningtheBiological WeaponsConvention,BriefingPaperNo6:ArticleX:SomeBuildingBlocks,”March1998,availableat www.brad.ac.uk/acad/sbtwc.SeealsotheUniversityofBradfordGenomicsGatewaywebsite,availableat www.brad.ac.uk/acad/sbtwc/gateway/. 8 ForacopyoftheCode,seehttp://binas.unido.org/binas/regulations/unido_codes.pdf 9 TheConventionusestheterm“livingmodifiedorganisms.”Forthetext,seehttp://www.biodiv.org. 10 TheUNEPGuidelinesareavailableathttp://www.unep.org/unep/program/natres/biodiv/irb/unepgds.htm. 11 WorldHealthOrganization.LaboratoryBiosafetyManual,ThirdEdition(Geneva:WorldHealth Organization,2004). 12 NSDM35,November25,1969;andU.S.DepartmentofDefense,OfficeoftheSpecialAssistantfor GulfWarIllnesses,MedicalReadiness,andMilitaryDeployments,“Nuclear,BiologicalandChemical WarfareDefense,”January8,2002,availableathttp://deploymentlink.osd.mil/faq/faq_nbc.shtml. 13 P.L.104-132,April24,1996,Section511. 14 P.L.107-56,October26,2001,Section817. 15 P.L.107-188,June12,2002. 16 Forthefinalregulations,see42CFR73.12and9CFR121.12;fortheBMBL,seeUSDepartmentof HealthandHumanServices,“BiosafetyinMicrobiologialandBiomedicalLaboratories,FourthEdition,” (Washington,DC:USGPO,1999). 17 IBCsareresponsibleforensuringthesafetyofrecombinantDNAresearch,whileIRBsfocusonthe safetyofresearchinvolvinghumansubjects. 18 See,forexample,RonaldM.Atlas,“ApplicabilityoftheNIHRecombinantDNAAdvisoryCommittee ParadigmforReducingtheThreatofBioterrorism,”April2002. ControllingDangerousPathogensReport 79 19 SunshineProject,“MandateforFailure:TheStateofInstitutionalBiosafetyCommitteesinanAgeof BiologicalWeaponsResearch,October2004,availableathttp://www.sunshineproject.org/biodefense/ibcreport.html. 20 NIHGuidelines,April2002,availableathttp://www4.od.nih.gov/oba/rac/guidelines/guidelines.html. 21 42CFR73.13and9CFR121.13. 22 NationalResearchCouncil,“BiotechnologyResearchinanAgeofTerrorism,”(Washington,DC: NationalAcademiesPress),October2003,availableathttp://www.nap.edu/books/0309089778/html/ 23 InformationontheNSABB,includingcopiesofpresentationsgivenatitspublicmeetings,areavailable athttp://www.biosecurityboard.gov/ 24 ThedraftguidancedocumentsfromthethreeNSABBworkinggroupsareavailableat www.biosecurityboard.gov. 25 See,“ConceptualizinganOversightFrameworkforDual-UseResearch,”October25,2006,availableat www.biosecurityboard.gov. 26 7CFR340.3;7CFR340.4;and9CFR122.2. 27 40CFR172.45;40CFR725.255;40CFR725.234;and40CFR725.238. 28 InformationonNEPAisavailableathttp://www.epa.gov/compliance/nepa/ 29 ArmyRegulation385-69,BiologicalDefenseSafetyProgram;and32CFR627. 30 StatutoryInstrument2001(No.4019)TheAnti-terrorism,CrimeandSecurityAct2001 (CommencementNo.1andConsequentialProvisions),availableathttp://www.opbw.org/. 31 DonaldFredrickson,TheRecombinantDNAControversy,AMemoir:Science,Politics,andthePublic Interest,1974-1981(WashingtonDC:ASMPress,2001),40-41,101. 32 StatutoryInstrument2000(No2831)TheGeneticallyModifiedOrganisms(ContainedUse)Regulations, availableathttp://www.opbw.org/. 33 Anamendmenttothe2000regulationallowsinformationprovidedinnotificationsorotherwisepartof thepublicregistertobekeptconfidentialfornationalsecurityreasons.Statutory2002(No.63)The GeneticallyModifiedOrganisms(ContainedUse)(Amendment)Regulations,availableat http://www.opbw.org/. 34 StatutoryInstrument1992(No.3280)TheGeneticallyModifiedOrganisms(DeliberateRelease) Regulations;StatutoryInstrument2002(No.2443)TheGeneticallyModifiedOrganisms(Deliberate Release)Regulations,availableathttp://www.opbw.org/. 35 ThesearediscussedinmoredetailinGrahamS.PearsonandMalcolmR.Dando,“Strengtheningthe BiologicalWeaponsConvention,BriefingPaperNo7:ArticleX:FurtherBuildingBlocks,”March1998, availableatwww.brad.ac.uk/acad/sbtwc. 36 StatutoryInstrument2002(No.2677)TheControlofSubstancesHazardoustoHealthRegulations, availableathttp://www.opbw.org/. 37 ThisisdiscussedinPearsonandDando,“BriefingPaperNo7,”pp.6-7. 38 The1980regulationisdiscussedinPearsonandDando,“BriefingPaperNo.7,”pp.4-5;Statutory Instrument1998(No.463)TheSpecifiedAnimalPathogensOrder,availableathttp://www.opbw.org/. 39 SeeParliamentaryOfficeofScienceandTechnology,“GMAnimals,”Postnote,Number157,June2001 availableathttp://www.parliament.uk/post/pn157.pdf.TheActisavailableat http://www.homeoffice.gov.uk/animalsinsp/reference/legislation/index.htm.Informationonlocalreviewis availableathttp://www.homeoffice.gov.uk/animalsinsp/reference/erp/erp_statement.htm. 40 ThisdiscussionofadvisorycommitteesdrawsfromGrahamS.PearsonandMalcolmR.Dando, “StrengtheningtheBiologicalWeaponsConvention,BriefingPaperNo4:NationalImplementation Measures,”January1998,availableatwww.brad.ac.uk/acad/sbtwc. 41 Informationavailableathttp://www.hse.gov.uk/aboutus/hsc/iacs/acgm. 42 Informationavailableathttp://www.defra.gov.uk/environment/acre. 43 Informationavailableathttp://www.doh.gov.uk/acdp. 44 See,forexample,RoyalSociety,“PaperforUNFoundationmeetingontheindividualandcollective rolescientistscanplayinstrengtheninginternationaltreaties,”RSpolicydocument05/04,April2004; RoyalSociety,“Donoharm:reducingthepotentialforthemisuseoflifesciencesresearch,”RSpolicy document29/04,October2004;andRoyalSociety,“Theroleofscientificcodesinpreventingthemisuse ofscientificresearch,”RSpolicydocument03/05,May2005. 80 ControllingDangerousPathogensReport 45 ThisdiscussiondrawsonJonathanTuckerandStacyOkutani,“GlobalGovernanceof‘Contentious’ Science:TheCaseoftheWorldHealthOrganization’sOversightofSmallpoxVirusResearch.”The WeaponsofMassDestructionCommission(December2004),Paper#18. 46 WorldHealthOrganization,“Smallpoxeradication:destructionofvariolavirusstocks,”NinthPlenary Meeting,WHA52.10.,24May1999. 47 WHO,“ReportofthemeetingoftheAdHocCommitteeonOrthopoxvirusInfections,”(Geneva, Switzerland:WHO,9September1994). 48 Ascientificsubcommitteereviewsallresearchproposals.OkutaniinterviewwithDr.RiccardoWittek, Lausanne,Switzerland(May2004). 49 WorldHealthOrganization,WHOAdvisoryCommitteeonVariolaVirusResearch,“ReportofaWHO Meeting,”Geneva:6-9December,1999,WHO/CDS/CSR/2000.1 50 WorldHealthOrganization,WHOAdvisoryCommitteeonVariolaVirusResearch,“ReportoftheSixth Meeting,”Geneva(4-5November2004),WHO/CDS/CSRARO/2005.4 51 MartinEnserink,“WHAGivesYellowLightforVariolaStudies,”Science308(May27,2005):1235. 52 RobertH.Sprinkle,“TheBiosecurityTrust,”BioScience53,no.3(March2003). 53 ThisissueisexploredinAlexGreninger,“TheDefinitionandMeasurementofDangerousResearch,” July2004,availableathttp://www.cissm.umd.edu/documents/Greninger%20Paper%2007-16-04.pdf. 54 ThisisdiscussedinmoredetailinKathrynNixdorff,NeilDavison,PiersMillet,andSimonWhitby, “TechnologyandBiologicalWeapons:FutureThreats,”availableat http://www.brad.ac.uk/acad/sbtwc/ST_Reports/ST_Report_No_2.pdf 55 NationalResearchCouncil,“BiotechnologyResearchinanAgeofTerrorism,”p.5. 56 Thiscanbefoundathttp://ohsr.od.nih.gov/irb/protocol.html 57 Thefollowingprojectswerepeerreviewedbysometwentyscientistsandsecurityexperts:Cloningof MHCIImmunomodulatorsintoVacciniaVirus;EnhancementofVirulenceandTransmissibilityof InfluenzaVirus;ImmunosuppressionandImmuno-TransitioninPlague-MouseModel;Manipulationof TemperateSensitivityinPospiviroidae;and,ExploringNewNon-LethalIncapacitationOptions. 58 SeeRoyalSociety,“Theroleofscientificcodesinpreventingthemisuseofscientificresearch,”RS policydocument03/05,May2005. 59 USNationalAcademiesofScience,“ScientificCommunicationandNationalSecurity,”(Washington, DC:NationalAcademyPress),1982,availableathttp://www.nap.edu/books/0309033322/html/ 60 MartinEnsirenk,“EnteringtheTwilightZoneofWhatMaterialtoCensor,”Science,November22, 2002. 61 TheIAEA’sStandingAdvisoryGrouponSafeguardsImplementation,whichprovidesimpartialadvice ontheefficacyofsafeguards,mightbeausefulmodelforthislattergroup. 62 ThisisdiscussedinBarryKellman,“MechanismsforImpellingCompliancewiththeBRSS,”March 2005. 63 Astheworkingpapermakesclear,theseareroughestimatesonly,astheauthordidnotscreenforallof thecategoriesofresearchinvolvingnon-listedagentsbecauseoftheoverallnumberofpapersandthe absenceofasuitablesearchstrategy.Thefiguresalsodonotreflectthebroaderdefinitionofdenovo synthesisusedinthefinalversionoftheResearchCategoriesTable.Atthesametime,theauthoralmost certainlyincludedsomescientistsandfacilitiesthatwerepartofresearchprojectsoutsideoftheUS, simplybecausetheywereAmericanoraffiliatedwithanAmericanresearchfacility.Althoughitis difficulttoestimate,thesefactorscouldwellincreasethenumberofprojectssubjecttolocaloversight,in particular,byahundredormore.SeeJensH.Kuhn,“QualitativeandQuantitativeAssessmentofthe ‘DangerousActivities’CategoriesdefinedbytheCISSMControllingDangerousPathogensProject,” CISSMWorkingPaper,December2005. 64 SeeBrianRappert,“TowardsaLifeSciencesCode:CounteringtheThreatfromBiologicalWeapons,” BradfordBriefingPaper(2ndseries)No.13,2004,availableat http://www.brad.ac.uk/acad/sbtwc/briefing/BP_13_2ndseries.pdf;andRoyalSociety,“Theroleofscientific codesinpreventingthemisuseofscientificresearch,”RSpolicydocument03/05,May2005. 65 WorldMedicalAssociation,“DeclarationofWashingtononBiologicalWeapons,”Document17.400, September2001,availableathttp://www.wma.net/e/policy/b1.htm 66 AmericanMedicalAssociation,“OpinionoftheCouncilonEthicalandJudicialAffairs:Guidelinesto PreventMalevolentUseofBiomedicalResearch,”CEJAOpinion1-I-04,availableathttp://www.amaassn.org/ama1/pub/upload/mm/465/cejo1i04.doc ControllingDangerousPathogensReport 81 67 InternationalCommitteeoftheRedCross,“PrinciplesofPractice,”in“PreventingHostileUseofthe LifeSciences:Fromethicsandlawtobestpractice,”November11,2004. 68 MargaretA.SomervilleandRonaldM.Atlas,“Ethics:AWeapontoCounterBioterrorism,”Science, vol.307,March25,2005,availableat http://www.sciencemag.org/cgi/content/full/307/5717/1881?maxtoshow=&HITS=10&hits=10&RESULTFOR MAT=&fulltext=atlas%2Band%2Bsomerville&searchid=1120837341834_5746&stored_search=&FIRSTIND EX=0#ref6 69 InterAcademyPanel,“IAPStatementonBiosecurity,”November7,2005,availableat http://www4.nationalacademies.org/iap/iaphome.nsf/weblinks/WWWW6JPDTY/$file/IAP_Biosecurity.pdf?OpenElement 70 ThePoliticsandLifeSciencescourseisavailableat http://www.politicsandthelifesciences.org/Biosecurity_course.html;InformationontheFASmodulesis availableathttp://www.fas.org/main/content.jsp?formAction=297&contentId=150 71 MedicalResearchCouncil,“Organizationsaddressbiomedicalresearchmisusethreat,”MediaRelease, September8,2005,availableathttp://www.mrc.ac.uk/prn/public-press_08_sept_2005TheMedical ResearchCouncilappearstobeusingtheFinkCommittee’ssevenexperimentsofconcerntodefinethe typesofresearchthatshouldbereviewedfordual-userisks,butitisunclearwhethertheotherUK fundingagenciesaretakingasimilarapproach.TheMRCstatementisavailableat http://www.mrc.ac.uk/doc-bioterrorism_biomedical_research.doc 72 HarvardProfessorMatthewMeselsonhasmadeasimilarproposal,suggestingthatlocaloversightbodies beestablishedatallinstitutionsconductingconsequentiallifesciencesresearch. 73 Weintendtoworkwithvariousinstitutionstotestourdatamanagementsoftwareinthehopethattheir adoptionofourprototypewillhelplaythegroundworkforthetypeofcomprehensiveoversight arrangementoutlinedinthismonograph. 74 ForabriefdiscussionofOECDactivitiesinthisarea,seeJonathanTucker,“Biosecurity:Limiting TerroristAccesstoDeadlyPathogens,”USInstituteofPeace,November2003. 75 AsummaryofthediscussionattheFrascatimeetingcanbefoundat http://www.oecd.org/dataoecd/30/56/33855561.pdf;theorganization’sbiosecuritywebsiteisat http://www.biosecuritycodes.org 76 ForinformationonWHO’sactivitiesonthehealthaspectsofbiologicalweapons,see http://www.who.int/csr/delibepidemics/en/ 77 SeeWorldHealthOrganization,“Lifesciencesresearch:opportunitiesandrisksforpublichealth,” WHO/CDS/CSR/LYO/2005.20,2005availableat http://www.who.int/csr/resources/publications/deliberate/WHO_CDS_CSR_LYO_2005_20.pdf 78 ThiswasalsooneofthepriorityareasidentifiedbyascientificworkinggroupconvenedbyWHOin October2006.See,WorldHealthOrganization,“SummaryReportfromtheScientificWorkingGroup MeetingonLifeSciencesResearchandGlobalHealthSecurity(Draft).”December2006. 79 See“IssuesinBiosecurityandBiosafety,”Science308,no.5730,June24,2005foralettersignedby elevenscientists. 80 PhilipChandler,thechairoftheMedicalCollegeofGeorgiaIBC,hasbeenquotedassayingthatthe NIHGuidelinesgiveinstitutionstoomuch“poeticlicense”andreplacingthemwithalawwould“remove theinconsistencies”andmoreeffectivelydiscouragepeoplefromfloutingtherules.KellyField, “BiosafetyCommitteesComeUnderScrutiny,”ChronicleofHigherEducation51,Issue34,April29, 2005. 81 JonathanTuckerhasendorsedfacilitylicensingaspartofhisproposalforstrengtheningcontrolson accesstodangerouspathogens.See,JonathanTucker,“Biosecurity:LimitingTerroristAccesstoDeadly Pathogens,”USInstituteofPeace,November2003. 82 GigiKwikGronvalloftheUPMCCenterforBiosecurityhasendorsedlicensingbiologistsinanumber ofpublicappearancesinrecentyears.OutsideoftheUS,theBritishMedicalAssociationcalledfor licensingbiologistsinapresentationinGenevainJune2005asdidthejournalNatureinaneditorialthe followingmonth.See“RulesofEngagement,”Nature436,No7047,July7,2005. 83 See,UnitedStatesInstituteofPeace,“AmericanInterestsandUNReform:ReportoftheTaskForceon theUnitedNations,”Washington,DC,2005,availableathttp://www.usip.org/un/report/usip_un_report.pdf TheTaskForce,whichwaschairedbyformerSpeakeroftheHouseNewtGingrichandformerSenator GeorgeMitchell,recommendeddoingthisundertheauspicesofanewUNorganizationforbiological weaponsissues. 82 ControllingDangerousPathogensReport The Center for International and Security Studies at Maryland (CISSM) School of Public Policy University of Maryland College Park, Maryland 20742 Telephone: 301.405.7601 Fax: 301.403.8107 cissm.umd.edu

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