Biodefense research: NIH role, NIH management, oversight of safety, oversight of security,

and oversight of dual-use implications

Title

Richard H. EbrightHoward Hughes Medical Institute, Waksman Institute, Department of Chemistry

Rutgers University

itle

Biodefense research

Outline

•NIH role

•oversight of safety•oversight of security•oversight of dual-use implications

•NIH management

Biodefense research: NIH roleoverview

NIH role-overview

•NIH has the potential to make critical contributions to biodefense. •NIH has the potential to make unique contributions to biodefense.

Biodefense research: NIH rolepotential strengths

NIH role-potential strengths

•basic research •peer-review process

Biodefense research: NIH rolepotential strengths, basic research (bacteriology)

NIH role-potential strengths, basic

research

•research on pathogenic microorganisms•research on model microorganisms

•model microorganisms

•advantages•cost-effective

•standard experimental workhorses (E. coli, B. subtilis)•exceptionally well-characterized•exceptionally well-developed experimental tools•nonpathogenic, or minimally pathogenic

•rapid•raise no safety issues•raise no security issues

•outputs•detection systems•diagnostic systems•countermeasures•all R&D up to final testing

origin of recombinant DNA technology and biotechnology industryorigin of current detection systems, diagnostic systems, and antibiotics

Biodefense research: NIH rolepotential strengths, peer-review process

NIH role-potential strengths, peer

review

•ensures quality•effective

Biodefense research: NIH managementoverview

NIH management-overview

•has not exploited potential strengths in basic research and peer review•has had negative impact on basic research and peer review

(1) Biodefense responsibility was assigned to a single NIH institute (NIAID).More than half of NIH bacteriology research is carried out by other NIH institutes. This research inappropriately has been excluded from biodefense planning and support.

Biodefense research: NIH managementmanagement errors

NIH management-management errors

(2) Biodefense was defined narrowly as work with bioweapons agents.Model-microorganisms research and non-bioweapons-agents-pathogens research inappropriately have been excluded from biodefense planning and support.

(3) The standard peer review process was circumvented.To review biodefense proposals, special review panels were created, with special review procedures and special, generous review standards.As a result, sub-par research has been funded. As a further result, an incentive structure has been created that has diverted scientists out of highly promising, biodefense-relevant, model-microorganisms and non-bioweapons-agents-pathogens research (where funding is tight and competitive) into less promising bioweapons-agents research (where funding is loose and easy).

Biodefense research: NIH managementconsequences

NIH management-consequences

•massive inflow of funding, institutions, and investigators into work on category-A bacterial bioweapons agents--i.e., the agents that cause anthrax, plague, and tularemia

•1400% increase in number of grant awards (from 32 in 1996-2000 to 465 in 2001-Jan 2005)

•massive outflow of funding, institutions, and investigators from work on non-bioweapons-agents basic bacteriology

•41% decrease in number of grant awards for laboratory research onmodel microorganisms (Microbial Physiology and Genetics 1 and 2)(from 490 in 1996-2000 to 289 in 2001-Jan 2005)

•27% decrease in number of grant awards for laboratory research onnon-bioweapons-agents pathogenic microorganisms(Bacteriology and Mycology 1 and 2)(from 627 in 1996-2000 to 457 in 2001-Jan 2005)

Biodefense research: NIH managementnegative impacts

NIH management-negative impacts

•negative impacts on biodefense•ineffective (minimal biodefense bang for biodefense buck)

•negative impacts on public health

•counterproductive•20-fold increase in number of institutions with bioweapons agents•20-fold increase in number of individuals with bioweapons agents•20-fold increase in safety, security, and dual-use concerns

•negative impacts on science

•failure to exploit existing strengths•erosion of existing strengths

•funding of subpar research

Biodefense research: NIH managementrequests for corrective action

NIH management-requests for

corrective action

•In February 2005, a letter requesting corrective action was submitted to the NIH Director by 758 researchers who have served on, or received grants reviewed by, the NIH Microbial Physiology and Genetics and NIH Bacteriology and Mycology Initial Review Groups.

•Signers included nearly two-thirds of researchers who have served on, or received grants reviewed by, the NIH Microbial Physiology andGenetics and NIH Bacteriology and Mycology Initial Review Groups in 1996-2005.

•In March 2005, a letter requesting corrective action was submitted to the NIH Director by 76 intramural-NIH bacteriology researchers.

•Signers included the president-elect and seven past presidents of the American Society for Microbiology.

Signers included nearly nine-tenths of intramural-NIH bacteriology researchers.

Biodefense research: NIH managementrequired corrective action

NIH management-required corrective

action

•Re-assign authority for NIH biodefense from NIAID to inter-Institute office.•Broaden NIH-Institute participation in biodefense research.•Broaden NIH definition of biodefense research.•Consolidate all bioweapons-agents review panels withnon-bioweapons-agents review panels.•Seek, and accept, input from scientific community.

Biodefense research: oversight of safetybackground

safety-background

•20-fold increase in number of institutions with bioweapons agents(>300 registered institutions)•20-fold increase in number of individuals with bioweapons agents (>11,000 registered individuals)•institutions without prior experience•individuals without prior experienceincreased risk of accidental release

recent precedents:5/2004, Boston University Medical Center, tularemia exposures, infections6/2004, Oakland Children's Hospital Research Institute, anthrax exposures8/2004, Boston University Medical Center, tularemia exposures, infection2/2005, Rocky Mountain Laboratory, Q-fever exposures

Biodefense research: oversight of safetycurrent regulatory status

safety-current regulatory status

•no applicable federal laws or regulations•no universally applicable federal guidelines

•for most institutions: no coverage•for institutions that both (1) receive NIH support and (2) perform recombinant-DNA research: coverage under voluntary guidelines(NIH Guidelines for Research Involving Recombinant DNA Molecules)

Biodefense research: oversight of safetyInstitutional Biosafety Committee (IBC) system

safety-current regulatory status,

IBC system

•created under NIH Guidelines for Research Involving Recombinant DNA Molecules (for subset of institutions subject to NIH Guidelines)•charged with reviewing protocols for safety

•limited specified practices and procedures

•large-scale violations

•local, intra-institution review panels•ineffective

•institutions without IBCs•institutions with non-functioning IBCs

•limited or no monitoring•limited or no enforcement

Biodefense research: oversight of safetyInstitutional Review Board (IRB) system

safety-current regulatory status,

IRB system

•created under federal law (45 CFR part 46)

•charged with reviewing human-subjects research protocols

•specified practices and procedures

•local, intra-institution review panels•effective

•monitoring•enforcement

•universally applicable•mandatory

Biodefense research: oversight of safetyrequired corrective action

safety-required corrective action

•legislation to establish universally applicable, mandatory local-level review(along lines of IRB system)

In contrast to nuclear or chemical weapons, biological weapons involve propagative, self-replicating materials. A single viral particle or cell--diversion of which can be neither prevented nor detected--can serve as a seed to produce effectively unlimited quantities and thus can provide the means to mount an attack.

Biodefense research: oversight of securitybackground

security-backround 1

•20-fold increase in number of institutions with bioweapons agents(>300 registered institutions)•20-fold increase in number of individuals with bioweapons agents (>11,000 registered individuals)increased risk of deliberate release

The simplest, most likely, path for a sub-state adversary, such as AlQaeda, to acquire bioweapons capability is to obtain bioweapons agents and training by penetration of a bioweapons-agents research project in a US laboratory. One well-placed graduate student, post-doctoral fellow, or technician. No cost (salary being provided courtesy of the US taxpayer). No risk. No difficulty.

Biodefense research: oversight of securitybackground

security-background 2

•20-fold increase in number of institutions with bioweapons agents(>300 registered institutions)•20-fold increase in number of individuals with bioweapons agents (>11,000 registered individuals)increased risk of deliberate release

•Interim Final Rule on Possession, Use, and Transfer of Select Agents(CFR 42 part 73; effective 2/03)

Biodefense research: oversight of securitycurrent regulatory status

security-current regulatory status

•Public Health Security and Bioterrorism Preparedness Act of 2002(PL 107-188; effective 6/02)

•Final Rule on Possession, Use, and Transfer of Select Agents(CFR 42 parts 72-73; effective 4/05)

•no requirement for exclusion of non-screened persons from laboratory[requirement for exclusion present in Interim Final Rule, but removed from Final Rule]

Biodefense research: oversight of securitycurrent regulatory status, security gaps

security-current regulatory status,

gaps, security

•no specific requirements apart from requirement for lock on door[requirement for locks on storage containers present in Interim Final Rule, but removed from Final Rule]

•insufficient requirements for physical security

•no specific requirements for multi-level access control, for security personnel, or for video surveillance

•insufficient requirements for personnel security

•de minimis personnel screening (database search only--watch-list, immigration, criminal, mental-health, and military-service records)

•no requirement for enhanced transportation security•insufficient requirements for transportation security

•no requirement for enhanced transportation monitoring•no requirement for immediate incident reporting

Biodefense research: oversight of securitycurrent regulatory status, coordination gaps

security-current regulatory status, gaps, coordination

•no disclosure of registration information permitted•insufficient coordination with state and local governments

•no disclosure of transfer/transportation information permitted

•state and local governments cannot know possible threats•state and local governments cannot properly equip first responders•state and local governments cannot properly train first responders

•state and local governments cannot know possible threats•state and local governments cannot properly equip first responders•state and local governments cannot properly train first responders

Biodefense research: oversight of securityrequired corrective action

security-required corrective action

•rulemaking or legislation to address coverage and security gaps•legislation to address coordination gaps

Biodefense research: oversight of dual-use implicationsbackground

dual-use implications-background 1

•identification of new vulnerabilities--inadvertent or intentional

•difficulty of addressing new vulnerabilities

net increased vulnerability

•20-fold increase in research activities with bioweapons agents

•antibiotic-resistance•vaccine-resistance•increased lethality•increased transmissibility•increased deliverability•increased environmental stability

Biodefense research: oversight of dual-use implicationsbackground, NAS "experiments of concern"

dual-use implications-background 2

•Would demonstrate how to render a vaccine ineffective•Would confer resistance to therapeutically useful antibiotics•Would enhance virulence of pathogen or render nonpathogen virulent•Would increase transmissibility of a pathogen•Would alter host range of a pathogen•Would enable evasion of diagnostic/detection modalities•Would enable weaponization of a biological agent or toxin

•National Academies of Science report: Biotechnology Research in an Age of Terrorism: Confronting the Dual Use Dilemma (released 10/03)•Seven "experiments of concern"

Biodefense research: oversight of dual-use implicationscurrent regulatory status

dual-use implications-current regulatory status 1

• "Experiments utilizing recombinant DNA that involve the deliberate transfer of a drug resistance trait to select agents that are not known to acquire the trait naturally, if such acquisition could compromise the use of the drug to control disease agents in humans, veterinary medicine, or agriculture"• "Experiments involving the deliberate formation of recombinant DNA containing genes for the biosynthesis of select toxins lethal for vertebrates at an LD50 < 100 ng/kg body weight."

•requirement for national-level approval for two narrowly defined experiments of concern

•Final Rule on Possession, Use, and Transfer of Select Agents(CFR 42 parts 72-73)

•possible requirement for national-level approval for other experiments of concern under study["Experiments will be proposed for addition to the listing of restricted experiments, as warranted, through the publication of a proposedamendment for public comment."]

Biodefense research: oversight of dual-use implicationscurrent regulatory status

dual-use implications-current regulatory status 2

• "deliberate transfer of a drug resistance trait to microorganisms that are not known to acquire the trait naturally...if such acquisition could compromise the use of the drug to control disease agents in humans, veterinary medicine, or agriculture"• "deliberate formation of recombinant DNA containing genes for the biosynthesis of toxin molecules lethal for vertebrates at anLD50 less than 100 nanograms per kilogram body weight."

•requirement for national-level approval of two narrowly defined experiments of concern

•NIH Guidelines for Research Involving Recombinant DNA Molecules

Biodefense research: oversight of dual-use implicationscurrent regulatory status, select-agent rule

dual-use implications-current regulatory status 3

•no other applicable federal laws or regulations•no other applicable federal guidelines

Biodefense research: oversight of dual-use implicationsrequired corrective action

dual-use implications,

required corrective action

•rulemaking or legislation to establish mandatory national-level review of NAS experiments of concern involving select agents(e.g., by adding NAS experiments of concern to list of restricted experiments in amendment to Final Rule on Possession, Use, and Transfer of Select Agents)•legislation to establish mandatory local-level review of NAS experiments of concern involving any biological agent

Biodefense research: NIH role, NIH management, oversight of safety, oversight of security,

and oversight of dual-use implications

Title

Richard H. EbrightHoward Hughes Medical Institute, Waksman Institute, Department of Chemistry

Rutgers University

itle