i
t
l
e
Title
Biodefense research:
oversight of safety, oversight of security,
and oversight of dual-use implications
Richard H. Ebright
Howard Hughes Medical Institute, Waksman Institute, Department of Chemistry
Rutgers University
safety-background
Biodefense research: oversight of 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
(>16,000 registered individuals)
•institutions without prior experience
•individuals without prior experience
increased risk of accidental release
recent precedents:
5/2004, Boston University Medical Center, tularemia exposures, infections
6/2004, Oakland Children's Hospital Research Institute, anthrax exposures
8/2004, Boston University Medical Center, tularemia exposures, infection
2/2005, Rocky Mountain Laboratory, Q-fever exposures
9/2005, Public Health Research Institute, missing plague-infected mice
safety-current
regulatory status
Biodefense research: oversight of 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)
safety-current
regulatory status,
IBC system
Biodefense research: oversight of safety
Institutional Biosafety Committee (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
•local, intra-institution review panels
•often ineffective
•large-scale violations
•institutions without IBCs
•institutions with non-functioning IBCs
•limited specified practices and procedures
•limited or no monitoring
•limited or no enforcement
safety-current
regulatory status,
IRB system
Biodefense research: oversight of safety
Institutional Review Board (IRB) system
•created under federal law (45 CFR part 46)
•universally applicable
•mandatory
•charged with reviewing human-subjects research protocols
•local, intra-institution review panels
•effective
•specified practices and procedures
•monitoring
•enforcement
safety-required
corrective action
Biodefense research: oversight of safety
required corrective action
•legislation to establish universally applicable, mandatory local-level review
(along lines of IRB system)
security-backround 1
Biodefense research: oversight of security
background
•20-fold increase in number of institutions with bioweapons agents
(>300 registered institutions)
•20-fold increase in number of individuals with bioweapons agents
(>16,000 registered individuals)
increased risk of deliberate release
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.
security-background
2
Biodefense research: oversight of security
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)
increased risk of deliberate release
The simplest, most likely, path for a sub-state adversary, such as Al
Qaeda, 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.
security-current
regulatory status
Biodefense research: oversight of security
current regulatory status
•Public Health Security and Bioterrorism Preparedness Act of 2002
(PL 107-188; effective 6/02)
•Interim Final Rule on Possession, Use, and Transfer of Select Agents
(CFR 42 part 73; effective 2/03)
•Final Rule on Possession, Use, and Transfer of Select Agents
(CFR 42 parts 72-73; effective 4/05)
security-current
regulatory status,
gaps, security
Biodefense research: oversight of security
current regulatory status, security gaps
•insufficient requirements for physical 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]
•no specific requirements for multi-level access control, for security
personnel, or for video surveillance
•insufficient requirements for personnel security
•no requirement for exclusion of non-screened persons from laboratory
[requirement for exclusion present in Interim Final Rule, but removed
from Final Rule]
•de minimis personnel screening (database search only--watch-list,
immigration, criminal, mental-health, and military-service records)
•insufficient requirements for transportation security
•no requirement for enhanced transportation security
•no requirement for enhanced transportation monitoring
•no requirement for immediate incident reporting
security-current
regulatory status,
gaps, coverage
Biodefense research: oversight of security
current regulatory status, coverage gaps
•insufficient coverage of select-agent nucleic acids
•no coverage of genome segments
[coverage present in Interim Final Rule but removed from Final Rule]
•no coverage of gene and genome synthesis technologies
•no coverage of gene and genome synthesis services
security-current
regulatory status,
gaps, coordination
Biodefense research: oversight of security
current regulatory status, coordination gaps
•insufficient coordination with state and local governments
•no disclosure of registration 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
•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
security-required
corrective action
Biodefense research: oversight of security
required corrective action
•rulemaking or legislation to address coverage and security gaps
•legislation to address coordination gaps
dual-use
implicationsbackground 1
Biodefense research: oversight of dual-use implications
background
•20-fold increase in research activities with bioweapons agents
•identification of new vulnerabilities--inadvertent or intentional
•antibiotic-resistance
•vaccine-resistance
•increased lethality
•increased transmissibility
•increased deliverability
•increased environmental stability
•difficulty of addressing new vulnerabilities
net increased vulnerability
dual-use
implicationsbackground 2
Biodefense research: oversight of dual-use implications
background, NAS "experiments of concern"
•National Academies of Science report: Biotechnology Research in an
Age of Terrorism: Confronting the Dual Use Dilemma (released 10/03)
•Seven "experiments of concern"
•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
dual-use
implications-current
regulatory status 1
Biodefense research: oversight of dual-use implications
current regulatory status
•Final Rule on Possession, Use, and Transfer of Select Agents
(CFR 42 parts 72-73)
•requirement for national-level approval for two narrowly defined
experiments of concern
• "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."
•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 proposed
amendment for public comment."]
dual-use
implications-current
regulatory status 2
Biodefense research: oversight of dual-use implications
current regulatory status
•NIH Guidelines for Research Involving Recombinant DNA Molecules
•requirement for national-level approval of two narrowly defined
experiments of concern
• "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 an
LD50 less than 100 nanograms per kilogram body weight."
dual-use
implications-current
regulatory status 3
Biodefense research: oversight of dual-use implications
current regulatory status
•no other applicable federal laws or regulations
•no other applicable federal guidelines
dual-use
implications,
required corrective
action
Biodefense research: oversight of 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
i
t
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Title
Biodefense research:
oversight of safety, oversight of security,
and oversight of dual-use implications
Richard H. Ebright
Howard Hughes Medical Institute, Waksman Institute, Department of Chemistry
Rutgers University
public-health
relevance,
bioweapons agents
Biodefense research: NIH management
public-health relevance, prioritized agents
anthrax:
average US cases/year: 3* (includes 22 bioterrorism-related cases in 2001)
average US deaths/year: 1* (includes 5 bioterrorism-related deaths in 2001)
tularemia:
average US cases/year: 122
average US deaths/year: 0
plague:
average US cases/year: 5
average US deaths/year: 0
data for 1996-2003:
http://www.cdc.gov/mmwr/PDF/wk/mm4553.pdf;
http://www.cdc.gov/mmwr/PDF/wk/mm4654.pdf; http://www.cdc.gov/mmwr/PDF/wk/mm4753.pdf;
http://www.cdc.gov/mmwr/PDF/wk/mm4853.pdf; http://www.cdc.gov/mmwr/PDF/wk/mm4953.pdf;
http://www.cdc.gov/mmwr/PDF/wk/mm5053.pdf; http://www.cdc.gov/mmwr/PDF/wk/mm5153.pdf;
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5330a6.htm
public-health
relevance,
bioweapons agents
Biodefense research: NIH management
public-health relevance, non-prioritized agents
tuberculosis: 17,403
salmonellosis: 42,457
shigellosis: 22,567
borreliosis: 17,642
legionellosis: 1,334
ehrlichiosis: 591
pertussis: 8,252
syphilis: 38,007
gonorrhea: 346,765
chlamydia: 685,508
meningococcal infection: 2,290
streptococcal infection, invasive: 4,371
streptococcal infection, invasive, drug-resistant S. pneumoniae: 3,083
average US cases per year; data for 1996-2003:
http://www.cdc.gov/mmwr/PDF/wk/mm4553.pdf;
http://www.cdc.gov/mmwr/PDF/wk/mm4654.pdf; http://www.cdc.gov/mmwr/PDF/wk/mm4753.pdf;
http://www.cdc.gov/mmwr/PDF/wk/mm4853.pdf; http://www.cdc.gov/mmwr/PDF/wk/mm4953.pdf;
http://www.cdc.gov/mmwr/PDF/wk/mm5053.pdf; http://www.cdc.gov/mmwr/PDF/wk/mm5153.pdf;
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5330a6.htm
NIH role-overview
Biodefense research: NIH role
overview
•NIH has the potential to make critical contributions to biodefense.
•NIH has the potential to make unique contributions to biodefense.
NIH role-potential
strengths
Biodefense research: NIH role
potential strengths
•basic research
•peer-review process
NIH role-potential
strengths, basic
research
Biodefense research: NIH role
potential strengths, basic research (bacteriology)
•research on pathogenic microorganisms
•research on model microorganisms
•model microorganisms
•standard experimental workhorses (E. coli, B. subtilis)
•exceptionally well-characterized
•exceptionally well-developed experimental tools
•nonpathogenic, or minimally pathogenic
•advantages
•cost-effective
•rapid
•raise no safety issues
•raise no security issues
•outputs
origin of recombinant DNA technology
and biotechnology industry
•detection systems
•diagnostic systems
origin of current detection systems,
•countermeasures
diagnostic systems, and antibiotics
•all R&D up to final testing
NIH role-potential
strengths, peer
review
Biodefense research: NIH role
potential strengths, peer-review process
•ensures quality
•effective
NIH managementoverview
Biodefense research: NIH management
overview
•has not exploited potential strengths in basic research and peer review
•has had negative impact on basic research and peer review
NIH managementmanagement errors
Biodefense research: NIH management
management errors
(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.
(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-agentspathogens research (where funding is tight and competitive) into less promising
bioweapons-agents research (where funding is loose and easy).
NIH managementconsequences
Biodefense research: 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 on
model 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 on
non-bioweapons-agents pathogenic microorganisms
(Bacteriology and Mycology 1 and 2)
(from 627 in 1996-2000 to 457 in 2001-Jan 2005)
NIH managementnegative impacts
Biodefense research: NIH management
negative impacts
•negative impacts on biodefense
•ineffective (minimal biodefense bang for biodefense buck)
•funding of subpar research
•failure to exploit existing strengths
•erosion of existing strengths
•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 public health
•negative impacts on science
NIH managementrequests for
corrective action
Biodefense research: 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 and
Genetics and NIH Bacteriology and Mycology Initial Review Groups in
1996-2005.
•Signers included the president-elect and seven past presidents of the
American Society for Microbiology.
•In March 2005, a letter requesting corrective action was submitted to the
NIH Director by 76 intramural-NIH bacteriology researchers.
Signers included nearly nine-tenths of intramural-NIH bacteriology
researchers.
NIH managementrequired corrective
action
Biodefense research: 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 with
non-bioweapons-agents review panels.
•Seek, and accept, input from scientific community.
NIH managementNIAID statementsprioritization 1
Biodefense research: NIH management
NIAID statements
"There is a dearth of investigators involved in research on some of the most
important pathogens that could potentially be used in a bioterrorist attack.
For example, relatively few bench scientists in the country are currently
working on the bacterium that causes tularemia, Francisella tularensis, one
of the six Class A agents. There are several reasons behind the shortage of
biodefense research personnel. First, substantial research funding targeted
to these pathogens became available only in the past 5 years. Relatively
little attention was paid to these uncommon infections until the mid-1990s,
when officials became concerned about the possible dispersal of biological
agents from the former Soviet Union weapons program. Prior to that, greater
funding urgency was deservedly assigned to widespread emerging
infections, such as HIV/AIDS, tuberculosis, and malaria. The number of
Americans living with HIV/AIDS is approaching 1 million; the number
reported to be infected with plague in 1999 was only 9."
[Tara Palmore, Greg Folkers, Carole Heilman, John La Montagne, and
Anthony S. Fauci, The NIAID Research Agenda on Biodefense, ASM News,
August 2002 (http://www.niaid.nih.gov/director/pdf/biod_agenda.pdf)]
NIH managementNIAID statementsprioritization 2
Biodefense research: NIH management
NIAID statements
"This funding is the largest single increase of any disease of any institute in
the history of the NIH, and that includes the war on cancer. It includes all of
the acceleration with HIV/AIDS. That is really really quite impressive, and it's
going to be sustained, I can assure you."
[Anthony S. Fauci, AEI Newsletter, August 2002
(http://www.aei.org/news/newsID.15154/news_detail.asp)]
"Investigators should not hesitate to put in applications for grants or
respond to RFPs and contracts....You'd be making a big mistake because
you may miss a grant or contract cycle if you do that....This will be the
largest single increase of any discipline, in any institute, for any disease in
the history of NIH."
[Anthony S. Fauci, The Scientist, December 5, 2002
(http://www.biomedcentral.com/news/20021205/04/)]
NIH managementNIAID response 1a
Biodefense research: NIH management
requests for corrective action, NIAID response
NIAID has asserted that non-bioweapons-agents microbial research has
remained "rock-solid."
•There has been a 40% reduction in number of competing awards, and a
40% reduction in inflation-adjusted dollar volume of competing awards, for
NIH extramural laboratory research in non-bioweapons-agents microbial
physiology, genetics, and pathogenesis.
•The crash in number and inflation-adjusted dollar volume of awards
occurred in a single one-year interval: between FY2002 and FY2003
(i.e., in the same one-year interval corresponding to the prioritization of
bioweapons-agents research).
•There has been no, zero, recovery from the crash.
NIH managementNIAID response 1b
Biodefense research: NIH management
requests for corrective action, NIAID response
NIH Microbial Physiology and Genetics 1 and 2 and NIH Bacteriology and
Mycology 1 and 2 study sections (new or competing awards,
inflation-adjusted first-year costs):
•before prioritization of bioweapons-agent research:
FY1999: 216 awards, $64.3 M
FY2000: 221 awards, $68.5 M
FY2001: 226 awards, $66.5 M
FY2002: 222 awards, $66.7 M
•after prioritization of bioweapons-agent research:
FY 2003: 138 awards, $40.2 M
FY 2004: 116 awards, $38.1 M
NIH managementNIAID response 2
Biodefense research: NIH management
requests for corrective action, NIAID response
NIAID has asserted that "support for basic bacterial physiology research has
increased substantially."
•NIAID includes as "basic bacterial physiology research" not only
non-bioweapons-agents laboratory research, but also bioweapons-agents
laboratory research, epidemiological research, psychosocial research, and
other research.
[awards under biodefense special emphasis panels, and awards under
Epidemiology and Disease Control, Epidemiology of Chronic Diseases,
Epidemiology of Clinical Disorders and Aging, Behavioral and Social
Consequences of HIV/AIDS, Psychosocial Risk and Disease Prevention,
Alcohol and Toxicology, Neurotoxicology and Alcohol, Synapses
Cytoskeleton and Trafficking, Human Embryology, Tropical Medicine and
Parasitology, Experimental Virology, and Virology study sections]
•NIAID omits all non-NIAID research.
NIH managementNIAID response 3
Biodefense research: NIH management
requests for corrective action, NIAID response
•The president-elect of the American Society for Microbiology
has described the NIAID response as a "stubborn reiteration of past
statements." A former president of the American Society for Microbiology
has described the NIAID response as "circle-the-wagons" and noted that he
was "not persuaded by the argument." Another former president of the
American Society for Microbiology has described the NIAID response as
"duplicity." Other scientists have described the NIAID response as
"stonewalling," "damage control," and "sleazy."
•The intramural-NIH open letter was circulated after the NIAID response,
and signed by 70+ intramural-NIH scientists after the NIAID response.
Scientists have not found the NIAID response persuasive.
NIH managementNIAID response 4
Biodefense research: NIH management
requests for corrective action, NIAID response
•The facts are clear to scientists who have served on study sections in the
discipline, submitted proposals to study sections in the discipline, or
attended scientific meetings in the discipline.
•The facts are clear to scientists who have examined the award and cost
numbers in NIH databases.
To scientists, any response that denies those facts must be considered
uninformed or untruthful.
NIH managementNIAID response 5a
Biodefense research: NIH management
requests for corrective action, NIAID response
NIAID has asserted that the Microbial Physiology and Genetics 1 and 2 and
Bacteriology and Mycology 1 and 2 study sections were responsible only for
a small part of non-bioweapons-agents, basic bacterial research in the
period under consideration.
•The Microbial Physiology and Genetics 1 and 2 and Bacteriology and
Mycology 1 and 2 study sections were the only study sections within the
Infectious Diseases and Microbiology Integrated Review Group expressly
related to laboratory research on bacterial physiology, genetics, and
pathogenesis in the period under consideration.
•The Microbial Physiology and Genetics 1 and 2 and Bacteriology and
Mycology 1 and 2 study sections were the only study sections, barring
special circumstances, to which proposals with primary focus on laboratory
research on bacterial physiology, genetics, and pathogenesis were referred
by the NIH Center for Scientific Review-Office of Referral and Review).
NIH managementNIAID response 5b
For a listing of the Scientific Review Administrator and membership roster for each study section,
click on the study section roster next to the study section name under a IRG listed below or go to
the study section index (study sections listed alphabetically) and click on the specified roster next
to the name of the study section.
Last updated on 24th July, 2003
Biodefense research: NIH management
requests for corrective action, NIAID response
Referral & Review
Infectious Diseases and Microbiology IRG [IDM]
The Infectious Diseases and Microbiology [IDM] IRG reviews
applications in the following areas: Mechanisms of pathogenesis of
viruses, rickettsia, bacteria, fungi, protozoa and other parasites of
humans; basic molecular biology, physiology, and Genetics of these
pathogenic organisms; basic molecular biology, physiology, and
Genetics of non-pathogenic bacteria, archae, yeasts, and viruses with
bb
non- human hosts.
The following study sections are included within the IDM IRG:
Bacteriology and Mycology 1 Study Section [BM-1]
Bacteriology and Mycology 2 Study Section [BM-2]
Experimental Virology Study Section [EVR]
Microbial Physiology and Genetics 1 Study Section [MBC-1]
Microbial Physiology and Genetics 2 Study Section [MBC-2]
Tropical Medicine and Parasitology Study Section [TMP]
Virology Study Section [VR]
IDM Small Business Activities