Biodefense research: oversight of safety, oversight of security, and oversight of dual-use...

Biodefense research: 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

Title

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 (>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, infections6/2004, Oakland Children's Hospital Research Institute, anthrax exposures8/2004, Boston University Medical Center, tularemia exposures, infection2/2005, Rocky Mountain Laboratory, Q-fever exposures9/2005, Public Health Research Institute, missing plague-infected mice

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

•often 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



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



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

•no coverage of genome segments[coverage present in Interim Final Rule but removed from Final Rule]

Biodefense research: oversight of securitycurrent regulatory status, coverage gaps

security-current regulatory status, gaps, coverage

•insufficient coverage of select-agent nucleic acids

•no coverage of gene and genome synthesis technologies

•no coverage of gene and genome synthesis services

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 proposed amendment for public comment."]



• "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."

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

•NIH Guidelines for Research Involving Recombinant DNA Molecules



•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: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

Title

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: 122average US deaths/year: 0

plague:average US cases/year: 5average US deaths/year: 0

Biodefense research: NIH managementpublic-health relevance, prioritized agents

public-health relevance,

bioweapons agents

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

http://www.cdc.gov/mmwr/PDF/wk/mm4654.pdf

http://www.cdc.gov/mmwr/PDF/wk/mm4753.pdf

tuberculosis: 17,403salmonellosis: 42,457shigellosis: 22,567borreliosis: 17,642legionellosis: 1,334ehrlichiosis: 591pertussis: 8,252syphilis: 38,007gonorrhea: 346,765chlamydia: 685,508meningococcal infection: 2,290streptococcal infection, invasive: 4,371streptococcal infection, invasive, drug-resistant S. pneumoniae: 3,083

Biodefense research: NIH managementpublic-health relevance, non-prioritized agents

public-health relevance,

bioweapons agents

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

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 industry

origin 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 and Genetics 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.

"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)]

Biodefense research: NIH managementNIAID statements

NIH management-NIAID statements-

prioritization 1

http://www.niaid.nih.gov/director/pdf/biod_agenda.pdf

"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)]

Biodefense research: NIH managementNIAID statements

NIH management-NIAID statements-

prioritization 2

"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/)]

http://www.aei.org/news/newsID.15154/news_detail.asp

http://www.biomedcentral.com/news/20021205/04/

Biodefense research: NIH managementrequests for corrective action, NIAID response

NIH management-NIAID response 1a

•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.

NIAID has asserted that non-bioweapons-agents microbial research has remained "rock-solid."


NIH management-NIAID response 1b

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 MFY2000: 221 awards, $68.5 MFY2001: 226 awards, $66.5 MFY2002: 222 awards, $66.7 M

•after prioritization of bioweapons-agent research:FY 2003: 138 awards, $40.2 MFY 2004: 116 awards, $38.1 M

[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]


NIH management-NIAID response 2

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.

•NIAID omits all non-NIAID research.

•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.

•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.

To scientists, any response that denies those facts must be considered uninformed or untruthful.



•The facts are clear to scientists who have examined the award and cost numbers in NIH databases.


NIH management-NIAID response 5a

•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.

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, 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 management-NIAID response 5b

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Scientific Areas of Integrated Review Groups (IRGs)

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 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 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

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