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

and oversight of dual
-
use implications

Title

Richard H. Ebright

Howard Hughes Medical Institute, Waksman Institute, Department of Chemistry

Rutgers University

T
i
t
l
e

Biodefense research

Outline


NIH role


oversight of safety


oversight of security


oversight of dual
-
use implications


NIH management

Biodefense research: NIH role

overview

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 role

potential strengths

NIH role
-
potential
strengths


basic research


peer
-
review process

Biodefense research: NIH role

potential 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 role

potential strengths, peer
-
review process

NIH role
-
potential
strengths, peer
review


ensures quality


effective

Biodefense research: NIH management

overview

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 management

management 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 management

consequences

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)

Biodefense research: NIH management

negative 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 management

requests 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 management

required 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 with

non
-
bioweapons
-
agents review panels.


Seek, and accept, input from scientific community.

Biodefense research: oversight of safety

background

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 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

Biodefense research: oversight of safety

current 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 safety

Institutional 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 safety

Institutional 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 safety

required 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 security

background

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 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.



Biodefense research: oversight of security

background

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 security

current 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 security

current 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 security

current 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 security

current 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 security

required 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 implications

background

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 implications

background, 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 implications

current 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."]

Biodefense research: oversight of dual
-
use implications

current 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 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

Biodefense research: oversight of dual
-
use implications

current regulatory status

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 implications

required 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. Ebright

Howard Hughes Medical Institute, Waksman Institute, Department of Chemistry

Rutgers University

T
i
t
l
e

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

Biodefense research: NIH management

public
-
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

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



Biodefense research: NIH management

public
-
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

"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 management

NIAID statements

NIH management
-
NIAID statements
-
prioritization 1

"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 management

NIAID 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/
)]

Biodefense research: NIH management

requests 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."

Biodefense research: NIH management

requests for corrective action, NIAID response

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 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


[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]

Biodefense research: NIH management

requests for corrective action, NIAID response

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."

Biodefense research: NIH management

requests for corrective action, NIAID response

NIH management
-
NIAID response 3


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.

Biodefense research: NIH management

requests for corrective action, NIAID response

NIH management
-
NIAID response 4


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

Biodefense research: NIH management

requests for corrective action, NIAID response

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).

Biodefense research: NIH management

requests for corrective action, NIAID response

NIH management
-
NIAID response 5b

bb

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, proto
zoa 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]

Bacter
iology and Mycology 2 Study Section [BM
-
2]


Experimental Virology Study Section [EVR]


Microbial Physiology and Genet
ics 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