Biodefense research:

1
Title
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
2
safety-background
Biodefense research oversight of
safety background

• 20-fold increase in number of institutions with
  bioweapons agents
• (gt300 registered institutions)

• 20-fold increase in number of individuals with
  bioweapons agents (gt16,000 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
3
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)

4
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

5
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

6
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)

7
security-backround 1
Biodefense research oversight of
security background

• 20-fold increase in number of institutions with
  bioweapons agents
• (gt300 registered institutions)

• 20-fold increase in number of individuals with
  bioweapons agents (gt16,000 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. 
8
security-background 2
Biodefense research oversight of
security background

• 20-fold increase in number of institutions with
  bioweapons agents
• (gt300 registered institutions)

• 20-fold increase in number of individuals with
  bioweapons agents (gt11,000 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. 
9
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)

10
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

11
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

12
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

13
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

14
dual-use implications-background 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

• difficulty of addressing new vulnerabilities

net increased vulnerability
15
dual-use implications-background 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"

16
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

• 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."

17
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."

18
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

19
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

20
Title
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
21
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
plagueaverage 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 h
ttp//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
22
public-health relevance, bioweapons agents
Biodefense research NIH management public-health
relevance, non-prioritized agents
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  
average US cases per year data for
1996-2003 http//www.cdc.gov/mmwr/PDF/wk/mm4553.p
df 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
23
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.

24
NIH role-potential strengths
Biodefense research NIH role potential strengths

• basic research

• peer-review process

25
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, diagnostic
systems, and antibiotics

• countermeasures

• all RD up to final testing

26
NIH role-potential strengths, peer review
Biodefense research NIH role potential
strengths, peer-review process

• ensures quality

• effective

27
NIH management-overview
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

28
NIH management-management 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-agents-pat
hogens research (where funding is tight and
competitive) into less promising
bioweapons-agents research (where funding is
loose and easy).
29
NIH management-consequences
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)

30
NIH management-negative 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

31
NIH management-requests 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.
32
NIH management-required 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.

33
NIH management-NIAID statements-prioritization 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_a
genda.pdf)
34
NIH management-NIAID statements-prioritization 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_de
tail.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/)
35
NIH management-NIAID 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.

36
NIH management-NIAID 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
  researchFY1999 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
  researchFY 2003 138 awards, 40.2 MFY 2004
  116 awards, 38.1 M

37
NIH management-NIAID 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-agent
  s 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.

38
NIH management-NIAID 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.
39
NIH management-NIAID 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.
40
NIH management-NIAID 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).

41
NIH management-NIAID response 5b
Biodefense research NIH management requests for
corrective action, NIAID response
bb