Transcript RonAtlasUGCONF02 - American Society for Microbiology

Bioterrorism:
Educators Response to the Threat
Ronald M. Atlas
ASM President Elect and Co-Chair ASM Task Force
on Biological Weapons
Graduate Dean, Professor of Biology, and Co-Chair of
Center for Deterrence of Biowarfare and Bioterrorism
University of Louisville, Louisville KY
The Threat of Bioterrorism
Before September 11th--Predictions of Bioterrorism
We were... “ at the brink of a new age—what some experts call
catastrophic terrorism...I do not believe it is a question of whether a
lone terrorist or terrorist group will use infectious disease agents to
kill unsuspecting citizens; I’m convinced it’s really just a question of
when and where.” Michael Osterholm, Former State Epidemiologist
for Minnesota
After September 11th--Reality of Bioterrorism
Attack with Anthrax through the mail
Fear grips the Nation--5 die, mail stops, buildings close
Science is needed but scientists also become suspects
Educational needs change
Public demands information but authoritative information is
withheld due to criminal investigation
Questions arise as to what to tell whom
Estimates of casualties from a hypothetical
biological attack based upon the release of
50 kg of various agents by an aircraft flying
along a 2-km path upwind of a city of half a
million people
Agent
Brucellosis
Q fever
Tularemia
Anthrax
Casualties
125,000
125,000
125,000
125,000
Fatalities
500
150
30,000
95,000
Economics of Biological Weapons:
The Poor Man’s Nuclear Bomb
Comparative cost of civilian casualties per square kilometer

$2,000 with conventional weapons
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$800 with nuclear weapons
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$1 with biological weapons
Economic impact of an aerosol bioterrorist attack on a US city
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$477.7 million per 100,000 people exposed to Brucella species
(brucellosis)
$26.2 billion per 100,000 people exposed to Bacillus anthracis
(anthrax)
Potential Uses of Biological Weapons
Biological Warfare

Microbes can be weapons of mass destruction
Bioterrorism


50kg of anthrax can kill nearly 100,000 people over
a large area
Yelling anthrax creates terror
Biocrimes

A single injection of a toxin can kill an individual
NIH bioterrorism Research Funding
TOTAL 2001
TOTAL 2002
TOTAL 2003
$25M
$275M
$1,748M
Basic research and development
$440.6M
Drug/vaccine discovery and development $591.9M
Clinical research
$194.3M
Research facilities intramural
$371.1M
Research facilities extramural
$150.0M
TOTAL
$1,747.9M
Agents of Most Concern for Bioterrorism
Smallpox virus
Bacillus anthracis (anthrax)
Yersinia pestis (plague)
Botulinum toxin
Francisella tularensis (tularemia)
Hemorrhagic Fever Viruses
Recombinant Pathogens
Smallpox Strategic Questions
If smallpox is the greatest threat because it has been
eradicated and vaccination was stopped, should we cease
efforts to eliminate other diseases like measles and polio?
Is smallpox really the greatest threat?
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Do North Korea, Iran, and Iraq have smallpox?
Are the Russian stocks secure?
Should Russia and US eliminate remaining stocks?
What should we do about vaccination?

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Given high rate of adverse reactions, should we institute
mandatory vaccination--estimates are that it would result in 4001,000 deaths in US--at what point is the threat high enough?
How can we ensure efficacy of a new safer vaccine?
Current strategy is to produce enough vaccine within a year for
all Americans--but will ring vaccination work after an attack?
Anthrax Attack 2001
Anthrax spores sent via mail from Trenton
Letters sent to news media and Congress
11 cases cutaneous (skin) anthrax, 11 cases
of inhalational anthrax, 5 deaths
Tens of thousands given prophylactic doses
of antimicrobics
Ames strain, highly refined powder

Ames strain never in Iowa
Anthrax: Overview
Primarily disease of herbivores
Natural transmission to humans by contact with
infected animals or contaminated animal products
Soil reservoir
Woolsorter’s disease (inhalation anthrax)
No person-to-person transmission of inhalational anthrax
CDC: Gram stain of
B. anthracis
CDC Case Definition of Anthrax
CDC definition of a confirmed case of
anthrax:
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A clinically compatible case of cutaneous,
inhalational, or gastrointestinal illness that is
laboratory confirmed by isolation of B.
anthracis from an affected tissue or site, or
Other laboratory evidence of B. anthracis
infection based on at least two supportive
laboratory tests.
Anthrax: Cutaneous
 Most common form (95%)
 Inoculation of spores under skin
 Incubation: hours to 7 days
 Small papule  ulcer surrounded by
vesicles (24-28h)
 Painless eschar with edema
 Death 20% untreated; rare if treated
USAMRICD: Eschar with
surrounding edema
Anthrax: Inhalational
Inhalation of spores
Incubation: 1 to 43 days
Initial symptoms
(2-5 d)

fever, cough, myalgia, malaise
Terminal symptoms (1-2d )

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
High fever, dyspnea, cyanosis
hemorrhagic
mediastinitis/pleural effusion
Rapid progression to
CDC: CXR with widened mediastinum
shock/death
of inhalational anthrax
Mortality rate ~95%
Anthrax: Treatment
Antibiotics
 Doxycycline, Ciprofloxacin
 Multiple antibiotics for inhalational anthrax

Disease is toxin mediated--antibiotics not always
successful--recent attack mortality was 50%-previously 90+%
Supportive care
Standard precautions, no quarantine needed
Anthrax Attack 2001 Unknowns
Who sent the letters?
How many spores are required to cause
inhalational anthrax
Best prophylactic treatment
Appropriate method for safeguarding the
mail
How to communicate to the public
What is the prevalence of anthrax in soils?
CDC Approach
Increase funding to States for Public Health

Increase education and response capability
Enhance surveillance

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Build Health Alert Network
Build Laboratory response network
Level D La bo ratories
Agentspecif ic
laboratory
Level C
laboratory
Agentspecif ic
laboratory
Agentspecif ic
laboratory
Rapid-response
and adv anced
technology laboratory
Level B
laboratory
Level A
laboratory
Specimen testing and referral
Training and consultation
CDC Biological Threat Categories
The Centers for Disease Control and Prevention
(CDC) has divided biological agents that are the
critical biothreat agents into categories based upon
their risks for causing mass casualties in the event
of a bioterrorist attack.
CDC Biological Threat Category A
The highest priority agents that pose a risk to
national security
Easily disseminated or transmitted person-toperson
Cause high mortality
Potential for major public health impact
Might cause public panic & social disruption
Require public health preparedness
CDC Biological Threat Category A Agents
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Variola major (smallpox)
Bacillus anthracis (anthrax)
Yersinia pestis (plague)
Clostridium botulinum toxin (botulism)
Francisella tularensis (tularaemia)
Filoviruses
Ebola hemorrhagic fever
Marburg hemorrhagic fever
Lassa (Lassa fever)
Junin (Argentine hemorrhagic fever)
CDC Biological Threat Category B

Moderately easy to disseminate

Cause moderate morbidity and low mortality
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
Require specific enhancements of CDC’s
diagnostic capacity
Enhanced disease surveillance
CDC Biological Threat Category B Agents
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Coxiella burnetti (Q fever)
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Brucella species (brucellosis)
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Burkholderia mallei (glanders)
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Alphaviruses

Venezuelan encephalomyelitis

Eastern and western equine encephalomyelitis
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Ricin toxin from Ricinus communis (castor beans)
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Epsilon toxin of Clostridium perfringens

Staphylococcus enterotoxin B
CDC Biological Threat Category B Agents
(Subset List)
Food- or water-borne pathogens include but
are not limited to:

Salmonella species

Shigella dysenteriae

Escherichia coli O157:H7

Vibrio cholerae

Cryptosporidium parvum.
CDC Biological Threat Category C
Includes emerging pathogens that could be engineered
for mass dissemination in the future due to:

Availability

Ease of production and dissemination

Potential for high morbidity and mortality

Major health impact
Preparedness for List C agents requires ongoing
research to improve disease detection, diagnosis,
treatment, and prevention.
CDC Biological Threat Category C Agents
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Nipah virus
Hantaviruses
Tick-borne hemorrhagic fever viruses
Tick-borne encephalitis viruses
Yellow fever
Multidrug-resistant tuberculosis
Clinical Laboratories as Sentinels
for Bioterrorism
ER’s and their labs are key sentinels
Laboratory personnel require training
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Methods to rule out non-BT agents
Mechanism to forward the balance
Safety for laboratory personnel
Variability in states’ training
Uniform procedures ideal
Laboratory Response Network
Mission: Systemically and rapidly
galvanize bioterrorism laboratory readiness
in order to: Develop critical laboratory
capacity in public health laboratories,
Foster appropriate linkages with, and
capacity in, clinical laboratories, and
Integrate these capacities into overall
emergency preparedness.
Functional Levels of the LRN
Level A: RULE OUT AND REFER; RAISE
SUSPICION/NOTIFY INFECTION
CONTROL
Level B: RULE IN AND REFER
Level C: Advanced Testing, evaluation of new
tests and reagents, facilitate transfer of tests to
Level B
Level D: Highest level of containment (BSL-4),
specialized testing, archive strains, detect
genetically engineered agents
A
A
LaboratoryB Response
B Network
A
C
Clinical Laboratories
- A Level
A
Public Health
C LaboratoriesC- B Level
D
AdvancedB Public Health Laboratories B
- C Level
Federal Laboratories
C
C -D Level
A
(CDC, DOD, FBI, DOE)
B
A
B
A
A
National Security and Openness of Scientific Research
Are new mechanisms needed to govern scientific research
so as to lessen the probability of the development of
advanced biological weapons?

If so what should be done?
The research and national security communities have
different objectives, cultures, and norms, and are likely to
weigh the costs and benefits of proposed policy measures
differently

What should the National Academy and scientific societies like the
American Society for Microbiology do to foster the critical dialog
among these communities?
Controlling Biological Warfare Threats: Resolving Potential Tensions Among the Research
Community, Industry, and the National Security Community. Gerald L. Epstein. Critical
Reviews in Microbiology, 27 (2001)
Role of Scientific Community in
Identifying Misconduct
Responsibility
 What obligation do members of the research community
have to identify, call attention to, or clarify activities of
others that may appear suspicious?
Transparency
 Are there areas of research or types of experiment that
pose such sensitivity regarding potential bioweapons
application that they merit extraordinary obligations for
transparency and openness?
Ethical Responsibility of
Scientists and Physicians
Past development of biological weapons has
involved microbiologists and physicians

Key leaders of the Aum Shinrikyo were scientists

Ken Alibek, former first deputy chief of Biopreparat
• Before I became an expert in biological warfare I was
trained as a physician. The government I served perceived
no contradiction between the oath every doctor takes to
preserve life and our preparations for mass murder. For a
long time neither did I.

Such violations of the fundamental ethical principles
of physicians and microbiologists must not be
tolerated
ASM Resolution on Bioethics
The Council Policy Committee of the American Society for
Microbiology affirms the longstanding position of the
Society that microbiologists will work for the proper and
beneficent application of science and will call to the
attention of the public or the appropriate authorities misuses
of microbiology or of information derived from
microbiology.
ASM members are obligated to discourage any use of
microbiology contrary to the welfare of humankind,
including the use of microbes as biological weapons.
Bioterrorism violates the fundamental principles expressed
in the Code of Ethics of the Society and is abhorrent to the
ASM and its members.
Suggested Policy Mechanisms to Reduce
Future Biological Weapons Threats
Tighten restrictions on access to dangerous
pathogens
Impose restrictions on the conduct and publication
of “contentious research,” i.e. fundamental
biological or biomedical investigations that produce
organisms or knowledge that could have immediate
weapons implications
Restrict access and dissemination of “relevant
information”
Controlling Biological Warfare Threats: Resolving Potential Tensions Among the Research
Community, Industry, and the National Security Community. Gerald L. Epstein. Critical
Reviews in Microbiology, 27 (2001)
Restrictions on Access to Select Agents
 Possession of potentially dangerous biological agents
should be regulated more tightly
 Are there individuals that should not be permitted to
conduct certain categories of research, or that should not
be given access to dangerous pathogens?
Physical security at institutions that maintain cultures of
potentially dangerous biological agents needs to be
reexamined to provide not only legal but also physical
barriers to help prevent unauthorized individuals from
obtaining such agents
 Are locks enough?
 Should armed guards secure laboratories with select
agents?
CDC Laboratory Registration/
Select Agent Transfer Program
These regulations place shipping and handling
requirements on laboratory facilities that transfer or
receive select agents capable of causing substantial
harm to human health. They are designed to ensure
that select agents are not shipped to parties who are
not equipped to handle them appropriately or who
lack proper authorization for their requests.
Currently regulates shipment of 36 select agents and
their disease related genes
Requires adherence to CDC biosafety manual
In effect since April 1997
USA Patriot Act
Imposes restrictions on possession of select agents
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Restricts aliens from countries designated as supporting
terrorism from possessing select agents within the United
States
Restricts individuals who are not permitted to purchase
handguns, e.g. some individuals with a history of mental
illness or a criminal record, from possessing select agents
No provision for exemptions under any circumstances
Does not require registration for possession of select
agents
Requires that requests by law enforcement be kept
confidential so as not to alert would-be terrorists.
In effect since October 26, 2001
Definition of a Restricted Person
 is under indictment for a crime punishable by imprisonment for a term
exceeding one year;
 has been convicted in any court of a crime punishable by
imprisonment for a term exceeding one year;
 is a fugitive from justice;
 is an unlawful user of any controlled substance;
 is an alien illegally or unlawfully in the US;
 has been adjudicated as a mental defective or has been committed to
any mental institution;
 is an alien who is a national of a country as to which the Secretary of
State has made a determination (that remains in effect) that such
country has repeatedly provided support for acts of international
terrorism; or
 has been discharged from the Armed Services of the United States
under dishonorable conditions.
Patriot Act and Legitimate Research
The USA Patriot Act also makes it an offense for a
person to knowingly possess any biological agent,
toxin or delivery system of a type or in a quantity
that, under the circumstances, is not reasonably
justified by prophylactic, protective, bona fide
research or other peaceful purpose.
Senator Patrick Leahy warned during passage of the
Patriot Act, this provision could have unanticipated
ramifications depending upon how one defined
“bona fide” or “reasonably justified.”
U Conn case raises questions
Concern Over Scientific Information
ASM posted information about bioterrorism and anthrax at
its web site for the education of the scientific community
 “The principle right now is one of openness in science--if
someone wants to publish a legitimate research paper
we’re not going to be the censor.” Ronald Atlas-President elect ASM
Position of openness of science draws scorn
Eric Lichtblau Response to Terror: Rising Fears That What We Do
Know Can Hurt Us, Los Angeles Times November 18, 2001

“We have to get away from the ethos that knowledge is
good, knowledge should be publicly available, that
information will liberate us...Information will kill us in
the techno-terrorist age, and I think it's nuts to put that
stuff on Web sites.” Arthur Caplan--U. Penn. bioethicist
Antibiotic Resistance of Bacillus anthracis
 The American Society for Microbiology's Web site includes the
abstracts of the 4th International Conference that was organized by
scientists from the U.S. Army Medical Research Institute, the British
Defense Research Agency, NIH, and the Pasteur Institute.
 Board 42A. In Vitro Selection and Characterization of High-Level
Fluoroquinolone Resistance in Bacillus anthracis. L. Price, A. G.
Vogler, S. James, and P. Keim. Northern Arizona State University
• increasing exposure to ciprofloxacin resulted in evolution of
fluoroquinolone resistance in Bacillus anthracis
• antibiotic resistant B. anthracis can be intentionally produced
• multiple antibiotic treatment was warranted in cases of
inhalational anthrax
 Should this abstract have been published?
 Should it have been removed after Sept. 11?
Smallpox Virus Genome
 The entire DNA genome of a highly virulent Variola is
constituted of 186,102 base pairs
 Sequence analysis shows 187 closely spaced open reading
frames specifying putative major proteins containing >= 65
amino acids.
 150 proteins have > 90% identity to major gene products
encoded by Vaccinia virus, the smallpox vaccine.
 Variola virus has a group of proteins that are truncated
compared with Vaccinia virus counterparts and a smaller group
of proteins that are elongated.
 The terminal regions encode several novel proteins and
variants of other poxvirus proteins potentially augment variola
virus transmissibility and virulence for its only natural host,
humans.
Massung RF., et al. Analysis of the complete genome of smallpox
variola major virus strain Bangladesh-1975. Virology.
201(2):215-40, 1994 Jun.
 Should the genome have been published?--ASM position was Yes
Mousepox--Immune System Suppression
 Expression of IL-4 by a thymidine kinase-positive mousepox virus
suppresses cytolytic responses of natural killer (NK) and a strong
CD8(+) cytotoxic T-lymphocyte (CTL) and expression of gamma
interferon.
 Genetically resistant mice infected with the IL-4-expressing virus
develop acute mousepox accompanied by high mortality.
Jackson RJ. et al. 2001. Expression of mouse interleukin-4 by a recombinant
ectromelia virus suppresses cytolytic lymphocyte responses and overcomes genetic
resistance to mousepox. J. Virology 75:1205-10.
Conclusions
 Virus-encoded IL-4 not only suppresses primary antiviral cellmediated immune responses but also can inhibit the expression of
immune memory responses.
 A poxvirus can be simply genetically engineered for which
immunization will be totally ineffective.
 Should this research have been permitted?
ASM Publication Board Statement
 “The ASM recognizes that there are valid concerns
regarding the publication of information in scientific
journals that could be put to inappropriate use. The ASM
hopes to participate in the public debate on these issues.
Until a national consensus is reached, the rare manuscript
that might raise such issues will be reviewed by the ASM
Publications Board prior to the Society proceeding to
publication."
The editors of the ASM journals are trying to be responsible
stewards of scientific information and communication by
carefully balancing national security with the value of
advancing science for the benefit of humanity.
This is a policy of responsible citizenship--not one of
censorship
ASM Opinion on Secrecy
“Terrorism feeds on fear, and fear feeds on
ignorance. The best defense against anthrax or any
other infectious disease is information – information
in a form that can be used by scientists and by
members of the public to guide rational and
effective actions to ensure public safety. Placing
major new barriers in the path of the flow of
information between scientists and between
scientists and the public is more likely to contribute
to terrorism than to prevent it.”
Abigail Salyers, President American Society for Microbiology
Concluding Remarks
Infectious diseases and bioterrorism present major threats
to national and global security
By enhancing global epidemiological surveillance
systems, by developing advanced diagnostics, and by
discovering new and better vaccines, antibacterials and
antivirals we will have the tools needed to combat both
natural outbreaks of infectious disease and bioterrorism
We need to effectively communicate knowledge, i.e. teach
students and educate the public, about the bioterrorist
threat and biothreat disease recognition, prophylaxis,
treatment, and public health response
By providing responsible and accurate information
educators reduce unwarranted fear and enhance the
effectiveness of the medical and public health response