Bioterrorism: Educators Response to the Threat Ronald M. Atlas ASM President Elect and Co-Chair ASM Task Force on Biological Weapons Graduate Dean, Professor.

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 BioterrorismWe 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 BioterrorismAttack with Anthrax through the mailFear grips the Nation--5 die, mail stops, buildings closeScience is needed but scientists also become suspectsEducational needs change

Public demands information but authoritative information is withheld due to criminal investigationQuestions 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 Casualties FatalitiesBrucellosis 125,000 500Q fever 125,000 150Tularemia 125,000 30,000Anthrax 125,000 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

$800 with nuclear weapons

$1 with biological weapons

Economic impact of an aerosol bioterrorist attack on a US city $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 $25M TOTAL 2002 $275M TOTAL 2003 $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? 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? Given high rate of adverse reactions, should we institute

mandatory vaccination--estimates are that it would result in 400-1,000 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

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

Anthrax: Overview

CDC: Gram stain of B. anthracis

CDC Case Definition of Anthrax

CDC definition of a confirmed case of anthrax: 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 )

High fever, dyspnea, cyanosis hemorrhagic

mediastinitis/pleural effusion Rapid progression to

shock/death Mortality rate ~95%

CDC: CXR with widened mediastinum of inhalational anthrax

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 Build Health Alert Network Build Laboratory response network

Level D Laboratories

Agent-specific

laboratory

Agent-specific

laboratory

Agent-specific

laboratory

Rapid-responseand adv anced

technology laboratory

Level Blaboratory

Level Claboratory

Level Alaboratory

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.

The highest priority agents that pose a risk to national security

Easily disseminated or transmitted person-to-person

Cause high mortality

Potential for major public health impact

Might cause public panic & social disruption

Require public health preparedness

CDC Biological Threat Category A

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 A Agents

CDC Biological Threat Category B

Moderately easy to disseminate

Cause moderate morbidity and low mortality

Require specific enhancements of CDC’s diagnostic capacity

Enhanced disease surveillance

Coxiella burnetti (Q fever)

Brucella species (brucellosis)

Burkholderia mallei (glanders)

Alphaviruses

Venezuelan encephalomyelitis

Eastern and western equine encephalomyelitis

Ricin toxin from Ricinus communis (castor beans)

Epsilon toxin of Clostridium perfringens

Staphylococcus enterotoxin B

CDC Biological Threat Category B Agents

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 B Agents (Subset List)

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.

Nipah virus Hantaviruses Tick-borne hemorrhagic fever viruses Tick-borne encephalitis viruses Yellow fever Multidrug-resistant tuberculosis

CDC Biological Threat Category C Agents

Clinical Laboratories as Sentinels for Bioterrorism

ER’s and their labs are key sentinels Laboratory personnel require training

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

D

C

C

C

C

A

A

A

A

AA

A

A

C

B

B B

B B

B

Laboratory Response NetworkLaboratory Response NetworkClinical Laboratories - A LevelClinical Laboratories - A Level

Public Health Laboratories - B LevelPublic Health Laboratories - B Level

Advanced Public Health Laboratories - C LevelAdvanced Public Health Laboratories - C Level

Federal Laboratories -D Level Federal Laboratories -D Level

(CDC, DOD, FBI, DOE)(CDC, DOD, FBI, DOE)

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

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?

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

Smallpox Virus Genome

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 cell-

mediated 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