Bioterrorism: Educators Response to the Threat

Ronald M. AtlasASM President Elect and Co-Chair ASM Task Force

on Biological WeaponsGraduate Dean, Professor of Biology, and Co-Chair of Center for Deterrence of Biowarfare and Bioterrorism

University of Louisville, Louisville KY

The Threat of BioterrorismBefore 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 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 WarfareMicrobes can be weapons of mass destruction

Bioterrorism50kg of anthrax can kill nearly 100,000 people over a large areaYelling anthrax creates terror

BiocrimesA single injection of a toxin can kill an individual

NIH bioterrorism Research FundingTOTAL 2001 $25MTOTAL 2002 $275MTOTAL 2003 $1,748M

Basic research and development $440.6MDrug/vaccine discovery and development $591.9MClinical research $194.3MResearch facilities intramural $371.1MResearch facilities extramural $150.0MTOTAL $1,747.9M

Agents of Most Concern for Bioterrorism

Smallpox virusBacillus anthracis (anthrax)Yersinia pestis (plague)Botulinum toxinFrancisella tularensis (tularemia)Hemorrhagic Fever VirusesRecombinant Pathogens

Smallpox Strategic QuestionsIf 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 TrentonLetters sent to news media and Congress11 cases cutaneous (skin) anthrax, 11 cases of inhalational anthrax, 5 deathsTens of thousands given prophylactic doses of antimicrobicsAmes strain, highly refined powder

Ames strain never in Iowa

Primarily disease of herbivoresNatural transmission to humans by contact with infected animals or contaminated animal productsSoil 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. anthracisinfection based on at least two supportive laboratory tests.

Anthrax: CutaneousMost common form (95%)Inoculation of spores under skinIncubation: hours to 7 daysSmall papule ulcer surrounded by vesicles (24-28h)Painless eschar with edemaDeath 20% untreated; rare if treated

USAMRICD: Eschar with surrounding edema

Anthrax: InhalationalInhalation of sporesIncubation: 1 to 43 days Initial symptoms(2-5 d)

fever, cough, myalgia, malaiseTerminal symptoms (1-2d )

High fever, dyspnea, cyanosishemorrhagic mediastinitis/pleural effusionRapid progression to shock/death

Mortality rate ~95%

CDC: CXR with widened mediastinumof inhalational anthrax

Anthrax: TreatmentAntibiotics

Doxycycline, CiprofloxacinMultiple antibiotics for inhalational anthraxDisease is toxin mediated--antibiotics not always successful--recent attack mortality was 50%--previously 90+%

Supportive careStandard precautions, no quarantine needed

Anthrax Attack 2001 Unknowns

Who sent the letters?How many spores are required to cause inhalational anthraxBest prophylactic treatmentAppropriate method for safeguarding the mailHow to communicate to the publicWhat is the prevalence of anthrax in soils?

CDC ApproachIncrease funding to States for Public Health

Increase education and response capabilityEnhance surveillance

Build Health Alert NetworkBuild Laboratory response network

Le v el D Laboratories

Agent-specif ic

laboratory

Agent-specif ic

laboratory

Agent-specif ic

laboratory

Rapid-responseand adv anced

technology laboratory

Le v el Blaboratory

Le v el Claboratory

Le v el Alaboratory

Specimen testing and referralT raining 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-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 Agents

Variola major (smallpox)Bacillus anthracis (anthrax)Yersinia pestis (plague)Clostridium botulinum toxin (botulism)Francisella tularensis (tularaemia)FilovirusesEbola hemorrhagic feverMarburg hemorrhagic feverLassa (Lassa fever)Junin (Argentine hemorrhagic fever)

CDC Biological Threat Category B

Moderately easy to disseminate

Cause moderate morbidity and low mortality

Require specific enhancements of CDC’sdiagnostic capacity

Enhanced disease surveillance

CDC Biological Threat Category B Agents

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 (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

Nipah virusHantavirusesTick-borne hemorrhagic fever virusesTick-borne encephalitis virusesYellow feverMultidrug-resistant tuberculosis

Clinical Laboratories as Sentinels for Bioterrorism

ER’s and their labs are key sentinelsLaboratory personnel require training

Methods to rule out non-BT agentsMechanism to forward the balanceSafety for laboratory personnel

Variability in states’ trainingUniform 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 LRNLevel A: RULE OUT AND REFER; RAISE SUSPICION/NOTIFY INFECTION CONTROLLevel B: RULE IN AND REFERLevel C: Advanced Testing, evaluation of new tests and reagents, facilitate transfer of tests to Level BLevel 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 Clinical Laboratories -- A LevelA Level

Public Health Laboratories Public Health Laboratories -- B LevelB Level

Advanced Public Health Laboratories Advanced Public Health Laboratories -- C LevelC Level

Federal Laboratories Federal Laboratories --D Level 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

ResponsibilityWhat obligation do members of the research community have to identify, call attention to, or clarify activities of others that may appear suspicious?

TransparencyAre there areas of research or types of experiment that pose such sensitivity regarding potential bioweaponsapplication 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 scientistsKen 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 BioethicsThe 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 pathogensImpose 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 implicationsRestrict 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 AgentsPossession of potentially dangerous biological agents

should be regulated more tightlyAre 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 genesRequires adherence to CDC biosafety manualIn effect since April 1997

USA Patriot ActImposes restrictions on possession of select agents

Restricts aliens from countries designated as supporting terrorism from possessing select agents within the United StatesRestricts 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 agentsNo provision for exemptions under any circumstancesDoes not require registration for possession of select agentsRequires 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 Statesunder dishonorable conditions.

Patriot Act and Legitimate ResearchThe 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 InformationASM 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 anthracisThe 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 pairsSequence 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 variolavirus transmissibility and virulence for its only natural host, humans.

Massung RF., et al. Analysis of the complete genome of smallpoxvariola 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 SuppressionExpression 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 recombinantectromelia virus suppresses cytolytic lymphocyte responses and overcomes genetic resistance to mousepox. J. Virology 75:1205-10.

ConclusionsVirus-encoded IL-4 not only suppresses primary antiviral cell-mediated immune responses but also can inhibit the expression ofimmune 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 RemarksInfectious diseases and bioterrorism present major threats to national and global securityBy enhancing global epidemiological surveillance systems, by developing advanced diagnostics, and by discovering new and better vaccines, antibacterials andantivirals we will have the tools needed to combat both natural outbreaks of infectious disease and bioterrorismWe need to effectively communicate knowledge, i.e. teach students and educate the public, about the bioterroristthreat and biothreat disease recognition, prophylaxis, treatment, and public health responseBy providing responsible and accurate information educators reduce unwarranted fear and enhance the effectiveness of the medical and public health response