1. 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

2. 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

3. 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

4. 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)

5. 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

6. NIH bioterrorism Research Funding
TOTAL $25M
TOTAL $275M
TOTAL $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
Although I have focused on the United States national responses, clearly the war on terrorism is a global effort.

7. Agents of Most Concern for Bioterrorism
Smallpox virus
Bacillus anthracis (anthrax)
Yersinia pestis (plague)
Botulinum toxin
Francisella tularensis (tularemia)
Hemorrhagic Fever Viruses
Recombinant Pathogens

8. 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?
Although I have focused on the United States national responses, clearly the war on terrorism is a global effort.

9. 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

10. 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

11. 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.

12. 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

13. 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

14. 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

15. 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?

16. CDC Approach Increase funding to States for Public Health
Increase education and response capability
Enhance surveillance
Build Health Alert Network
Build Laboratory response network
Although I have focused on the United States national responses, clearly the war on terrorism is a global effort.

17. 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.

18. 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

19. CDC Biological Threat Category A Agents
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)

20. 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

21. 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

22. 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.

23. 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.

24. CDC Biological Threat Category C Agents
Nipah virus
Hantaviruses
Tick-borne hemorrhagic fever viruses
Tick-borne encephalitis viruses
Yellow fever
Multidrug-resistant tuberculosis

25. 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
With covert, dispersed bioterrorism attacks the key sentinels will be the laboratories in hospitals throughout the nation. Since covert, dispersed attacks are quite likely, laboratory staff must be well trained to serve as surrogate “first responders”.
Training is important to rule out a host of non-bioterrorism agents. This will remove the load from the system of false signals that may occur without such training.
Shipping regulations and transport conditions that will preserve the viability of the bacteria must be supplied to the laboratory staff, as well as lists of sites to receive shipments.
Safety is key. Laboratory staff that are comfortable that their protection is important will continue to work.
Training has been spotty throughout the nation and should be systematized and distributed uniformly.

26. 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.

27. 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

28. Laboratory Response Network
Clinical Laboratories - A Level
Public Health Laboratories - B Level
Advanced Public Health Laboratories - C Level
Federal Laboratories -D Level
(CDC, DOD, FBI, DOE)

29. 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)

30. 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?

31. 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
It is very troubling that some scientists and physicians have been willing to turn from good to evil.
In his book Destroying the World to Save it, Robert Lifton analyzes why scientists and physicians in the Aum Shinrikyo cult were willing to try to spread anthrax and botulinum toxin in Tokyo. Lifton concludes that when an individual can hold life in his or her hand to save it, he or she can also destroy it for apocolyptic causes.
We also see this in the statement from Ken Alibek who, before he defected to the United States, headed the biological weapons program of the former Soviet Union that employed over 50,000 bioweaponeers and produced tons of anthrax and smallpox.

32. 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.
The ASM Public and Scientific Affairs Board after the October anthrax attacks passed a resolution that reaffirmed the longstanding ethical cannons of the Society that microbiologists must only work for the betterment of humankind.

33. 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)

34. 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?

35. 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
Among the regulations that we must follow is the Select Agent Transfer rule for the transfer of select agents.
Right now the select agent rule applies only to the exchange of cultures within the United States. A different set of export regulations apply to foreign exchanges
We need to consider how to extend such controls internationally so that we have a harmonized set of regulations that permit exchanges of agents needed by legitimate researchers while lessening the likelihood that they might be sent to terrorists

36. 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
We need to pay very careful attention to the USA Patriot Act which went into effect on October 26th. This law restricts who may possess select agents. Essentially it says if you are not permitted to buy a handgun you may not possess anthrax. If you are from a country that the United States designates as supporting terrorism, you are not permitted to have access to select agents. If you do not have a legitimate bona fide reason for possessing a pathogen you are in violation of this law. We need to see how this is applied in the case of a Connecticut student who was told to autoclave the cultures of anthrax and decided to save some in the freezer and now faces possible charges of illegal possession of a dangerous pathogen.

37. 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.
We need to pay very careful attention to the USA Patriot Act which went into effect on October 26th. This law restricts who may possess select agents. Essentially it says if you are not permitted to buy a handgun you may not possess anthrax. If you are from a country that the United States designates as supporting terrorism, you are not permitted to have access to select agents. If you do not have a legitimate bona fide reason for possessing a pathogen you are in violation of this law. We need to see how this is applied in the case of a Connecticut student who was told to autoclave the cultures of anthrax and decided to save some in the freezer and now faces possible charges of illegal possession of a dangerous pathogen.

38. 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
We need to pay very careful attention to the USA Patriot Act which went into effect on October 26th. This law restricts who may possess select agents. Essentially it says if you are not permitted to buy a handgun you may not possess anthrax. If you are from a country that the United States designates as supporting terrorism, you are not permitted to have access to select agents. If you do not have a legitimate bona fide reason for possessing a pathogen you are in violation of this law. We need to see how this is applied in the case of a Connecticut student who was told to autoclave the cultures of anthrax and decided to save some in the freezer and now faces possible charges of illegal possession of a dangerous pathogen.

39. 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
Turning from the question of controlling access to biothreat agents so that terrorists do not acquire dangerous pathogens, questions have also arisen about whether we also need to control information that might be misused by terrorists. Should we shut down the world wide web? Should we eliminate the methods sections of our manuscripts so that no-one could repeat and potential misuse what we have done? Should we stop exchanging information about the basis for pathogenicity and of antimicrobial resistance because someone might misuse the information for harm rather than the intended purpose of improving human health.

40. 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?

41. 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 Virology. 201(2):215-40, 1994 Jun.
Should the genome have been published?--ASM position was Yes
Smallpox Virus Genome

42. 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 Expression of mouse interleukin-4 by a recombinant ectromelia virus suppresses cytolytic lymphocyte responses and overcomes genetic resistance to mousepox. J. Virology 75:
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?

43. 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
A few weeks ago a I asked the editors of ASM’s 11 journals to advise me on how to respond to the concerns about the communication of scientific information and the potential for misuse.

44. 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
I think the following statement from Abigail Salyers, the current ASM President summarizes the opinion of many in the scientific community.

45. 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
Although I have focused on the United States national responses, clearly the war on terrorism is a global effort.