6
Scientific and Policy Tools for Countering Bioterrorism

OVERVIEW

Several scientific, scientific policy, and legal tools that were presented and discussed during the workshop but have not been addressed elsewhere in this report summary are included here. These include innovative surveillance; detection and diagnostic tools and technology; scientific policy issues unique to bioterrorism response preparedness; and, bioterrorism-related legal needs and obstacles. These ideas include multiple components of the individual sessions and have cross-cutting implications for an overall response to biological threats.

Surveillance

Surveillance and rapid detection are crucial to an effective response to a bioterrorist attack. Delayed detection results in delayed prophylaxis and aggressive treatment measures. Because it is practically impossible to predict when or where a bioterrorist attack is going to happen, there are limitations to the “dropin” terrorism surveillance systems that have been used to monitor specific places or events such as the Super Bowl or Democratic National Convention. Nor can bioterrorism surveillance be solved simply with pentium chips. Comprehensive bioterrorism surveillance will require integrating human resources, laboratory resources, and information management in innovative, legal, and acceptable ways that allow for early detection and characterization of threats.

There are several innovative surveillance systems in use or being developed. ESSENCE, for example, is an automated syndromic surveillance system that initially relied on the already extant automated health care information system across D.C., Maryland, and Virginia. Since September 11, ESSENCE has



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Biological Threats and Terrorism: Assessing the Science and Response Capabilities - Workshop Summary 6 Scientific and Policy Tools for Countering Bioterrorism OVERVIEW Several scientific, scientific policy, and legal tools that were presented and discussed during the workshop but have not been addressed elsewhere in this report summary are included here. These include innovative surveillance; detection and diagnostic tools and technology; scientific policy issues unique to bioterrorism response preparedness; and, bioterrorism-related legal needs and obstacles. These ideas include multiple components of the individual sessions and have cross-cutting implications for an overall response to biological threats. Surveillance Surveillance and rapid detection are crucial to an effective response to a bioterrorist attack. Delayed detection results in delayed prophylaxis and aggressive treatment measures. Because it is practically impossible to predict when or where a bioterrorist attack is going to happen, there are limitations to the “dropin” terrorism surveillance systems that have been used to monitor specific places or events such as the Super Bowl or Democratic National Convention. Nor can bioterrorism surveillance be solved simply with pentium chips. Comprehensive bioterrorism surveillance will require integrating human resources, laboratory resources, and information management in innovative, legal, and acceptable ways that allow for early detection and characterization of threats. There are several innovative surveillance systems in use or being developed. ESSENCE, for example, is an automated syndromic surveillance system that initially relied on the already extant automated health care information system across D.C., Maryland, and Virginia. Since September 11, ESSENCE has

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Biological Threats and Terrorism: Assessing the Science and Response Capabilities - Workshop Summary been extended to over 300 installations around the world. Every 24 hours, 30,000 ambulatory diagnoses from these various installations are downloaded, automatically analyzed, prioritized based on expected values from historic data, and visualized using geographic information systems. However, none of the systems currently being developed are likely to be adequate in and of themselves. The best solution will probably be a system of systems that is sensitive enough to detect specific conditions and even small outbreaks. Detection and Diagnosis In terms of environmental and clinical detection and diagnosis, although reasonably good assays are available for a limited range of specific agents, the immense diversity of microorganisms, including bioengineered pathogens, presents a major challenge. There can be considerable variability even within a strain, let alone a species. Pathogens are a natural part of the environment and can confuse detection efforts. For both environmental and clinical settings, we need rapid, standardized methods that allow for the detection of a broad spectrum of potential biological weapons in a quantitative fashion. Rapid detection and diagnosis requires access to an extensive sequence database and high throughput laboratories. Biotechnological barriers in the public health infrastructure must be identified so that the proper tools can be appropriately distributed or accessed. Academia, industry, and government laboratories must all be brought in at appropriate levels and in appropriate ways to help build new capabilities. Specimen collection needs to standardized and automated. For example, there is no standardized collection method for samples from the inside of a computer. Indeed, specimen collection is often the major obstacle to rapidly processing a large number of samples and the weak link in what seems to be an otherwise very promising detection and diagnosis technology. The capability to use molecular sequences to rapidly detect and identify bioterrorist agents could serve as an important form of deterrence and might possibly prevent bioterrorist attacks from occurring in the first place. One vision is an international molecular forensics lab that would rely on a molecular fingerprint global database to identify the source of the bioterrorist agent. This capability could provide the biological equivalent of the threat of nuclear retaliation. Again, it must be emphasized that bioterrorism is a national security issue and bioterrorism preparedness efforts are a strategic defense. Scientific Policy Issues The fact that bioterrorism preparedness is a national security imperative raises many important and new scientific policy issues:

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Biological Threats and Terrorism: Assessing the Science and Response Capabilities - Workshop Summary It was suggested that we need a new peer review system for screening new bioterrorism defense research ideas. There needs to be improved communication between scientists in the clinical response laboratories and law enforcement personnel, for example with regards to resolving crime scene versus public health needs and ensuring that the physicians or other individuals who have provided samples can receive results in a timely manner. Law enforcement investigators need to be educated about relevant microbiological issues, and the scientific and public health communities need to be informed of how criminal investigations proceed. There is concern about who should have access to certain scientific materials, equipment, and information and whether access to select agents should be restricted. At the same time, it is crucial that as much information as possible be in the hands of the biomedical community so that scientists can conduct the type of research that is necessary to build a strong biodefense arsenal. Finally, computational modeling is an important but undervalued scientific component of bioterrorism defense preparedness. New computational capabilities can be used to model interactions between digital microbes (as opposed to actual, biological microbes) and digital immune systems. This kind of simulation approach could be used in guiding decisions about experimental design as well as in testing various policy and response scenarios. Legal Issues Bioterrorism preparedness as a national security imperative also raises many important legal issues. The first step toward evaluating the necessity of a legal strategy for bioterrorism is to assess the adequacy of the existing legal infrastructure for dealing with bioterrorism issues. Do provisions in the law exist that enable authorities to do what needs to be done in the context of a bioterrorism event, for example decontaminating a building or quarantining individuals? Are there any legal obstacles that would interfere with a public health response to bioterrorism? The primary legal authority for bioterrorism preparedness and response is at the state level. Recently, the Center for the Study of Law and the Public Health at the Georgetown Law Center and Johns Hopkins University prepared a model state emergency health powers act (see Appendix G) in an effort to facilitate the analysis of public health law at the state level. The proposal is being given to states for their consideration either for adoption or simply as a tool for review of their own public health statutes in the context of bioterrorism. The proposal has stimulated much controversy. Indeed, this controversy may be a reflection of the importance of the legal infrastructure for an effective public health response to bioterrorism.

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Biological Threats and Terrorism: Assessing the Science and Response Capabilities - Workshop Summary INNOVATIVE SURVEILLANCE METHODS FOR MONITORING DANGEROUS PATHOGENS Julie A. Pavlin, M.D., M.P.H.,1 Patrick Kelley, M.D., Dr.P.H.,1 Farzad Mostashari, M.D., M.S.P.H.,2 Mark G. Kortepeter, M.D., M.P.H.,3 Noreen A. Hynes, M.D., M.P.H.,4 Rashid A. Chotani, M.D., M.P.H.,5 Yves B. Mikol, Ph.D.,6 Margaret A. K. Ryan, M.D., M.P.H.,7 James S. Neville, M.D., M.P.H.,8 Donald T. Gantz, Ph.D.,9 James V. Writer, M.P.H.,1 Jared E. Florance, M.D., M.S.,10 Randall C. Culpepper, M.D., M.P.H.,3 Fred M. Henretig, M.D.11 Historically, emergent public health problems have been recognized by astute health care providers who then report their suspicions to public health authorities, rather than the reverse (Thacker, 1994; Thacker and Berkelman, 1998). Even with luck, this approach usually falls short of optimal public health care. Outbreak surveillance seeks to reduce reliance on the epidemiological insights of individual practitioners or facilities and to significantly decrease the time needed to collect and assess data, thereby allowing officials to be alerted more rapidly of an emerging threat. A review of some recent disease outbreaks will help define the requirement for more timely, high-quality systems. Past epidemics have characteristics that can help identify the epidemiological, behavioral, and political factors that affect the detection of and response to an emerging infectious disease epidemic. Many emerging infections present as syndromes that initially do not point to a specific underlying pathogen. Potential bioterrorism events could also pose similar challenges of delayed recognition (see Table 6-1). In addition to earlier detection of events, surveillance systems for emerging infections, including bioterrorism, are essential for focusing limited response assets and for providing evidence-based information for governmental risk communicators attempting to manage community concerns. Plans to improve 1   Department of Defense Global Emerging Infections System, Silver Spring, MD 2   New York City Department of Health, New York, NY (current affiliation OutbreakDetect, Inc., New York, NY) 3   US Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD 4   Human Health Services Division, Food Safety and Inspection Service, Washington, DC 5   Johns Hopkins University Applied Physics Laboratory, Laurel, MD 6   New York City Department of Environmental Protection, Valhalla, NY 7   Naval Health Research Center, San Diego, CA 8   Air Force Institute for Environment, Safety and Occupational Health Risk Analysis, Brooks Air Force Base, TX 9   George Mason University, Fairfax, VA 10   Prince William County Health District, Manassas, VA 11   Clinical Toxicology and Poison Control, Children’s Hospital of Philadelphia, Philadelpia, PA

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Biological Threats and Terrorism: Assessing the Science and Response Capabilities - Workshop Summary public health capabilities to identify and address such disease emergencies must include determining how surveillance systems can be made more timely, flexible, and sensitive without overly compromising other aspects of quality. A recent meeting addressing innovative, responsive surveillance systems focused on three areas: 1) defining the existing functional capabilities in need of improvement, 2) examining existing prototype systems attempting to meet these needs, and 3) identifying the ideal features of a “system of surveillance systems” that would meet the need for more timely, sensitive, and flexible detection and response (Pavlin et al., 2001). Examples of Recently Developed Innovative Surveillance Systems In recent years, agencies and municipalities have attempted to improve public health capabilities with novel and innovative approaches to surveillance (see Table 6-2). New York City—911 Calls Beginning in March 1998, the New York City Department of Health, in collaboration with the Mayor’s Office of Emergency Management and the Fire Department’s Emergency Medical Services, began monitoring the chief clinical complaints noted in daily 911 calls as a citywide health indicator. The intent was timely detection of public health events, with particular emphasis on influenzalike illness. Several complaints, such as “difficulty breathing” and “sick”— thought to represent influenza-like illness—were selected. A review of data from 1991 to 1998 found a temporal association between the onset of annual influenza epidemics and a rise in the volume of the selected call-types. Thresholds were developed that “detected” all four annual influenza epidemics from 1994 to 1998. In addition, the system generated very few false-negative alarms—times when the expected threshold was exceeded outside of periods of peak influenza activity. This system indicated the 1999–2000 influenza epidemic approximately two weeks before recognition by traditional influenza surveillance systems. New York City—Diarrheal Diseases Surveillance New York City also developed three independent and complementary systems to monitor for community-wide gastrointestinal outbreaks: 1) sales of antidiarrheal medications, 2) submission of stool samples for laboratory tests, and 3) incidence of gastroenteritis in nursing home populations. Monitoring sales of antidiarrheal medication approximates the incidence of diarrheal illness in a community. Large increases in sales of anti-diarrheal medicines have been reported during outbreaks of gastrointestinal diseases (Proctor et

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Biological Threats and Terrorism: Assessing the Science and Response Capabilities - Workshop Summary al., 1998; Collin et al., 1981; Rodman et al., 1997; Miller and Mikol, 1999). Volume of over-the-counter medication sales is obtained from a regional distributor and a chain of drugstores (see Figure 6-1). Sales data are received weekly and analyzed for unexpected variation. The number of stool specimens examined for 1) bacterial culture and sensitivity (three laboratories); 2) ova and parasites (three laboratories) (see Figure 6-2); and 3) Cryptosporidium parvum (one laboratory) is collected daily and indicates the incidence of gastrointestinal illness in the population. This information is provided in addition to test results for giardiasis and cryptosporidiosis from active disease surveillance. The number of new cases of gastrointestinal disease in nursing homes provides information on the incidence of illness in a population with limited exposure to the wider community. Twelve nursing homes participate in the program, with 1,850 residents. Numbers of new cases of gastrointestinal disease are provided daily. DoD-GEIS Electronic Surveillance System for the Early Notification of Community-based Epidemics (ESSENCE) The DoD-GEIS monitors patient data from medical facilities for changes in disease incidence in the National Capital Area (see Figure 6-3). For every outpatient encounter within the DoD medical system in the US, the provider electronically enters a code describing the reason for the patient visit. All encounters are coded at or near the time of service, even if the definitive cause of illness is not established during the visit. Most codes chosen by providers reflect this prompt diagnosis and may include syndrome-based codes such as cough and fever in addition to empiric diagnoses such as pneumonia. All personal identifiers are removed from the data when received and the diagnoses are categorized, if applicable, into one of nine syndromic clusters. The frequency of outpatient visits in the different syndromic categories is then plotted and compared to previous years’ experience. It can also be depicted geographically through geographic information systems (GIS) software. Sandia National Laboratory—Rapid Syndrome Validation Project (RSVP) The RSVP is an Internet-based reporting system, intended for daily routine use by physicians and epidemiologists. The system features rapid data input of clinical and demographic information via a touch sensitive monitor, automated screening of reports for signs and symptoms correlated with reportable diseases and subsequent instantaneous notification of public health officials if indicated, and rapid feedback to clinicians of the geographic and temporal distribution of recent similar syndromes in their community in recent weeks. Public health offi-

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Biological Threats and Terrorism: Assessing the Science and Response Capabilities - Workshop Summary cials may use RSVP to inform users of current disease outbreaks of public health importance, specific to each of six syndromes. RSVP is easily expandable to multiple sites, requires no specialized client software other than a web browser, and may be operated as an intranet or for general data sharing. Expectations for a Health Indicator Surveillance System The variety of information used to monitor the health of a community can be called “health indicator” surveillance. The requirements of different users should be documented while these new systems are still in development. National Needs Surveillance systems can assist federal public health management of epidemics in many ways, not only in the traditional detection of outbreaks and monitoring of the effectiveness of preventive measures, but in determining how to assist and augment local health and emergency response activities. The systems should be capable of being integrated with other surveillance systems at all levels of government. Local Needs The ability of the local health department to identify, evaluate, and contain the effects of disease outbreaks is dependent on the timeliness and accuracy of reporting. Optimally, a surveillance system should contrast local data with data from other sources (e.g., CDC, nearby states, other jurisdictions, and military installations). Surveillance systems with greater sensitivity, completeness, and timeliness than existing systems are needed to allow the most effective identification of unexpected events across jurisdiction boundaries. U.S. Military The military services maintain centralized health-related surveillance systems for routine public health policy and disease control. However, more rapid and sensitive recognition of a disease outbreak wherever U.S. forces are located requires enhancements to both the level of detail available and the speed of data transmission and analysis. New health indicator surveillance systems for military communities should cooperate with civilian public health personnel since disease outbreaks do not respect military installation boundaries.

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Biological Threats and Terrorism: Assessing the Science and Response Capabilities - Workshop Summary Specific Needs for Bioterrorism Surveillance To maximize patient survival after a bioterrorist attack, we need surveillance systems that: 1) facilitate the rapid recognition of a bioterrorist event, 2) assist in determining the site of exposure, 3) maximize efficient delivery of limited medical countermeasures to the infected population, and 4) assess containment and mitigation. Expansion and improvement of surveillance systems for bioterrorism will likely have a dual benefit of strengthening the public health infrastructure for detection of naturally occurring infectious disease outbreaks and emerging diseases. Needs for Animal and Plant Surveillance There are many points along the farm-to-table continuum at which infectious agents can arise from or be introduced into the food supply. The increasingly centralized nature of food production in the United States, with subsequent widespread distribution, means that the impact of contaminated products would be national (and potentially international) in scope rather than regional. This argues for an integrated human-animal pathogen and antimicrobial resistance surveillance system providing rapid feedback to public health and foodregulatory agencies. Food monitoring data for microbial pathogens and food recall information are already collected by federal and state regulatory agencies and could be integrated into existing food-borne disease and outbreak surveillance systems. This system could 1) enhance the speed with which outbreaks are identified and control measures implemented, 2) identify patterns of product contamination that would lead to more rapid intervention, and 3) identify unusual illness patterns and pathogens that are dispersed but possibly related. The use of information on disease in animals, both wild and domestic, can prove a useful tool in monitoring the health of human populations (Jaroff, 1999; Steele et al., 2000; CDC, 1999). A surveillance system will include data on animal morbidity and mortality to achieve the greatest sensitivity. Key Issues for Developing a Surveillance System Data Sources Health indicator surveillance is the foundation for early recognition of an emerging infectious disease. There is a critical need for a system of systems, with the flexibility to fit the needs of each level and locality. Measurable alterations in personal behaviors within the first hours or days of illness can assist early detection of an event or epidemic. These include work or school absenteeism, changes in usage of public transportation or toll roads, and the purchase of over-the-counter remedies. Data about delivery of medical care have value not only for outbreak detection but also for the ongoing management of an epidemic

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Biological Threats and Terrorism: Assessing the Science and Response Capabilities - Workshop Summary (Rodman et al., 1998). These include emergency response calls, required disease reporting, outpatient clinic and emergency room activity, inpatient and intensive care unit records, and laboratory and prescription drug requests. An infrastructure for pre-clinical or many types of clinical data is not readily available but might use data already collected for other purposes such as billing, inventory control, or resource management. Concerns over ownership may block access to existing data deemed valuable for surveillance. Resolving these issues will require high-level leadership, commitment, and prioritization. The following questions addressed the usefulness of health surveillance data. Are the data sufficiently representative of the entire population of interest? Are there important sub-populations that will not be captured by this surveillance system? Are the data timely? How much time will elapse between the onset of symptoms and detectable change in the data? Are the data available electronically? Electronic data can be transferred and analyzed more quickly than paper reports. Can the data be categorized as symptom clusters or syndromes? Summary data (e.g., total number of admissions or transit ridership) may indicate an event is occurring, but interpretation of the cause will be difficult in the absence of more specific information. Are retrospective data available? Without baseline data, it will be difficult to assess whether the data can detect new events. Furthermore, alarm thresholds using historic data obviate the need for a lengthy “run-in” period. Improvement in Active Patient Data Collection Although use of existing data sources can help, some situations, geographic areas, or types of medical practices may require additional data for an effective surveillance system. If a system requires new data collection, it is imperative to work closely with medical practitioners to achieve a workable solution and to provide feedback so they can benefit from their participation. Possible features of an active data-entered, real-time surveillance system include: Syndrome-based reporting from a pre-determined list of signs and symptoms; Touch screen or personal digital assistant (PDA)-based electronic data reporting, collection, and submission; Graphical presentation of data based on GIS and temporal information; Automatic alerts to public health officials of specific signs and symptoms (e.g., fever with skin rash in young adults) suggestive of serious communicable disease; and,

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Biological Threats and Terrorism: Assessing the Science and Response Capabilities - Workshop Summary Alerts from public health officials to health care providers that can be easily updated. The Need for a System of Systems Ideally, a surveillance system will be sensitive enough to identify the emergence of an outbreak, categorize its nature, and identify those affected so that the outbreak can be quickly and effectively contained. Bringing together information from various health indicator data sets can allow the public health practitioner to 1) evaluate many indicators simultaneously, 2) compare variations and identify common trends, and 3) track confounding factors and reduce noise. The compilation of information provided by independent and complementary data sources allows inter-system comparisons. Comparing the data from several indicators, some of which are more sensitive than others for different scenarios, can enable a trend observed in any single system to be confirmed by the systems. Simultaneous unexpected but concordant variations in multiple data sets may suggest actual emergence of an outbreak. Clinical reports are needed for confirmation. The importance of collecting data through an intricate surveillance system is to use it to quickly identify and respond to an adverse event rather than to develop an archive. Ideally one organization would collect, compile, integrate, and analyze all data. Moreover, this data would need to be shared effectively and efficiently at different levels of the existing health systems. Of utmost importance, the fundamental issue of personal and organizational privacy needs to be addressed when setting up such a system.

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Biological Threats and Terrorism: Assessing the Science and Response Capabilities - Workshop Summary TABLE 6-1 Selected infectious disease outbreaks characterized by delayed recognition, characterization, or response Disease Outbreak Characteristics Influenza Worldwide, 1918–19193,4(pp153–191) Rapid spread over large geographic area Overwhelms health care system Overwhelms essential services (e.g., burial of dead) Person-to-person transmission No available treatment Legionellosis (Legionnaires’ Disease) Pennsylvania, 19765 Common-source Exposed population disperses from point of exposure throughout the state of Pennsylvania Unknown agent Rapid spread and demise Mimics a biological terrorist attack Acute Respiratory Distress Syndrome (Hantavirus)4(pp538–549),6 Southwest US Affects small population spread over a large geographic area Cultural concerns Zoonotic Salmonellosis Oregon, 1984, US, 19937 Bioterrorism attack that mimics naturallyoccurring outbreak Unrecognized as bioterrorism at time Community-wide outbreak Common agent Encephalitis (West Nile virus) New York City, 19998,9 Zoonotic (birds are first victims) Initial diagnosis wrong Limited geographic area affected (humans) Specific population group affected (elderly humans) New agent to New York City Suspicion of bioterrorism

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Biological Threats and Terrorism: Assessing the Science and Response Capabilities - Workshop Summary Besides questions about communication of scientific information Gerald Epstein also discusses the possibility of constraining research, i.e., restricting researchers from conducting certain types of research. Are there areas of research or types of experimentation that should not be conducted at all? Are there others that should require advance approval? Is molecular biology a threat—will recombinant DNA technology be used to create horrific biothreat agents? Should certain molecular biology experiments and methodologies be prohibited? Much of this concern emanates from experiments in which IL-4 genes were inserted into mousepox viruses. The result was suppression of the immune response to a much greater extent than anyone had predicted. 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. The implications for possible genetic engineering of a horrific strain of smallpox virus are enormous. In hindsight some have asked whether this research should have been permitted? Shouldn’t we have known in advance how dangerous the results might have been. Others who clearly were surprised by the results feel that this study alerts us to the need for more research on the immune response and antiviral drugs. Yet other concerns have been raised about DNA shuffling because of its potential power to create new biothreat agents. Some point to the fact that this methodology potentially allows the rapid production of numerous biothreat agents with enhanced virulence. They raise the fear that DNA shuffling increases threat of being able to create a deadly new pathogen—intentionally or accidentally. They ask whether this methodology is too powerful and hence whether we should prohibit its use. But the potential benefits regarding new drug discoveries seem to outweigh these risks. In my view, the scientific community must move forward as quickly as possible in eliminating the threat of bioterrorism by finding effective preventative measures and cures so that infectious diseases are not a credible threat to humanity. Beyond the obvious need to further biomedical research and to strengthen the public health infrastructure, one can ask about the appropriate role of the scientific community in identifying misconduct. What obligation do members of the research community have to identify, call attention to, or clarify activities of others that may appear suspicious? There may be areas of research or types of experiments that pose such sensitivity regarding potential bioweapons application that merit extraordinary obligations for transparency and openness. There are clear aspects of bioethics that require scientists to be whistle blowers when public health is threatened. Concerning the area of bioethics, the Council Policy Committee of ASM passed a resolution following September 11 affirming 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

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Biological Threats and Terrorism: Assessing the Science and Response Capabilities - Workshop Summary 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 ASM and its members. In conclusion I want to share some thoughts from Abigail Salyers, the current President of ASM: “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 more likely may ultimately contribute to terrorism by interfering with our ability to prepare and to respond to the threat of the misuse of science by bioterrorists.” COORDINATING THE INTELLIGENCE, PUBLIC HEALTH, AND RESEARCH COMMUNITIES Craig Watz* Federal Bureau of Investigation An intentional biological terrorism event requires a law enforcement response. Regardless of whether it was for political, social, or other reasons, the responsible individuals inflicted terror, committed an act of terrorism, and need to be aggressively pursued, investigated and prosecuted. Otherwise, there may be a repeat incident. Thus the role of the FBI in the bioterrorism arena. The FBI’s capability to apprehend bioterrorists is based on effective laws, federal statutes, and the ability to enforce these laws. Recent legal initiatives include an expansion of the Biological Weapons Anti-Terrorism act, which now applies to the possession of a biological agent that is beyond reasonable means for peaceful prophylactic protective or bona fide research. And, as of November 1, 2001, sentencing guidelines became effective such that anyone who does violate the WMD statute enters into a matrix to determine the sentence received. Prior to that, sentencing was at the discretion of the judge. The new guidelines were established in hope that more structured sentencing would serve as a stronger deterrence factor. During recent events, it has become clear that more consideration must be given to educating prosecuting attorneys and investigators in microbiology. It is also very important that we utilize available resources, including experts within the scientific community. Equally important is educating the public health community, including public health and state epidemiologists, in how the FBI conducts their investiga- *   This statement reflects the professional view of the author and should not be construed as an official position of the Federal Bureau of Investigation.

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Biological Threats and Terrorism: Assessing the Science and Response Capabilities - Workshop Summary tions. For example, it is important that the FBI collects environmental swabs and maintains a strict chain of custody in order to ensure that that evidence is in the same or similar condition at the time of trial. The recent anthrax case has illustrated both a covert and an overt release which the FBI is still investigating. The D.C. incident is an example of an incident in which there existed a known crime scene so the FBI knew where to go and respond. The D.C. incident grew exponentially and also spread to the post offices and the Senate Building. Both types of releases have required the FBI to work very closely with public health and have illustrated the importance of communication, coordination, and the sharing of information—including intelligence information—between the FBI and public health. Finally, recent events have stressed the need to minimize the overlap between federal, state and local agencies; and the need to set aside personal or agency agendas in order to work together to protect the public and hopefully prevent repeat incidents. VIRTUALLY ASSURED DETECTION AND RESPONSE: UTILIZING SCIENCE, TECHNOLOGY, AND POLICY AGAINST BIOTERRORISM Scott P. Layne, M.D., Ph.D. Associate Professor, School of Public Health University of California, Los Angeles Homeland Security and the Biological Weapons Convention The United States must control bioweapons threats on two major fronts. Domestically, it must seek new ways to boost homeland security and respond to terrorists attacks in several American cities. Internationally, it must seek new ways to overhaul the long stalemated Biological Weapons Convention (BWC) Protocol or propose an alternative way to establish legally binding verification and compliance procedures. The challenges are enormous and demand rapid, reliable, and complete information on which to make decisions. The development of bioweapons requires three key elements: knowledge, equipment, and infectious agents. These elements have “dual uses” and thereby pose serious challenges to verification, compliance, and security. The general scientific knowledge required to develop bioweapons is conveyed in many microbiologic texts and is not feasible to remove. The United States seeks measures that thwart the migration of technical expertise and first-hand knowledge from past and present bioweapons programs. Likewise, the small-scale laboratory equipment required to create bioweapons is all but impossible to restrict. The United States supports regulations that block the export of industrial-scale

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Biological Threats and Terrorism: Assessing the Science and Response Capabilities - Workshop Summary laboratory equipment to potential proliferators. With the exception of variola major (smallpox), the various infectious agents required to create bioweapons are found in nature. The United States seeks regulations that constrains the sale of weaponizable seed stocks to qualified researchers and institutions. Yet the United States is only one of many countries that supply such knowledge, equipment, and infectious agents. For example, Bacillus anthracis is the subject of research in many countries and conventional forensic methods may not be able to identify the source of B. anthracis used in any particular biological weapon. However, science and technology have opened up an extremely powerful means to address this problem. Infectious disease agents from specific origins exhibit unique molecular fingerprints that are all but impossible to erase (Jackson et al., 1998; Keim et al., 2000). These fingerprints are inherent to many, if not all, bioweapons agents on the A-List, including bacteria and viruses against humans and animals. It is therefore feasible to sequence the genes of such agents, organize that information in large databases, and use this molecular information to strengthen future BWC agreements and homeland security efforts. The elements of the plan are as follows. Molecular Forensics The United States, the world’s leader in biotechnology, is in a position to create a new kind of high-throughput molecular forensics laboratory against bioweapons agents. Optimally, there would be two such facilities. The first would be domestically based, used to enhance homeland security, and serve as a model to states that are parties to the BWC. The second would be internationally based and offer improved verification and compliance capabilities to future BWC agreements. These two facilities could generate complementary and corroborative information. A dedicated high-throughput laboratory against bioweapons agents would offer several important capabilities. First, it would enable exhaustive molecular fingerprinting and taxonomic positioning for a broad spectrum of known threat agents. Second, it would perform such analyses in a consistent and chain-of-custody manner. Third, it would produce high-resolution information within hours to days after sample receipt. In addition, the domestic facility could operate with a “closed” compartment, offering capabilities to the national and homeland security communities, and a separate “open” compartment, offering capabilities to the scientific community. The international facility could operate with capabilities and compartments established by future BWC agreements. Such arrangements would enable the United States to maintain its own molecular forensics and database capability yet share powerful testing methods and technologies with states that are parties to the BWC. In 1992, the Australia Group identified nearly 100 bacteria, viruses, fungi, and toxins against people, animals, and plants with potentials for weaponization.

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Biological Threats and Terrorism: Assessing the Science and Response Capabilities - Workshop Summary To date, however, only about 20 infectious agents have been used to produce biological weapons. A realistic goal would be therefore to fingerprint and catalog this “low hanging fruit.” From a technical, economic, and political standpoint, the result would be to make it more difficult to mount and maintain a secret offensive bioweapons program. Available Technologies All the necessary technologies are available to build and operate a highthroughput molecular forensics laboratory and database system against bioweapons agents (Layne et al., 2001). More than a hundred companies manufacture the necessary equipment, which generally consist of flexible “plug-and-work” modules, and such technologies are often integrated into one of two kinds of system designs. The first are portable devices offering relatively simple and rapid tests. The second are high-throughput automation and robotic systems offering highly definitive tests. These larger systems must be housed in a semitractor trailer or suitable building, where samples must be brought to them. As outlined below, the optimal system would integrate both designs. Several portable laboratory devices are available that fit into a suitcase and perform simple (yes/no) detection tests on the spot. The tests are based on polymerase chain reaction (PCR) methods and utilize tailored molecular primers against specific biothreat agents, such as B. anthracis. A larger set of primers is capable of screening for a larger list of biothreat agents. Such portable devices are able to detect very small traces of organisms but cannot actually sequence their genes. They often incorporate a personal computer to control and monitor tests, an Internet link to enable real-time data acquisition, and a global positioning device to automatically track locations. With such technologies, a trained individual can screen about two dozen samples per hour. To increase testing capacity, multiple devices can be deployed. More definitive molecular forensics tests require more steps. A large assortment of automated and robotic equipment is available for this kind of work. Such industrial-scale technologies (e.g., robotic arms/conveyers, bar code readers, liquid handlers, incubators, genomic sequencers, flow cytometers, and image analyzers) are capable of performing all the procedures required by the proposed high-throughput molecular forensics laboratory. From a design standpoint, the various plug-and-work modules would be integrated into a flexible working system that could be upgraded with the latest commercial technologies. Incoming samples would follow an orderly flow, with different massanalysis lines focusing on different biothreat agents. Because of automation and miniaturization, the entire facility (which permits the growing, extracting, sequencing, and archiving of samples) would fit into a surprisingly compact space that contains biohazardous materials and safeguards workers.

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Biological Threats and Terrorism: Assessing the Science and Response Capabilities - Workshop Summary More sequence information is always better for molecular forensics, yet there are tradeoffs between laboratory productivity and definitive identifications. Complete viral genomes range in size from 10,000 to 300,000 DNA or RNA bases, whereas complete bacterial genomes range in size from 1,000,000 to 6,000,000 DNA bases. (In comparison, the human genome is composed of about 4,000,000,000 bases.) To fingerprint and taxonomically position biothreat virus, the molecular forensics laboratory would have to sequence and analyze 50 percent to 100 percent of each isolate’s genome. On the other hand, to do this for biothreat bacteria, the laboratory would have to sequence only 5 percent to 10 percent of each isolate’s genome. Current technologies would enable a highthroughput molecular forensics laboratory to sequencing about 10,000,000 bases per day. This would correspond roughly to fingerprinting and positioning about 500 viruses or 50 bacteria per day. Such procedures could be completed within hours or days after receiving samples. The high-throughput laboratory would also be able to perform the simpler (yes/no) PCR-based tests described above. A surge capacity of 10,000 samples per day would be feasible with current technologies. At such rates, however, the limiting factors would be sample collection and transportation rather than rapid testing. The high-throughput molecular forensics laboratory would generate a sizeable database within a few years. In addition to cataloguing molecular fingerprints, the laboratory would also be able to analyze the taxonomic position and natural genetic history of threat agents (genealogies). In reach-back and attribution scenarios, genealogies could prove to be more powerful than fingerprints alone. The most recent generation of teraflop computers, which can achieve speeds of 30 x 1012 calculations per second, would be well suited to analyze the threat agent database. Domestically, the goal would be to support decisionmaking processes and offer surge capacity for public health, emergency medical, agricultural, and law enforcement efforts. Internationally, the goal would be to support United States national security and intelligence operations as well as future BWC agreements. The toolbox for such undertakings includes currently available tracking, mapping, and modeling technologies. Virtually Assured Detection And Response (VADAR) The United States has mature policies to deter nuclear attacks, set forth as mutual assured destruction (MAD). It also has established policies to deter conventional attacks, set forth by the ability to fight on one or two major fronts and several minor fronts at once. But the United States has few well-developed policies to deter biological attacks. A high-throughput molecular forensics laboratory and database facility would help to fill this gap by enabling a new policy of virtually assured detection and response (VADAR) regarding biological attacks. The framework is as follows.

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Biological Threats and Terrorism: Assessing the Science and Response Capabilities - Workshop Summary The collapse of the system of two opposing superpowers has led to an uncertain world order characterized by one global ultrapower, a majority of responsible governments, several rogue states, multiple religious fringe groups, and some shadowy international syndicates that are forming new networks and posing new challenges to global security. Today, at least 17 countries are known to be developing or producing bioweapons and the list may be expanding. The scale of global trade also poses a major challenge. For example, more than 14,000 loaded 40-foot marine containers enter the United States each day (Flynn, 2000). Containers routinely travel through the country before reaching a port of entry and the system tracking their intended course and location is rudimentary. Furthermore, few containers undergo any form of inspection and, even when this occurs, specialized inspection technologies are rarely used. The ease of smuggling bioweapons constitutes a significant threat to homeland security, in part because the problems associated with marine containers represents only the “tip of the iceberg” in our leaky border controls. The foot-and-mouth disease outbreak in Great Britain and Europe, where the economic loss is estimated above £25 billion, reflects another aspect of the problem. Current methods of disease control, which rely on veterinarians inspecting animals for signs of infection, collecting mucosal and blood samples, and analyzing them with manual laboratories, have cycle times of three to five days. Foot-and-mouth disease can spread from one location to another, however, in far less time. Consequently, the current system with manual laboratories cannot support science-based decisions on quarantine zones, animal destruction, and resource allocation. At the heart of the problem is a lack of rapid, accurate, and complete information on which to make dependable decisions. A quantum leap in threat agent surveillance and data analysis is needed. In a bioattack on the United States, as few as 50 sickened people in one major city could stretch public health, emergency medical, and law enforcement services beyond local capabilities. Larger attacks involving major metropolitan areas would be overwhelming and require the delivery of tons of antibiotics to exposed persons within days, challenging national capabilities. A coherent program that strengthens homeland security thus requires sizeable laboratory and informatic resources that can be organized in terms of four overall phases. First, in preventing attacks, the United States would rely on the ability to fingerprint and catalogue bioweapons agents with high-throughput technologies. An extensive database of molecular fingerprints and associated origins would offer a new means of rapid attribution and therefore deterrence. It would put rogue states, religious fringe groups, and international syndicates on notice that there is little chance to evade blame for bioattacks. Second, in the unfortunate event of an attack, public health laboratories would be overwhelmed simply because there would be too many samples to analyze quickly. Manual laboratories would be unable to answer even the simplest questions: Is the agent present? How many different infectious agents were

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Biological Threats and Terrorism: Assessing the Science and Response Capabilities - Workshop Summary released? How do they differ? What are the best initial therapies to treat those afflicted and exposed? Information from high-throughput laboratories would reduce confusion and save lives by offering rapid testing in acute situations. Third, in the aftermath of an attack, public health, agricultural, and law enforcement officials would need accurate answers to another set of questions. What are the geographic boundaries of each infectious agent? What are their stabilities? What are the effects on animals and plants? Information from highthroughput laboratory and mapping systems would speed the recovery process by offering testing for cleanup and investigatory operations. Fourth, in response to the attack, law enforcement officials must collect evidence in accordance with chain of custody procedures. Intelligence agencies and military services must make accurate attributions and take swift actions to protect national security. Information from high-throughput laboratories and their associated databases could prevent further attacks by rapidly pinpointing suspected sources. The relatively small anthrax attacks in a few American cities flooded the bioterrorism response network. Thousands of samples were sent to a patchwork of state and federal laboratories which, at best, were equipped to handle about 100 samples per day (Kahn et al., 2000). Even with many laboratories working around-the-clock, they could not keep pace with emergency testing demands. Implementation Strengthening homeland security against bioterrorism needs enhanced public health and emergency medical preparedness at home and expanded human intelligence capabilities abroad. Moving beyond the BWC Protocol stalemate requires reliable disclosure of dual use facilities, timely inspection of suspicious programs, and systematic testing for certain (i.e., a short A-List) weaponizable agents. The common element among such undertakings is rapid, complete, and reliable information on which to make assessments and decisions. A high-throughput molecular forensics laboratory and database facility would cost several hundred million dollars to build and operate over the first five years. Since the needed technologies already are available, it could be operational within two years. Such a facility could be operated under the newly created Homeland Security Council. The mission of this new national medical forensics and intelligence support laboratory would be to complement and cooperate with existing government agencies such as health, agriculture, emergency management, justice, defense, intelligence, and the national laboratories. It would support public health, law enforcement, and homeland security programs without usurping their long-established missions. It would provide needed surge capacity in the acute and cleanup phases of terrorist bioattacks. It would also have mechanisms to support certain scientific and technical research.

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Biological Threats and Terrorism: Assessing the Science and Response Capabilities - Workshop Summary In building the first molecular forensic laboratory against bioweapons agents, the overall testing methods and high-throughput capabilities would be shared with the scientific community. The design of certain molecular primers against specific biothreat agents and resulting fingerprint and genealogies, however, would be available to the national and homeland security communities only. Such open architectures would facilitate the development a second internationally-based laboratory that parallels the initial design. Conclusion In the aftermath of the terrorist attacks on the World Trade Center and Pentagon and organized anthrax attacks in several American cities, there has been renewed debate on the risks of further biological attacks. At present, the risk remains unclear. Yet it is clear that terrorist attacks have become more spectacular and lethal and have now reached our homeland soil. The question is: When will the shift to more devastating forms of bioterrorism take place? The United States now has the opportunity to organize effective prevention, deterrence, and response measures. The United States must also act on domestic and international fronts. In mitigating bioterrorism, is VADAR a perfect solution? No. Is it an improvement over existing methods and policies? Yes. Is it possible to circumvent? Yes. But with secret offensive bioweapons programs possibly assisting organized terrorism, can we afford to wait? RESEARCH AND THE PUBLIC HEALTH RESPONSE Eric Eisenstadt,* Ph.D. Defense Advanced Research Projects Agency Technology could help public health enormously; but to help focus the development of technology for public health (as well as for the FBI and other law enforcement agencies who cope with forensic issues that resemble the diagnostic ones faced by public health), the public health community needs to articulate its technology needs. Once these needs are defined, then the science and technology communities, including funding organizations such as (DARPA), can begin to define the science and technology programs required to develop the desired capability. In this way, bridges can be built between public health and the technical community. Indeed, agencies like DARPA are very good at assembling the kind of interdisciplinary scientific and technical efforts—involving academia, industry, and government laboratories—that are required to develop new capabilities. Suppose, for example, the case could be made for a routine molecular *   This statement reflects the professional view of the author and should not be construed as an official position of the Defense Advanced Research Projects Agency.

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Biological Threats and Terrorism: Assessing the Science and Response Capabilities - Workshop Summary diagnostic capability that would provide a point-of-care physician with the information needed to make a decision about which treatment to prescribe within 30 minutes of taking a blood sample from a patient. A research and development effort might then be mounted to develop this new diagnostic capability by assembling researchers from the appropriate technical and user communities—e.g., molecular biology, materials science, signal processing, and clinical microbiology—to work together to create a new technology. The challenge would be enormous but the magnitude of the development effort will be a strong function of how strongly the case had been made for doing it in the first place. Genomics-based technologies, for example, have great potential for improving public health. Fulfillment of this potential would be accelerated if the public health community participated in developing a vision of how the application of genomics information could enhance health care. Such a vision might serve to rally the nation to develop technological capabilities that enhance our ability to cope with many of the bioterrorism response and preparedness issues that have been identified in our discussions. During World War II, for example, it was recognized that radar had tremendous potential for identifying U boats. The proof of principle had been done, but the technology still needed to be developed. A vision of what radar might be capable of doing for the military led to the initiation of the radar program at MIT from which great science and technology emerged including the foundations of the microelectronics industry. Finally, it is very difficult to bound all of the bioterrorism response capabilities that have been discussed during this workshop. There are simply too many imaginable bioterrorist scenarios (multiple agents and multiple ways to create mischief with them). We do not have sufficient resources to address an unbounded set of problems. So we must try in some rational way to bound bioterrorism and define the set of bioterrorism issues that need to be addressed. We must focus and develop a big vision that the country can respond to. For example, why not identify as a national goal the removal of infectious disease as a public health threat? This does not mean that we need to define how to eliminate infectious disease. When, a few hundred years ago, the British parliament recognized the need “to find longitude” they didn’t know how it was going to be done. But by crisply stating the problem and offering a prize to the one who solved it, some fantastic science and technology emerged. Could we not rally the country behind a campaign to eliminate the infectious disease threat?

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