Biodefense Quarterly, March 2001
Volume 2, Number 4

Mousepox: A Warning for Our Times
Nat'l Report Summaries:  Hart-Rudman Commission  Gilmore Commission  Nat'l Intelligence Commision
Botulinum Toxin Fact Sheet   Recent Publications   Editorial Board
Editorial Policy & Disclaimer

Mousepox: A Warning for Our Times

D.A. Henderson, M.D., M.P.H.

A January report from Australian scientists documented an unexpected discovery that a genetically altered mousepox virus had a greatly heightened virulence when experimentally inoculated into mice. What implications this might have with respect to other viruses, especially the poxviruses, was of immediate concern both to the investigators themselves and to scientists around the world.

The scientists involved are at the Australian National University's John Curtin School of Medical Research and were engaged in research directed toward controlling the fertility of rodents. They created a recombinant mousepox virus that encoded an antigen for a component of the mouse egg. With this virus, they expected to induce antibody that would attack mouse egg protein and thereby reduce fertility. In an effort to heighten the response, they added a gene encoding interleukin-4, an important component of the immune system, hoping thereby to diminish the ability of the mouse immune system to clear the virus.

The effect was wholly unexpected in that the modified virus killed virtually all of the mice so infected as well as half of those that had previously been immunized. The profound effect induced by the introduction of a single gene alarmed the scientists themselves who spent many months reconfirming the findings and debating whether the studies should be published. Eventually, they decided that it was best to make the findings publicly available through publication (Journal of Virology) and to encourage a wider discussion of the bioweapons threat posed by this and other observations that will inevitably arise as biotechnology progresses.

Whether these findings are peculiar to the mousepox virus or might apply to other poxviruses, such as smallpox, if dealt with in a similar manner is unknown. The investigators note that similar results were not observed when vaccinia virus was similarly treated.

Irrespective of the further application of this particular technique, the important point to be made is that the future will inevitably bring countless other organisms that will be developed through genetic engineering. The techniques for doing so are comparatively straightforward and widely known. Most such organisms will be beneficial but others will not. However, just as the study of the atom has brought countless benefits to mankind, so there is a dark side in the form of nuclear weapons. So it is with the developing field of biology and biotechnology. The challenge is to anticipate the inevitable and to be prepared for it.

3 Recent Reports Address Future of National Security

Rita Grossman

Road Map for National Security: Imperative for Change
The Phase III Report of the U.S. Commission on National Security/21st Century
Co-Chairs: Gary Hart and Warren B. Rudman

In its final phase, the Hart-Rudman Commission has concluded that American power and influence cannot be sustained without significant and creative reforms to the U.S. national security structure. "That power and influence must be disciplined by strategy, defined as the systematic determination of the proper relationship of ends to means in support of American principles, interests and national purpose." In other words, in light of an altered geopolitical environment, as well as social, scientific, and intellectual changes, the United States must re-evaluate the definitions of threats to its national security and set standards for engaging in conflict, and assess the methods by which it achieves its goals.

The Commission has stressed the importance of broadening the definition of "national security." The term should encompass new factors facing the American homeland such as economics, technology, and education. If such issues are poorly addressed, the United States will rapidly lose its prominent success and status. To overcome the "institutional inertia" determining how the federal government operates, the report offers recommendations for organizational change in five key areas:

  • Ensuring the security of the American homeland
  • Recapitalizing America's strengths in science and education
  • Redesigning key institutions of the Executive Branch
  • Overhauling the U.S. government personnel system
  • Reorganizing Congress's role in national security affairs.

The Commission's recommendations include creating a new, independent National Homeland Security Agency responsible for planning, coordinating, and integrating various U.S. government activities. The Commission also recommends a new National Security Science and Technology Education Act to fund a comprehensive program to build up the numbers of science and technology professionals as well as qualified science and math teachers. The Secretary of Defense is advised to shift DoD from a threat-based force-sizing process to one which measures requirements against recent operational activity trends, actual intelligence estimates of potential adversaries' capabilities, and national security objectives as defined in the new administration's strategy.

Second Annual Report of the Advisory Panel to Assess Domestic Response Capabilities for Terrorism Involving Weapons of Mass Destruction
Chairman: James S. Gilmore, III

Phase II of the Gilmore Commission's report was released on December 15, 2000.

The Commission considers that a terrorist attack inside U.S. borders is inevitable and that responding to the threat is the responsibility of all levels of government. The threat of terrorism requires the unparalleled synchronized efforts of the federal, state and local levels, as well as constituent stakeholders. Coordination of these critical elements has not yet been accomplished.

The Commission identified five major findings and recommended ways for Congress to operationalize its suggestions.

1. Finding: The United States has no coherent, functional national strategy for combating terrorism.

Recommendation: Within one year of assuming office, the new President should develop and present to Congress a truly national strategy dealing with domestic conventional, cyber, chemical, biological, radiological, and nuclear terrorism. The strategy should carefully consider these elements from the perspectives of deterrence, prevention, preparedness and response.

2. Finding: The organization of the Federal government's programs for combating terrorism is fragmented, uncoordinated, and politically unaccountable.

Recommendation: The new President should establish a National Office for Combating Terrorism in the Executive Office of the President, and should seek a statutory basis for this office. The director of this office should provide a senior authority to be in charge of overall planning and preparation in the Federal Executive Branch. The office should have a substantial and professional staff, drawn from existing National Security Council offices and other relevant agencies.

3. Finding: The Congress shares responsibility for the inadequate coordination of programs to combat terrorism.

Recommendation: The Congress should consolidate its authority over programs for combating terrorism into a Special Committee for Combating Terrorism, and Congressional leadership should instruct all other committees to respect the authority of this new committee and to conform strictly to authorizing legislation.

4. Finding: The Executive Branch and the Congress have not paid sufficient attention to State and local capabilities for combating terrorism and have not devoted sufficient resources to augment these capabilities to enhance the preparedness of the nation as a whole.

Recommendation: The Executive Branch should establish a strong institutional mechanism for ensuring the participation of high-level State and local officials in the development and implementation of a national strategy for terrorism preparedness.

5. Finding: Federal programs for domestic preparedness to combat terrorism lack clear priorities and are deficient in numerous areas.

Recommendation: The Commission underscores six suggestions including the improvement of collecting intelligence, operational coordination, and health and medical considerations.

The Commission calls upon the National Office for Combating Terrorism to reevaluate the current U.S. approach to protecting public health and providing medical care in response to acts of terrorism, particularly bioterrorism. "A robust public health infrastructure is necessary to ensure an effective response to terrorist attacks, especially those involving biologic agents" (x). Key issues that need to be addressed are insufficient education and training in terrorism-related subjects, minimum capabilities in surge capacity and in treatment facilities, clear standards and protocols for laboratories and other activities, and vaccine programs. There is an urgent need for financial incentives and standards that will encourage the health sector to build and maintain necessary capabilities. Moreover, the Commission calls upon federal, state, and local governments to clarify legal and regulatory authorities for issues such as quarantine and vaccination.

The findings of the Gilmore and Hart-Rudman Commissions should provoke much needed dialogue on how best to ensure U.S. national security within conditions of the new millennium.

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Global Trends 2015: A Dialogue about the Future with Nongovernment Experts
National Intelligence Council, December 2000

Global Trends 2015 is a comprehensive effort of the National Intelligence Council to project what the international environment will be in fifteen years. The assessment was completed by the intelligence community and outside experts, and was intended to reflect the perspective of the national security policymaker. It examines trends likely to develop in the United States and other major regions, as well as their potential effects on the global community. The final analysis of GT 2015 derives from a series of workshops, conferences and dialogues among experts representing government and non-government, academic and private sectors. Resulting is a list of major drivers that will shape the world of 2015. The report predicts that all drivers identified will have varying degrees of staying power. Some trends will persist. Others will be less enduring and possibly change course due to a shift in governance or the global economy, or as a result of a population boom, or as an effect of the information revolution.

The key drivers identified are:

  1. Demographics
  2. Natural resources and environment
  3. Science and technology
  4. The global economy and globalization
  5. National and international governance
  6. Future conflict
  7. The role of the United States

Even though each driver is justifiably distinct, there seems to be one factor that creates a common significant linkage: economics. Increasing economic interdependence and awareness, globalization, the continual progress in information technology, biotechnology and materials technology can have an impact on other potential trends - positively and negatively. For instance, biotechnology breakthroughs will drive medical breakthroughs that will increase the lifespan of the world's wealthy. Genetically modified crops will also offer the possibility of helping the world's one billion mal-nourished people. Disaffected states, terrorists, and proliferators will take advantage of the new high-speed information environment and rapid advances in the diffusion of nanotechnology and the material sciences to enhance their ability to engage in biological warfare or bioterorrism. The globalization of information could undermine the viability of authoritarian regimes, as oppressed populations push their governments to adjust to the changing global environment and adopt more democratic processes.

Another projected trend is the heightened participation of multilateral corporations and non-government organizations with traditional government actors in national and international affairs. The sectors will intersect due to the increasingly transnational nature of national security priorities and because of necessary interdisciplinary policy responses.

There also exists a wide range of uncertainties. Specifically:

  1. Increasing reliance on computer networks will make critical U.S. infrastructures more attractive as targets.
  2. As the U.S. adapts to the changing global environment, most adversaries will recognize its information advantage and military superiority. Thus, adversaries will continue to find innovative ways to circumvent U.S. strengths and exploit perceived weaknesses.
  3. Achieving widespread and sustained high levels of global growth will be contingent on avoiding potential threats to growth. Plausible scenarios include:
    1. The U.S. suffers a loss in international confidence leading to a sharp economic downturn.
    2. Failure of Europe and Japan to manage populations adequately could lead to conflict over social services or immigration policies and dampened economic growth.
    3. Emerging market economies fail to sustain high growth.
    4. Global energy supplies suffer a major disruption.
  4. In the Middle East, most regimes are resistant to change; thus, many will not be inclined to make reforms. Based on linear trend analysis, there is little hope for positive change in the region, which raises the prospects of increased demographic pressures, social unrest, religious and ideological extremism, and terrorism directed both at home regimes and at Western supporters. However, nonlinear developments -- such as the rise of a Web-connected opposition or the emergence of enlightened leaders committed to good governance -- could change outcomes in individual countries.

Global Trends 2015 thoroughly examines the seven key drivers outlined above, addressing issues such as the effects of burgeoning population trends in India and potential downturns in Africa due to AIDS; global food and water distribution; genomic profiling and biomedical engineering; potential scenarios involving non-state actors, including both multinational corporations and terrorist groups; the influence of the private sector in domestic and international policies; and trends in global defense spending and armaments. Expanding upon and modifying conclusions drawn in the 1997 Global Trends 2010, it is a comprehensive assessment of the social, political and economic future.

Facts about Botulinum Toxin

Calvin Chue and Tom Inglesby

Editorial note: Readers are encouraged to review the full consensus statement of the Johns Hopkins Working Group on Civilian Biodefense. The article is entitled Botulinum Toxin as a Biological Weapon: Medical and Public Health Management, and it was published in The Journal of the American Medical Association, Volume 285, Number 8, pp. 1059-1070.

Botulinum toxin poses a major bioweapons threat because of its extreme potency and lethality; its ease of production, transport and misuse; and the potential need for prolonged intensive care in affected persons. Botulinum toxin is the single most poisonous substance known.

A number of states named by the U.S. State Department as "state sponsors of terrorism" have developed or are developing botulinum toxin as a biological weapon. Aum Shinrikyo tried but failed to use botulinum toxin as a biological weapon.

Botulinum toxin is derived from the genus of anaerobic bacteria named Clostridia. Seven antigenic types of botulinum toxin exist, designated from A through G. They can be identified based on antibody cross reactivity studies - i.e., anti-A toxin antibodies do not neutralize the B through G toxins.

Naturally occurring botulism is the disease that results from the absorption of botulinum toxin into the circulation from a mucosal surface (gut, lung) or a wound. It does not penetrate intact skin. The toxin irreversibly binds to peripheral cholinergic synapses, preventing the release of the neurotransmitter acetylcholine from the terminal end of motor neurons. This leads to muscle paralysis, and in severe cases, can lead to a need for mechanical respiration.

The incubation period for food-borne botulism can be from 2 hours to 8 days after ingestion, depending on the dose of the bacteria or the toxin. The average incubation period is 12-72 hours after ingestion. Patients with botulism typically present with difficulty speaking, seeing and/or swallowing. Prominent neurologic findings in all forms of botulism include ptsosis, diplopia, blurred vision, dysarthria and dysphagia. Patients typically are afebrile and do not have an altered level of consciousness. Patients may initially present with gastrointestinal distress, nausea, and vomiting preceding neurological symptoms. Symptoms are similar for all toxin types, but the severity of illness can vary widely, in part depending on the amount of toxin absorbed. Recovery from paralysis can take from weeks to months and requires the growth of new motor nerve endings. In the event botulism is suspected, the hospital epidemiologist and local and state health departments should be contacted immediately.

Natural cases of botulism are rare and typically result from food contamination. Many types of food have been associated in outbreaks in the past, with the common factor being that implicated food items were not heated or were incompletely heated. Heat > 85oC inactivates the toxin. The largest botulism outbreak in the U.S. in the past century occurred in 1977, when 59 people became ill from poorly preserved jalapeño peppers.

No cases of waterborne botulism have ever been reported. This is likely due to the large amount of toxin needed, and the fact that the toxin is easily neutralized by common water treatment techniques.

A deliberate aerosol or food-borne release of botulinum toxin could be detected by several features including: a large number of acute cases presenting all at once; cases involving an uncommon toxin type (C, D, F, G, or non-aquatic food associated E); patients with a common geographic factor but without a common dietary exposure; and, multiple simultaneous outbreaks without a common source.

Diagnosis and testing are available at the CDC and some local and state laboratories. The standard test for the toxin is the mouse bioassay. Unfortunately, this assay is time consuming. Future development is focused on rapid diagnosis/detection. Polymerase Chain Reaction (PCR) assays that can detect the Clostridia spp. bacterial DNA toxin sequences are currently under development. Enzyme Linked ImmunoSorbent Assays (ELISAs) are being developed to detect functionally active toxins.

In the event that there is a clinical suspicion of botulinum toxin, treatment with antitoxin should not be delayed for microbiological testing. In the U.S., licensed botulinum antitoxin is available from the CDC via state and local health departments. An investigational heptavalent antitoxin is held by the U.S. Army. Optimal therapy for botulism requires early suspicion of the disease and prompt administration of antitoxin in conjunction with supportive care. Supportive care for patients with botulism may include mechanical ventilators in the intensive care unit, parenteral nutrition, and treatment of secondary infections.

An investigational botulinum toxoid is used to provide immunity for laboratory workers. It has been used to provide immunity against botulinum toxin over the past 30 years. However, supply of the toxoid is limited, and use of it would eliminate possible beneficial uses of toxoid for medical purposes. The toxoid induces immunity over several months and so would not be effective for rapid, post-exposure prophylaxis.

Existing technologies could produce large reserves of human antibody against the botulinum toxin. Administration of such a therapy could provide immunity of up to a month or greater and obviate the need for rationing the equine antitoxin. The development of such a human antibody reserve would require sufficient resources be dedicated to this problem.

Reprints are available from lead authors Drs. Stephen Arnon and Robert Schechter of the Infant Botulism Treatment and Prevention Program, California Department of Health Services, 2151 Berkeley Way, Room 506, Berkeley, CA 94704-1011.

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Recent Publications about Biodefense

Compiled by Melissa Rosen

  1. Arnon SS, et al. 2001. Botulinum Toxin as a Biological Weapon: Medical and Public Health Management. JAMA. 285(8):1059-1070. Outlines the Working Group on Civilian Biodefense's recommendations for the diagnosis and management of weaponized botulinum toxin.
  2. Baillie L, TD Read. 2001. Bacillus anthracis, a bug with attitude! Current Opinion In Microbiology. 4(1):78-81. Remarks on the sequencing of Bacillus anthracis genome and virulence.
  3. Berche P. 2001. The threat of smallpox and bioterrorism. Trends in Microbiology. 9(1):15-18. Explains why smallpox poses such a tremendous threat to humanity.
  4. Fedorova VA, ZL Devadariani. 2001. Immunogeneity and structural organization of some pLCR-encoded proteins of Yersinia pestis. Journal of Medical Microbiology. Presents a new method of cultivating Yersina pestis which allowed for the establishment of immunological relationships.
  5. Homeland Defense Bulletin. 2001. 2(6) Feb 9. An e-bulletin which contains a large number of articles on various topics relating to threats to U.S. national security. This issue focuses on bioterrorism and contains such articles as "Strengthening National Preparedness for Smallpox: An Update," "Bioterrorism Threat Finds New Urgency" and "Statement by Director of Central Intelligence." Subscribe at http://www.homelanddefense.org/journal/HLDBulletin/dsp_BulletinForm.cfm
  6. Inglesby TV, et al. 2001. A Plague on Your City: Observations from TOPOFF. Clinical Infectious Diseases. 32(3):436-445. Reviews TOPOFF, a mock exercise aimed at finding out how prepared a U.S. city is to manage the outcomes of a biological attack.
  7. Moss JI. 2001. Many Gulf War illnesses may be autoimmune disorders caused by the chemical and biological stressors pyridostigmine bromide and adrenaline. Medical Hypotheses. 56(2):155-157. Proposes probable causes to explain the high incidence rates of Gulf War illnesses in veterans.
  8. Terriff CM, AM Tee. 2001. Citywide pharmaceutical preparation for bioterrorism. American Journal of Health-system Pharmacy. 58(3):233-7. Describes the one medical center pharmacy's plan for bioterrorism preparedness.
  9. Weber DJ, WA Rutala. 2001. Risks and Prevention of Nosocomial Transmission of Rare Zoonotic Diseases. Clinical Infectious Diseases. 32(3):446-456. Comments on increased exposure risks for Americans to such diseases as plague, anthrax and hemorrhagic fever through animal contact and presents recommendations for patient isolation.
  10. Whitby SM. 2001. The potential use of plant pathogens against crops. Microbes and Infection. 3(1):73-80. Discusses the threat of agroterrorism and evaluates the ability of the Biological and Toxin Weapons Convention to deal with this issue.

Editorial Board

Monica Schoch-Spana, Ph.D.
Managing Editor

Molly D'Esopo
Newsletter Coordinator

D.A. Henderson, M.D., M.P.H.
Director

Tara O'Toole, M.D., M.P.H.
Deputy Director

Tom Inglesby, M.D.
Assistant Professor

Rita Grossman
Staff Research Assistant

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