Abstract
Outbreaks of highly pathogenic agents such as those that cause anthrax, smallpox, influenza, and Ebola fever have affected humankind and animals throughout recorded history. These and other agents make up the so-called biological select agents and toxins (BSATs), a specific group of pathogens that pose a severe threat to human, animal, and plant health and are of significant concern as potential agents of biowarfare or bioterrorism. The BSAT list is published as part of the US Code of Federal Regulations (42 CFR 73.3). Other pathogens not on the current list are also significant causes of disease in humans and animals. Accordingly, research with these agents is subject to a number of safety, security, and regulatory requirements.
BSATs have been used as weapons of biological warfare for hundreds of years. 1,2,3 For example, historical records show that the Mongols hurled the bodies of plague victims over the city wall of Caffa during their war with the Genoese in the 14th century in an effort to infect the city’s inhabitants. In the late 19th century, British forces fighting in the French and Indian War were reported to have deliberately given Native Americans blankets believed to be infected with smallpox virus. A number of countries have conducted biological weapons programs during the 20th century. A watershed event occurred in 1972, when the production of biological weapons was outlawed by the Biological Weapons Convention, as signed by the United States and more than 100 other countries. In spite of the convention, research on offensive bioweapons has occurred since that time, as evidenced by the former Soviet program known as Biopreparat. 1 Interested readers are referred to a number of resources that document the history of biological warfare, such as those by Alibek, Eitzen, and Martin. 1,2,3
The use of biological agents as an act of terrorism is generally a more recent occurrence, highlighted by the mailing of the anthrax letters in 2001 that resulted in several human fatalities and caused great anxiety in the United States. Fears that terrorist groups such as al-Qaeda and others might obtain and use biological weapons have increased steadily since 2001. The US Commission on the Prevention of WMD Proliferation and Terrorism (http://www.preventwmd.gov) recently expressed great concern about the threat of bioterrorism and the international community’s efforts to deal with the threat. The commission issued its report
The dangers posed by BSATs and other hazardous pathogens, whether in nature or through intentional dissemination, require that a variety of vaccines, antibiotics, and other drugs and biologics be developed. However, many factors complicate the development of such medical countermeasures. Certainly, the scientific and regulatory challenges are extensive in bringing needed products to licensure for use in humans. There is also the necessity to handle these infectious agents and toxins safely and securely during research. Finally, there are political and societal issues related to research involving BSATs. For these and other reasons, efforts aimed at developing the medical products needed to prevent or treat pathogens of high consequence face many hurdles.
A limited number of institutions have the physical capabilities—including biocontainment facilities and other safety, security, and personnel systems—needed to conduct research involving BSATs. Historically, biodefense research in the United States has fallen on three agencies—the Department of Defense at the US Army Medical Research Institute of Infectious Diseases, the Department of Agriculture, and the Centers for Disease Control and Prevention. The number of biocontainment laboratories has proliferated significantly in recent years, however, owing to the increased concern about biological agents and the need to develop countermeasures to address these concerns. Recognizing that BSATs represent a significant threat to civilian populations, the US National Institute of Allergy and Infectious Diseases has taken on an increasingly greater role in biodefense research, including the development of a system of national and regional biocontainment laboratories (http://www.fas.org/programs/ssp/bio/resource/research.html). In addition, laboratories affiliated with other elements of the US government are in different stages of development. These include the National Biodefense Analysis and Countermeasures Center and the National Bio and Agro-Defense Facility, components of the Department of Homeland Security. The National Biodefense Analysis and Countermeasures Center is part of the new National Interagency Biodefense Campus located at Fort Detrick, Maryland, which includes components of the National Institute of Allergy and Infectious Diseases, the Department of Defense, the Department of Agriculture, and the Centers for Disease Control and Prevention. Additional biocontainment facilities have been developed in a number of other countries around the world. To effectively operate, these facilities will require expertise in a number of scientific disciplines, including veterinary pathology.
Because animals are affected by many of the same hazardous pathogens that infect humans, they provide informative models for understanding the pathogenesis of disease caused by these agents. In addition, animal models are useful as a means of testing any number of potential vaccines and therapeutic products that might be effective against threat agents in humans. The animal diseases are also important in their own right. This is especially true when they affect food-producing species or when animals serve to transmit the pathogens to humans. Research using animals is therefore a necessary component of biological defense, and it frequently makes extensive use of pathology. To aid in that effort, numerous sources of information pertain to a variety of aspects of biological warfare and biological terrorism, the BSATs themselves, and the diseases they cause in animals and humans. Whereas many of these sources provide useful information regarding the pathology of animal infections with BSATs, there is no source to date in which pathology has been the focus. One of the goals of this special issue of
An important and recent addition to efforts in the United States to develop medical countermeasures to BSATs for use in humans is the so-called animal rule. This rule is intended to permit the US Food and Drug Administration to consider appropriate animal efficacy studies in situations when human studies cannot be performed with these hazardous agents, for ethical reasons or otherwise. The institution of the animal rule has placed unusual prominence on animal models of BSATs and on the need to characterize them thoroughly and understand in detail the pathophysiological mechanisms of toxicity of the threat agents. In addition, the use of the animal rule for Food and Drug Administration licensure of products requires that efficacy studies in appropriate animal models be well controlled and performed in accordance with good laboratory practices. These matters—and other aspects of the animal rule as it pertains to biological defense—are discussed in the informative article by Phillip Snoy. It is worthwhile to consider other articles in this issue that review animal models of human disease in the context of the animal rule.
A key aspect of biothreat agents is the expectation that intentionally released pathogens will involve aerosol dissemination. Therefore, a major focus of animal model development is to understand the pathogenesis of disease following exposure to the respiratory tract. Aerosol studies need to address disease features such as infectivity for particular locations or cell types in the respiratory tract, the rapidity of disease progression, the severity of its manifestation, and immune correlates of protection relative to other routes of inoculation. Accordingly, aerobiology in relation to BSAT research is a major area of emphasis in this issue and is the subject of the special article by Julie Hutt and colleagues.
Most articles in this issue review the current state of knowledge about the pathology of infectious pathogens of high consequence that are primary animal pathogens or ones for which one or more animal species are considered useful models of human infection. This section includes articles addressing anthrax, severe acute respiratory syndrome, henipaviruses, flaviviruses, poxviruses, alphaviruses, and influenza virus. Each article should serve as a useful single source for pathology and related information not readily available elsewhere. A recent study involving experimental aerosol infection with Marburg virus is included to highlight current research in the field of the highly pathogenic filoviruses and to further illustrate the importance of aerosol infection. While no articles reviewing the pathology of biological toxins are included in this issue, applicable toxins like ricin, staph enterotoxins and botulinum toxin are nonetheless recognized as significant threat agents subject to many of the same research challenges as the infectious agents. Overall, I hope that this special issue of
Footnotes
Acknowledgement
At the time that this editorial was prepared and submitted, the author was not directly affiliated with any organization. The author’s current address is as follows: National Biodefense Analysis and Countermeasures Center, 110 Thomas Johnson Drive, Frederick, MD 21702. The views and opinions contained herein are those of the author and should not be construed as an official position, policy, or decision related to any agency of the United States government, unless so designated by other documentation.