Facing the global challenges posed by biological weapons

This review article examines the growing concern about the threat posed by the use of biological weapons by States or terrorist groups. The article analyzes the nature of the perceived risk from bioweapons, the historical attempts to control them, and the emerging policy and legal framework designed to deal with the bioweapon threat.     

The Leeuwenhoek Lecture 2001. Animal origins of human infectious disease

Since time immemorial animals have been a major source of human infectious disease. Certain infections like rabies are recognized as zoonoses caused in each case by direct animal-to-human transmission. Others like measles became independently sustained with the human population so that the causative virus has diverged from its animal progenitor. Recent examples of direct zoonoses are variant Creutzfeldt-Jakob disease arising from bovine spongiform encephalopathy, and the H5N1 avian influenza outbreak in Hong Kong. Epidemics of recent animal origin are the 1918-1919 influenza pandemic, and acquired immune deficiency syndrome caused by human immunodeficiency virus (HIV). Some retroviruses jump into and out of the chromosomal DNA of the host germline, so that they oscillate between being inherited Mendelian traits or infectious agents in different species. Will new procedures like animal-to-human transplants unleash further infections? Do microbes become more virulent upon cross-species transfer? Are animal microbes a threat as biological weapons? Will the vast reservoir of immunodeficient hosts due to the HIV pandemic provide conditions permissive for sporadic zoonoses to take off as human-to-human transmissible diseases? Do human infections now pose a threat to endangered primates? These questions are addressed in this lecture.     

The weapon potential of a microbe

The designation of a microbe as a potential biological weapon poses the vexing question of how such a decision is made given the many pathogenic microbes that cause disease. Analysis of the properties of microbes that are currently considered biological weapons against humans revealed no obvious relationship to virulence, except that all are pathogenic for humans. Notably, the weapon potential of a microbe rather than its pathogenic properties or virulence appeared to be the major consideration when categorizing certain agents as biological weapons. In an effort to standardize the assessment of the risk that is posed by microbes as biological warfare agents using the basic principles of microbial communicability (defined here as a parameter of transmission) and virulence, a simple formula is proposed for estimating the weapon potential of a microbe.     

Antitoxins: novel strategies to target agents of bioterrorism

Never before has there been such a strong possibility that biological agents might be used indiscriminately on civilian populations. This review focuses on the use of antitoxins - antibodies, receptor decoys, dominant-negative inhibitors of translocation, small-molecule inhibitors and substrate analogues - to counteract those biological weapons for which toxins are an important mechanism of disease pathogenesis.     

A proposal for the classification of biological weapons sensu lato

Due to historical and legislation reasons, the category of bioweapons is rather poorly defined. Authors often disagree on involving or excluding agents like hormones, psychochemicals, certain plants and animals (such as weeds or pests) or synthetic organisms. Applying a wide definition apparently threatens by eroding the regime of international legislation, while narrow definitions abandon several important issues. Therefore, I propose a category of ‘biological weapons sensu lato’ (BWsl) that is defined here as any tool of human aggression whose acting principle is based on disciplines of biology including particularly microbiology, epidemiology, medical biology, physiology, psychology, pharmacology and ecology, but excluding those based on inorganic agents. Synthetically produced equivalents (not necessarily exact copies) and mock weapons are also included. This definition does not involve any claim to subject all these weapons to international legislation but serves a purely scholarly purpose. BWsl may be properly categorized on the base of the magnitude of the human population potentially targeted (4 levels: individuals, towns, countries, global) and the biological nature of the weapons’ intended effects (4 levels: agricultural-ecological agents, and non-pathogenic, pathogenic, or lethal agents against humans).     

Nucleic acid approaches for detection and identification of biological warfare and infectious disease agents

Biological warfare agents are the most problematic of the weapons of mass destruction and terror. Both civilian and military sources predict that over the next decade the threat from proliferation of these agents will increase significantly. In this review we summarize the state of the art in detection and identification of biological threat agents based on PCR technology with emphasis on the new technology of microarrays. The advantages and limitations of real-time PCR technology and a review of the literature as it applies to pathogen and virus detection are presented. The paper covers a number of issues related to the challenges facing biological threat agent detection technologies and identifies critical components that must be overcome for the emergence of reliable PCR-based DNA technologies as bioterrorism countermeasures and for environmental applications. The review evaluates various system components developed for an integrated DNA microchip and the potential applications of the next generation of fully automated DNA analyzers with integrated sample preparation and biosensing elements. The article also reviews promising devices and technologies that are near to being, or have been, commercialized.     

Hazards,threats and risks: lessons from the past to a defensive attitude for the future

Since ever infectious diseases have been a major hazard for the armed forces in operations. Nowadays our nations are facing the threat of terrorism, including bioterrorism. This threat is much more related to the potential disorganization of the society than to the lethal effects of the agents. Biological weapons are considered more like terror weapons than like mass destruction weapons, hence the importance of preparing specific defence measures. The know-how acquired from the struggle against natural infectious diseases is a useful help to face the biological weapon threats and risks. Likewise, the defence attitude is based on three pillars: anticipating, managing, and restoring. This military as well as civilian defence attitude applies to six important functions: (1) alert, (2) detection, diagnosis and identification, (3) medical countermeasures (drugs, vaccines and sera), (4) medical care in hospital, (5) training and information, (6) research and development of dedicated technologies.     

Preparedness for an anthrax attack

Bacillus anthracis is a long-known bacterial organism with a uniquely stable spore stage. Its stability and the lethal disease which results when the spore is inhaled made it a favorite of state-sponsored biological weapons programs throughout the Cold War era. It is also believed to be high on the list of candidate microbial agents which could be used by terrorist groups or lone actors. Its unique characteristics make protection of humans, especially civilians, from an intentional biological attack very difficult. The author argues that an all-hazards/public health approach – which would also be needed for any natural or deliberate outbreak, no matter the agent – should serve as a foundation of preparation for the specific anthrax countermeasures. Because B. anthracis is a unique organism, specific countermeasures for anthrax detection, diagnostics, prophylaxis and therapy, should be developed in nations or regions where the threat of biological attack is believed to warrant such preparation. Other considerations for a nation interested in anthrax preparedness are discussed.     

Rapid diagnostic assays in the genomic biology era: detection and identification of infectious disease and biological weapon agents

In this special section of BioTechniques, we examine the role of rapid molecular technologies in the detection and identification of agents of infectious disease (ID) and biological weapons (BWs). Besides the threat posed by the global proliferation of BW technologies, there are numerous emerging and reemerging ID agents with significant public health consequences. Further compounding this already complicated situation are the estimated 600 million international tourists annually, many with the potential to the spread disease globally in a matter of hours. While clinical laboratories have key roles in the detection and identification of potential ID/BW agents, most staff are unfamiliar with these agents because of their rarity and the often laborious conventional methodologies needed to identify them. To meet this challenge, a vast array of rapid assay strategies has been developed for use in clinical diagnostics and environmental detection. Technologies have been developed or adapted to the challenges posed by these agents, permitting detection and identification in several minutes to hours. In particular, the development of improved reagents and detection systems has led to dramatic improvements in the sensitivity and specificity of immunological and nucleic acid-based systems, allowing an ever-increasing range of analytes to be identified and quantitated. In the accompanying articles, we have brought together experts from the many overlapping aspects of this arena in order to present a comprehensive and critical analysis of these technologies.     

Administrative issues related to infectious disease research in the age of bioterrorism

The recent unprecedented growth in infectious disease research funding and infrastructure has resulted in part from an outgrowth of concern about newly emerging and re-emerging diseases and the progressive development of antibiotic-resistant pathogens. However, the most compelling impetus is the suspected and demonstrated capability and will of unknown individuals, groups, or states to use biological agents and/or toxins as weapons. Although the actual number of known victims and fatalities from bioterrorism in the United States has been miniscule compared with many other daily hazards, biological agents have the potential to cause human mass casualties, severely damage segments of our economy or agricultural infrastructure, poison or compromise our food or water supply, and, perhaps most damaging, disrupt our society physically and psychologically. The significant institutional commitment necessary to participate in infectious disease research is described, with a focus on programs that involve research with pathogens thought to have potential for use by bioterrorists. Administrative considerations are described, and include obtaining necessary research funding to offset high operating costs; complying with "select agent" regulations, security screening of employees; building or renovating a biocontainment facility; finding skilled professional and technical manpower; providing adequate physical security in a threat environment; conducting targeted training; overcoming potential internal and external dissent; developing and/or providing sufficient occupational health and safety programs; achieving and maintaining compliance standards in a fluid regulatory environment; mitigating potentially hazardous working conditions; understanding personal and institutional liability; and reassuring and dealing with a concerned, skeptical, or even hostile public.     

Strengthening bioterrorism prevention: global biological materials management

The anthrax attacks of 2001 demonstrated that bioterrorism poses a significant threat to U.S. national security. This threat is increasing as a result of the rapid expansion in scale and technical capabilities of the global biotechnology industry, which is broadening the availability of materials, technologies, and expertise needed to produce a biological weapon and is lowering the barriers to biological weapons terrorism and proliferation. At the same time, there has been a rise of sophisticated yet loosely networked transnational terrorist groups that have shown an interest in bioterrorism. The United States must confront this convergence. Although the U.S. government pursues many different biodefense programs to bolster its ability to detect and respond to a bioterrorist attack, these efforts must be augmented with preventive measures to meet today's international challenges. U.S. Homeland Security Presidential Directive 10 of April 2004 defines "Prevention and Protection" as one of the four essential pillars of the U.S. response to the bioterrorist threat. However, while bioscience and policy experts have proposed a variety of preventive initiatives, the creation of such programs has been slow and limited. Global biological materials management, which would focus on identifying and protecting those biological materials at the greatest risk of being used maliciously, is one potential solution. Such an approach would augment current U.S. biodefense efforts, provide the international community an effective means of mitigating the global threat of bioterrorism, and strengthen the international community's battle against emerging infectious disease.     

Temperate Bacterial Viruses as Double-Edged Swords in Bacterial Warfare

It has been argued that bacterial cells may use their temperate viruses as biological weapons. For instance, a few bacterial cells among a population of lysogenic cells could release the virus and kill susceptible non-lysogenic competitors, while their clone mates would be immune. Because viruses replicate inside their victims upon infection, this process would amplify their number in the arena. Sometimes, however, temperate viruses spare recipient cells from death by establishing themselves in a dormant state inside cells. This phenomenon is called lysogenization and, for some viruses such as the λ virus, the probability of lysogenization increases with the multiplicity of infection. Therefore, the amplification of viruses leads to conflicting predictions about the efficacy of temperate viruses as biological weapons: amplification can increase the relative advantage of clone mates of lysogens but also the likelihood of saving susceptible cells from death, because the probability of lysogenization is higher. To test the usefulness of viruses as biological weapons, we performed competition experiments between lysogenic Escherichia coli cells carrying the λ virus and susceptible λ-free E. coli cells, either in a structured or unstructured habitat. In structured and sometimes in unstructured habitats, the λ virus qualitatively behaved as a “replicating toxin”. However, such toxic effect of λ viruses ceased after a few days of competition. This was due to the fact that many of initially susceptible cells became lysogenic. Massive lysogenization of susceptible cells occurred precisely under the conditions where the amplification of the virus was substantial. From then on, these cells and their descendants became immune to the λ virus. In conclusion, if at short term bacterial cells may use temperate viruses as biological weapons, after a few days only the classical view of temperate bacterial viruses as parasitic agents prevails.     

Botulinum toxin: therapeutic agent to cosmetic enhancement to lethal biothreat

The clinical effects of Clostridium botulinum and its extremely potent neurotoxin have been known for two centuries. The disease threat and the clinical uses are now well established. What's changed is the potential for botulinum neurotoxin to be used as a biological threat agent. The recent upsurge of illegal trafficking of reagent-grade toxin could, if bought in large enough quantities, be as serious a threat as other biothreat agents such as anthrax and smallpox, which have received much more attention. Fortunately, effective countermeasures are available.     

Crayfish,catfish and snails: the perils of uncontrolled biological control

A recent proposal that the Australian redclaw crayfish Cherax quadricarinatus and hybrid catfish could potentially control the snail hosts of schistosomiasis has been criticised on the grounds that crayfish pose a severe threat to aquatic ecosystems into which it might be introduced. This note examines the issue further, pointing out that both lack the host-specificity requirement to be a successful biological control agent. The catfish Clarias gariepinus is an omnivore and snails form only a small proportion of its diet; there is no evidence to suggest that it controls snail populations anywhere in Africa. The same applies to other species that have been proposed as biological control agents. Simple laboratory experiments are not an adequate guide to the efficiency of an animal as a biological control agent and detailed ecological investigations would usually demonstrate that few African fish species have this capability.     

The dual-use dilemma for the life sciences: perspectives, conundrums, and global solutions

The term "dual-use" traditionally has been used to describe technologies that could have both civilian and military usage, but this term has at least three different dimensions that pose a dilemma for modern biology and its possible misuse for hostile purposes: (1) ostensibly civilian facilities that are in fact intended for military or terrorist bioweapons development and production; (2) equipment and agents that could be misappropriated and misused for biological weapons development and production; and (3) the generation and dissemination of scientific knowledge that could be misapplied for biological weapons development and production. These three different aspects of the "dual-use dilemma" are frequently confused--each demands a distinct approach within a "web of prevention" in order to reduce the future risk of bioterrorism and biowarfare. This article discusses the nature of the different perspectives and divergent approaches as a contribution to finding a scientifically acceptable global solution to the problem posed by the dual-use dilemma. We propose that: (1) facilities that are intended for bioweapons development and production should be primarily prevented by a strengthened Biological and Toxin Weapons Convention (BTWC) effectively implemented in all nation states, one that includes provisions for adequate transparency to improve confidence and a mechanism for thorough inspections when there is sufficient cause, and enhanced law enforcement activities involving international cooperation and sharing of critical intelligence information; (2) potentially dual-use equipment and agents should be available to legitimate users for peaceful purposes, but strengthened national biosafety and physical and personnel biosecurity controls in all nations together with effective export controls should be implemented to limit the potential for the misappropriation of such equipment and materials; and (3) information should be openly accessible by the global scientific community, but a culture of responsible conduct involving the breadth of the international life sciences communities should be adopted to protect the ongoing revolution in the life sciences from being hijacked for hostile misuse of the knowledge generated and communicated by life scientists.     

Biological threat characterization research: a critical component of national biodefense

Biological warfare (BW) threat assessments identify and prioritize BW threats to civilian and military populations. In an ideal world, they provide policymakers with clear and compelling guidance to prioritize biodefense research, development, testing, evaluation, and acquisition of countermeasures. Unfortunately, the biodefense community does not exist in an ideal world. National security professionals responsible for crafting BW threat assessments often are challenged by factors that limit the clarity and/or timeliness of those assessments. Moreover, the potential for life science advances to enhance threats enabled by state programs and the possibility that non-state actors may pursue crude but effective BW methodologies will drastically expand the scope of the perceived threat. Appropriate investment of federal biodefense funds will require some mechanism for validating and prioritizing present and future threats. Ideally, such a mechanism will incorporate empirical data targeted to elucidate actual hazards. In this regard, the Department of Homeland Security's creation of a Biological Threat Characterization Program for the technical validation of threat agents will be a valuable addition to the nation's overall biodefense strategy. This article articulates the need for a coordinated national biological threat characterization program, discusses some of the principal challenges associated with such research, and suggests a few options for their resolution.     

The versatile roles of antibodies in Borrelia infections

Antibodies are the primary weapons of the mammalian immune system that are used against the tick-borne borreliae, the causative agents of relapsing fever and Lyme disease worldwide. Some antibody responses have 'traditional' functions, whereas others are more versatile and have novel functions and modes of action. At a time when the multiple functions of antibodies are being increasingly recognized and passive immunization is being revived as therapy for infectious and other diseases, the versatile nature of the antibody response to the borreliae fits well with this antibody renaissance.     

毒素战剂的生防疫苗简

毒素战剂是重要的生物战剂之一,其最大的威胁来自它的高毒性和缺乏有效的防治手段。在毒素战剂中,肉毒毒素、志贺毒素、蓖麻毒素、相思子毒素等属于致死性生物战剂,葡萄球菌肠毒素B属于失能性生物战剂。生防疫苗作为毒素战剂的一种重要的有效预防手段,一直备受关注,但目前绝大部分毒素战剂的疫苗都还在研制中,随着分子生物学技术的快速发展,几种重要毒素战剂的重组疫苗研究已获得重要突破。我们重点介绍肉毒毒素、志贺毒素、蓖麻毒素、相思子毒素、葡萄球菌肠毒素B等毒素战剂生防疫苗的研究与发展。     

Working with transmissible spongiform encephalopathy agents

The family of illnesses called transmissible spongiform encephalopathies (TSEs), or "prion" diseases, is composed of a small number of human and animal neurodegenerative diseases caused by unique pathogenic agents that are still not fully defined. They are best considered as "protein-misfolding diseases" (together with Alzheimer's disease, Parkinson's disease, and a few other rare examples) resulting from the conversion of a normal body protein into a misfolded amyloid multimer. The pathogenic agents display a unique resistance to conventional disinfection methods and an extraordinary environmental durability, which has led the US Department of Agriculture to designate the causative agent of bovine spongiform encephalopathy as a bioterrorism security threat. In this review, precautions and regulations concerning the handling of TSE agents are discussed in relation to personnel and environmental biosafety.     

Density-dependent interactions between the nematode Meloidogyne incognita and the biological control agent Agasicles hygrophila on invasive Alternanthera philoxeroides and its native congener Alternantera sessilis

BioControl - Biological invasions are a great threat to biodiversity. Invasive plants targeted for control with introduced biological control agents are also exposed to indigenous herbivores in the...