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Biological Toxins: A Bioweapon Threat in the 21st Century SEBESTYÈN GORKA and RICHARD SULLIVAN Security Dialogue 2002; 33; 141 DOI: 10.1177/0967010602033002003 The online version of this article can be found at: http://sdi.sagepub.com/cgi/content/abstract/33/2/141

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International Peace Research Institute, Oslo

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Biological Toxins: A Bioweapon Threat in the 21st Century SEBESTYÈN GORKA & RICHARD SULLIVAN* Centre for EuroAtlantic Integration and Democracy (CEID), Budapest, Hungary & Cancer Research UK, London, United Kingdom The last ten years have seen a resurgence in the socio-political focus on biological weapons (BWs) as a result of a perceived increase in the threat from nation-state and terrorist quarters. The formation of the Ad Hoc Committee, under the chairmanship of Ambassador Tibor Toth, to develop the 1975 Biological Weapons and Toxins Convention into a more effective and pragmatic international tool for combating the future threat of BWs has highlighted many issues, not least the difficulty of making informed threat assessments/risk stratifications in this field. There is also a vast corpus reinforcing the potential of various microorganisms to be weaponized. The open literature has, by and large, focused on the hostile use of replicating biological agents: bacteria, viruses and rickettsiae. However, biological toxins have also been weaponized for assassination and mass destruction. The huge repertoire of biological toxins, coupled with their unique properties, evolving developments in toxin biomedical research and the complexity of the associated science necessitate a balanced understanding of their peaceful uses and potential misapplication on the part of those involved in policy decisions within this area. This article concludes that threat assessments of toxins as potential BWs will require a network of interdisciplinary expertise that crosses traditional boundaries and areas of responsibilities, with access to classified and unrestricted information, in order to tackle the evolving asymmetry of capabilities and motivation.

Definitions and Concepts

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IOLOGICAL TOXINS are selective poisons produced by living organisms. They usually consist of an amino-acid chain of between a few hundred peptides to thousands of proteins. Certain low-weight organic compounds (which are not peptides) can also be classed as toxins. In nature, bacteria, fungi, algae, plants and animals produce a vast range of toxins, many with a lethality several orders of magnitude greater than nerve agents.1 However, unlike chemical toxins, these are usually non-volatile and dermally inactive (the exception being the mycotoxins); furthermore, they tend to be Security Dialogue © 2002 PRIO.

SAGE Publications, Vol. 33(2): 141–156.

ISSN: 0967-0106 [026873]


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more toxic per weight than many chemical agents. Both the Biological Toxins and Weapons Convention (BTWC) and the Chemical Weapons Convention (CWC) cover toxins regardless of their origins,2 and the differentiation between chemical and biological toxins is not applicable for the purposes of international security, where the relevant legislation needs to ensure that all toxins are covered through respective general-purpose criteria.3 There are a number of reasons why we are witnessing an increase in sociopolitical activities directed towards the threat of biological weapons (BWs), including politico-military post-Cold War refocusing, high-profile nation-state BW programmes (such as that of Iraq) and direct deployment (e.g. anthrax attacks in the USA). Broadly speaking, it is perhaps unsurprising that society has become obsessed with BWs. The question is whether developments in biomedicine will ultimately lead to an increase in the BW threat and, in particular, the use of toxins. But what has changed in recent times to require a reappraisal of toxins within the context of a BW threat? One of the primary reasons why NATO and the USSR lost interest in BWs per se as Weapons of Mass Destruction (WMD) was their inability to predict combat effectiveness and area containment. Toxins do not replicate and therefore are limited to their target(s), effectively negating the issue of collateral damage outside the immediate exposure area.4 The military utility of many biological toxins is also limited either by low inherent toxicity or by limits on the feasibility of manufacture if the toxin is in fact extremely toxic (i.e. in the case of toxins with low LD50s – the dose required to kill 50% of people who ingest it – such as saxitoxin). As a result, toxins are considered to be less suitable for dispersal on large scales and, up until now, their use as BWs has been operationally confined to sabotage or assassination, despite the fact that botulinum, Staphylococcus enterotoxin B (SEB) and T-2 mycotoxins have been weaponized by nation-states.5 However, quite apart from the increased threat from motivated terrorists searching for WMD, there has been clear evidence of serious BW research & development (R&D) by certain groups (e.g. cults, militias and survivalists) and nation-states (e.g. apartheid South Africa and Iraq). In addition, the attacks by fundamentalist Islamic terrorists on New York and Washington on 11 September 2001 raise the issue of whether willingness to use conventional WMD may also be reflected in an increased motivation to utilize BWs. Such an increase in motivation would not by itself be sufficient to warrant a threat increase if the biological state-of-knowledge (i.e. capability) had remained static. However, a revolution in the biological understanding of toxins has changed all that. The basic-science community has realized that toxins make valuable ‘tools’ for dissecting out various cellular pathways (toxins are very selective when it comes to their cellular targets), and the clinical community has begun to utilize the properties of toxins to treat disease, for example by targeting them to cancer cells. This demand has in turn driven the search for other naturally Downloaded from http://sdi.sagepub.com at PENNSYLVANIA STATE UNIV on April 16, 2008 © 2002 International Peace Research Institute, Oslo. All rights reserved. Not for commercial use or unauthorized distribution.

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occurring toxins, as well as research into making recombinant toxins as a way of bypassing natural-source extraction. In turn, a revolution in molecular biology has enabled research into completely novel toxin engineering. This, then, is what constitutes the threat of toxin BWs – increasing motivation and capability.

The Use of Toxins as Weapons The use of toxins as BWs is academically interesting, but historical bias can be a weak variable in threat assessments. Information from past attacks can be useful for some aspects of risk stratification, but technical evolutions and motivational changes can make historical data a complex variable to interpret. Furthermore, it is often impossible to determine from open sources the truth or falsehood of accounts of BW attacks and/or research programmes. One thing that can be said of the history of BWs is that it is corrupted by disinformation.6 Furthermore, the semi-overt nature of past nation-state BW programmes will give way in the future to covert dual-use programmes; thus, differentiation between peaceful and offensive research will become even more difficult. The early 20th century saw the first concerted modern efforts at deriving weapons from biological agents. BW programmes, including research into the manufacture and weaponizing of toxins, were started by Lenin in the USSR in 1919,7 and these continued after World War I under the People’s Health Commissariat. The next significant development of toxins as BWs was the Japanese programme that was started in the early 1930s under the auspices of Lieutenant General Shiro Ishii and General Yujiro Wakamatsu. Known as Detachment 731, and based at Pingfan, Manchuria, this programme conducted experiments on the Chinese population using plague, anthrax and botulinum toxins. This was probably the first time that toxins had been tested as potential BWs on human subjects, and it marked a watershed in the weaponizing of biological agents. The information derived from these experiments, especially work on the nascent science of aerobiology, later fell into the hands of the USA and the USSR, which used it to develop their own strategic BW programmes. Botulinum toxin was also chosen by the British during their offensive BW programme of 1940– 45, which was carried out in close collaboration with Canada and the USA.8 From the 1950s onwards, both the Soviet Union and the United States pursued offensive BW programmes.9 However, the major problem with the development of biological-toxin BWs was the inability to produce enough raw material, owing to a lack of knowhow and underdevelopment of relevant technology (there was no significant biopharmaceutical industry at the time). In the pre-genetics era, the only way to extract and purify toxins was through laborious and exhaustive protein-purification procedures. Despite the elucidation of the structure of the double-helix of DNA in 1953, it took the development of the bacteria Esterichia coli (E. coli) as a biological ‘workhorse’ (in 1970–73) and the Downloaded from http://sdi.sagepub.com at PENNSYLVANIA STATE UNIV on April 16, 2008 © 2002 International Peace Research Institute, Oslo. All rights reserved. Not for commercial use or unauthorized distribution.

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development of the process of transfection (the introduction of foreign DNA into a cell) to make recombinant-toxin production a viable and repeatable process. With these discoveries, biomedical science could take toxin genes and introduce them into E. coli (transfection) to produce large amounts of recombinant toxins. The growth in genetic bioengineering since this time has been exponential: a ‘working draft’ of the human genome is now available,10 and many toxin genes have already been sequenced. With this new genetic knowledge, and a general increase in proteomic (protein-engineering) technologies, have come new techniques for making novel recombinant toxins. It is therefore recent history – the beginnings of Human Genome Project and the creation of large genetic databases in the late 1980s – that indirectly has had the greatest impact on the threat of biological toxins within BW programmes.

Biological Toxins: Examples and Mechanisms Only four biological toxins – saxitoxin, botulinum toxin, ricin and SEB – are at present considered by Pearson and colleagues to be likely and reliable BW agents.11 The US Centers for Disease Control and Prevention (CDC) have taken this further by risk-stratifying toxins according to certain criteria – ease of transmission, morbidity:mortality ratios, public/social disruption and requirement for prior preparedness. The CDC’s latest review places botulinum toxin in Category A, while ricin, Clostridium perfringens epsilon toxin and SEB are listed in Category B.12 There is a significant corpus of literature on these toxins, which represent the ‘gold standard’ of the types of toxins which have been considered weaponizable. However, the last 25 years have been a biological lag phase in our understanding of molecular biology: the exponential rise in our knowledge about toxins has really been a recent phenomenon, and the explosion in academic research on bacterial, fungal and marine toxins as tools for basic science will have implications for the toxin BW threat. This important biomedical research utilizes a vast array of toxins – far beyond those included in the lists of proscribed BW agents. Indeed, the diversity of toxins in nature, the variety of their sources, the range of their mechanisms of action and the uses to which they are put in biomedical research and treatment are rarely appreciated. Bacteria There are now over 240 well-recognized bacterial toxins. A few of these are entirely responsible for the clinical illness that infection with the organism produces (e.g. botulinum toxin). The majority, however, are only components of a particular illness seen as a whole. Bacterial toxins cause damage through a wide variety of mechanisms. For example, Streptolysin-O – the toxin produced by streptoccocal bacteria (often responsible for producing acute tonsilitis) – Downloaded from http://sdi.sagepub.com at PENNSYLVANIA STATE UNIV on April 16, 2008 © 2002 International Peace Research Institute, Oslo. All rights reserved. Not for commercial use or unauthorized distribution.


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punches neat holes in the target cell, which results in the leakage of proteins and cellular death.13 The mechanisms targeting particular cellular processes also give rise to tissue-specific toxins – certain receptors and cellular processes are only found in certain tissues. Tetanus and botulinum toxins are some of the most potent toxins that directly attack the nervous system.14 The tetanus neurotoxin acts mainly on the central nervous system, while botulinum neurotoxin acts peripherally. However, despite the often fatal nature of botulinum toxin, it is used therapeutically to treat a number of conditions that cause severe muscular spasms.15 Some other clostridial bacteria produce a toxin that has a more widespread effect. These so-called C2 toxins target an important protein found in all human cells.16 C2 toxins and other bacterial toxins that selectively target intracellular proteins have been extensively used in biomedical research, especially for probing the various cell signalling pathways that allow cellular receptors to communicate with the nucleus. Plants Ricin and its cousin abrin are highly toxic plant proteins with similar structures and functions, and they inhibit protein synthesis in mammalian cells.17 Recent research has succeeded in isolating the regions of amino acids that actually make the Abrus protein toxic. This raises the spectre of designer toxins or enhanced pathogenicity. Indeed, persistence and stability certainly can be enhanced by relatively straightforward methods.18 However, this needs to be put in context. Ricin can easily be extracted from the beans of the plant Ricinus communis, which is cultivated worldwide for castor oil.19 Despite some early attempts to couple these lethal toxins to antibodies targeted at cancer cells (toxin immunoconjugates), these ‘magic bullets’ met with little success. However, they still remain essential tools for exploratory biology. Marine Organisms Marine organisms produce toxins for both defensive and offensive (preycatching) purposes, and in the past ten years science has succeeded in purifying many of them. Perhaps the most well-characterized marine toxin is derived from the puffer fish, Lagocephalus scleratus. Known as tetrodotoxin, this toxin is also present in a variety of other marine organisms and is produced by symbiotic bacteria.20 Marine cone snails also produce a range of potent toxins.21 These conotoxins, if ingested or injected, can lead to rapid paralysis and death. There are also a number of marine toxins, mostly from dinoflagellates (microalgae), that can lead to serious gastrointestinal poisoning.22 However, these are relatively complex compounds that are neither easily extracted nor easily manufactured as recombinant proteins.


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Interestingly, one of the most lethal toxins is to be found in the marine environment. A ciguateric herbivorous fish is responsible for producing, as a natural defensive measure, a complex toxin named maitotoxin.23 This toxin has an LD50 of a tiny 0.05 µg per kg; in other words, maitotoxin has an LD50 200 times lower than saxitoxin, which is one of the key proscribed agents in the BTWC. Although marine toxins are mostly used for basic biomedical research, there is increasing interest in the biomedical community in using them in the treatment of cancer. Fungi Despite their lethality, most fungal toxins have not been considered serious BW agents.24 However, natural fungal toxins (mycotoxins), particularly those derived from mouldy grain, are still a significant cause of morbidity and mortality in developing countries.25 These include toxins derived from the Aspergillus fungi – the aflotoxins – which are directly toxic to the liver.26 The fungus Aminata phalloides also produces a toxin, phalloidin, that binds to the intracellular protein actin, effectively ‘freezing’ the cell. This leads to cell death and massive tissue necrosis. However, both of these examples, along with many other fungal toxins, are complex to isolate and relatively unsuitable for development as BW agents. Fungal toxins have mainly found their place within basic-science research. Phalloidin is one of the most widely available and useful tools for studying the architecture of cells. Animals Venomous and poisonous animals are a significant cause of worldwide morbidity and mortality. Snakes – such as those in the viper, elapid (cobra-like), sea-snake, side-fanged viper and back-fanged colubrid groups – produce a wide variety of toxins that can cause blood-clotting defects and the destruction of muscle, nerves or kidneys. Some snake toxins, such as that of the green mamba, block the receptor for the neurotransmitter acetylcholine, which leads to rapid muscular paralysis and death.27 The cobra toxins, on the other hand, are powerful cardiac toxins, rapidly inducing death by directly destroying heart muscle. Other snake venoms affect the haemostatic mechanisms by causing blood coagulation, anticoagulation or haemorrhaging.28 Like the botulinum toxins, snake venom is beginning to have a therapeutic role.29

Biological Toxins: A Threat Assessment Capability: A Key Component in the Threat of Toxin BWs A recent threat analysis of over 395 toxins has revealed that as few as 17 of these are potentially weaponizable, mainly owing to scale-up difficulties or Downloaded from http://sdi.sagepub.com at PENNSYLVANIA STATE UNIV on April 16, 2008 © 2002 International Peace Research Institute, Oslo. All rights reserved. Not for commercial use or unauthorized distribution.


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aerosol instability.30 However, at this point it is worth placing toxins into an overall perspective. Natural human morbidity and mortality due to toxins tends to be at the individual level and the result of oral (e.g. botulism) or penetrated-skin (e.g. tetanus) entry. Secondary natural toxin-related morbidity/mortality may also be due to bacteria acquired by inhalation that subsequently release toxins as part of their pathophysiologies (e.g. endotoxin). No natural toxins have an inherent tendency to target the lungs. Toxins designed for aerosolizing (i.e. entry via lungs) can only have one purpose – the infliction of mass casualties.31 However, the oral route of entry provides another way of generating mass casualties – in this case, food-borne is far more realistic than water-borne since many toxins are water labile. In any case, in order to generate a toxin BW, advanced expertise across a number of different disciplines would be required.32 The question is whether the biomedical revolution will significantly alter the future toxin BW threat. Toxins can either be extracted from their natural reservoir or manufactured as recombinant toxins. Both methods have their drawbacks. The former, while not requiring any great knowledge of genetic engineering, does require extensive knowledge of protein purification and an abundant source from which to extract sufficient toxin. Furthermore, no alteration to the natural toxin can take place (other than post-purification stabilizing with exogenous compounds). Recombinant toxin production is without doubt the easier method. This is also the greatest threat when one considers the potential development of novel toxin BWs. Engineering novel toxins exhibiting a specific function is now a scientific reality.33 There is nothing particularly sinister about this. The very fact that toxins can activate or inhibit various receptors and intracellular proteins has made them enormously attractive tools for cell biologists. However, engineering novel toxins – or, more often, enhancing already naturally occurring ones – is a multidisciplinary process. It is clear, then, that biological-toxin production is at present a specialized discipline requiring certain levels of expertise in a number of advanced biomedical disciplines. It is, therefore, far easier to acquire the ready-made product than it is to produce it. The globalizing of biotechnology has led to a substantial increase in peaceful research into biological toxins to service the appetites of academic and commercial research, and many types of toxins can now be ordered from specialist firms for biomedical research. So how, then, might capability be enhanced? It is clear that, in the absence of a ready-made source, the key for existing toxins is to make their manufacture easier – that is, automation of the manufacturing process with in-built qualitycontrol systems and processes for stabilizing the final product. Biomedical science has also succeeded in creating toxin chimeras that can be produced in large amounts by ‘domesticated’ bacteria and then purified to industrial levels for the treatment of various diseases, including cancers and inherited disorders.34 The problem is that capability is not dependent on a single parameter but is rather Downloaded from http://sdi.sagepub.com at PENNSYLVANIA STATE UNIV on April 16, 2008 © 2002 International Peace Research Institute, Oslo. All rights reserved. Not for commercial use or unauthorized distribution.

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the product of a number of variables. Developing effective toxin BWs requires a number of separate enhancements, including easier production, greater environmental stability, enhanced targeting and enhanced lethality/incapacitating abilities. It is also possible that peaceful research will increase the BW threat by making biological toxins more attractive as ‘designer’ weapons. For instance, in an effort to develop compounds that selectively target specific organs or abnormal tissue (e.g. cancers), pH-responsive polymers that mimic the membranedisruptive properties of toxins have been developed.35 Chimeric toxins have also been created in an effort to increase initial penetration (through the lung mucosa) and targeting. Chimeric toxins are formed by connecting a protein toxin to a binding ligand, such as an antibody or growth factor.36 Furthermore, recombinant immunotoxins (toxins coupled to an antibody produced by bacterial ‘workhorses’) have been found to be far more specific than native chimeras.37 At the present time, developing and delivering targeted toxins requires specialized equipment and expertise. In the future, improved understanding of genetics and proteomics may allow ‘user friendly’ computer design of toxins and the potential for automated output. This will essentially eliminate one of the key hurdles to the development of a toxin BW – the knowledge factor. Of course, it is also important not to lose sight of the fact that this technological evolution will be of huge benefit to biomedicine. Enhancing Current Threat Assessments Ever since President Bill Clinton read The Cobra Event by Richard Preston – a fictional account of the deployment of biological weapons by terrorists – the USA has been expanding a potentially unjustified network of competing programmes intended to combat the threat of bioterrorism.38 We use the word ‘unjustified’ with reason, since in most cases the call to respond to the new threat has been based on assessments of vulnerability alone, and this has many limitations. How, then, should the threat of toxin BWs be assessed? Carl von Clausewitz’s oft-repeated adage from On War, ‘Knowledge must become capability’, is far too simplistic for the threat assessment of any form of emerging or evolving biomedical technology. Equally appropriate, but from the opposite end of the spectrum, is the mantra repeated by the ‘pure’ mechanists of science that all technology is essentially ‘value free’ until it is somehow corrupted by human misuse. There exist in the ‘fuzzy’ worlds of social science and business management various methodologies for quantifying a potential negative occurrence. These, in fact, all fundamentally boil down to the simple threat-assessment model used by military planners and intelligence analysts the world over. This model is striking in its brevity and clarity:



1. Assess the capabilities of ‘the enemy’

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2.

3.

Assess the motivation of ‘the enemy’

Compare his capabilities with my vulnerabilities If the enemy intends me harm

Figure 1. The classic threat-assessment model

Unfortunately, most of the hysteria that is driving the very profitable arena of bioterrorist research is based predominantly on a half-hearted combination of stages one and three. In fact, the worst-case scenarios are simply a combination of what is known about the ability of nation-states to create biological weapons and knowledge of how vulnerable unprotected civilian targets are to such weapons. As a result, the capabilities of non-nation-state actors or the question of whether they have any intention of launching a BW attack are left wholly unexamined. This can lead to the introduction of bias, with unjustifiable weight being given to the least plausible scenarios.39 The basic tenets of threat assessment can be encompassed by reference to heuristic questioning: • • • • •

What is the actual threat, and to what extent should it be taken as valid? If the threat is real, how does one protect against it? How can the threat of emerging biomedical technologies, such as bioinformatics, be integrated into existing defence planning? If the threat is credible, what risk-assessment and risk-management procedures need to be in place? What is the relationship between military and civilian society with reference to the threat?

The task of accurate threat assessment in this case is made doubly hard by the fact that the field of offensive use of toxin BWs is as badly understood as that of bioterrorism. Fashion has dictated that this is a topic that is little understood simply because the whole area is very new and most of the truly influential work is being carried out in a classified environment. In order to assess the layered impact of toxins on the whole question of the BW threat, one has in the first place to do two things: the first is to return to the classic method of threat assessment, and the second is to recognize from the start that the multidisciplinary nature of toxin research compounds any calculation. If today’s academic/commercial toxin R&D requires multidisciplinary expertise, so does assessment of the degree of threat posed by research in this field. Threat analysis of the future of toxin BWs is fraught with difficulties. A BW attack is a low-probability, high-consequence event, thus making historicism a poor parameter in threat analyses. Until now, attempts to create toxin BWs outside state-sanctioned R&D programmes have been hampered by the Downloaded from http://sdi.sagepub.com at PENNSYLVANIA STATE UNIV on April 16, 2008 © 2002 International Peace Research Institute, Oslo. All rights reserved. Not for commercial use or unauthorized distribution.

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generally low level of knowledge of the scientific and medical principles behind toxins.40 Neither the isolation and purification of natural toxins nor the development of recombinant or novel toxins is technically easy. Furthermore, as with all other potential BW agents (bacteria, viruses, etc.), stabilizing and delivery is still very complex. However, as we have already stated, in terms of the spectrum of complexity, toxin BWs are still probabilistically easier to produce and deploy than other types of biological agents. Furthermore, as Seth Carus has noted, terrorist groups are increasingly developing the enhanced resources and capabilities of nation-states, and thus ‘it … seems increasingly likely that some group will become capable of using biological agents to cause massive casualties’.41 Ultimately, the problem of anticipating who will carry out such an attack is almost insoluble.42 The limiting factor in hostile applications remains the need to carry out relatively complex biology and validation experimentation. It is neither peaceful biomedical research nor the raw genomic and proteomic data that constitutes the threat – rather it is the increasing ability provided by in silico design, experimentation and validation of toxins, coupled to the ever-expanding commercial availability of production kits or ready-made sources to individuals who might be interested in their hostile exploitation. Why this is important requires further expansion and clarification. Engineering novel proteins – toxin or otherwise – that exhibit predetermined folds and specific activities, using raw data fed into a PC-based system, is the ultimate goal for intelligent drugs.43 The hope is that, despite great evidence that determinism in biology may be unattainable (i.e. it is impossible to say with reasonable certainty what output will be generated by any given input or inputs), sufficient integrated, networked protein and gene data maps will allow predictive design and modelling of cellular constituents. Needless to say, this ‘Grand Biological Unified Theory’ is nothing more than a pipe dream at present, but there are indications that we are getting a lot better at designing novel toxins in silico, predicting what effects they might have and then validating these predictions using ‘traditional’ experimental methodologies.44 The risk is that this final step (i.e. actually carrying out the experiments) – which has until now been a major limiting step in toxin-BW development – might become redundant if computer-based development systems become sophisticated enough.45 All of the developments in the various fields that have been discussed will be driven by both the academic and the commercial sectors. On the whole, the academic community is concerned with specificity, ease of manufacture, and automation of production and experimentation, whereas the key problem in therapeutics (i.e. within the biopharmaceutical industry) is that of delivery to the correct site (i.e. liver, heart, tumour, etc.) at the right dosage. This latter focus is important in the present context since the technical challenge of delivery



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is one of the most significant hurdles in the way of the production of a toxin BW capable of inflicting mass casualties.46 It would be nigh impossible at this point to prognosticate the exact direction in which future toxin research will progress and what the eventual useable spin-offs will be – whether offensive or defensive. Nevertheless, if we approach the issue from the point of view of government, law enforcement or the intelligence community, there are steps that can be taken in the short to medium term. These focus around horizon-scanning and critical-mass/applicationviolation parameters. The former requires constantly reviewing developing technologies and turning the esoteric information thus obtained into usable intelligence. This process then feeds the latter parameters, enabling the development of potential signatures of offensive toxin use in a bioweapons context. The practice of ‘flagging’, as used in the last two decades by law enforcement agencies to identify and track potential offenders, has distinct applications in the threat assessment of emerging technologies like bioinformatics. Remaining within the bounds of constitutionality, one could envisage a system whereby a confluence of given indicators would trigger an alert within a given nation’s intelligence and law-enforcement community. Such indicators might be if a group or nation-state were to: • • • •

aggressively recruit or train individuals in scientific fields relevant to biological toxins; collect large sums of money for unspecified biological purposes; establish laboratory-type facilities to support software or hardware developments lacking a clearly peaceful purpose; or begin to use unusually aggressive rhetoric or speak of Armageddon-like scenarios involving the use of WMD.47

If two of more of the above were flagged in reference to one particular group, there would then be justification enough to take proactive measures – with the assistance of relevant experts. These would involve further threat assessments to convert information into intelligence – a process that would require rigorous collation (systems, design, standardizings, subject headings, cross-referencing), evaluation (reliability of source and accuracy of information) and interpretation (identification, activity, significance). In summary, threat assessments of toxin BWs, which will have to take into account evolving asymmetries in capability, including proliferation and motivation, would benefit from: • • • •

tactical warning/attack assessment (TW/AA); operational aspects of surveillance/horizon scanning (i.e. appropriately trained personnel); ‘red teams’ to test probabilities for misuse of emerging/evolving technologies; mapping and coordination of existing relevant information/intelligence; and


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application of interdisciplinary, multiprofessional groups and networks to defined threat assessments and risk stratifications.

Such are the inherent problems with controlling potentially hostile toxin research programmes and subsequent proliferation utilizing dual-use equipment that prevention of a toxin bioattack prior to deployment may well be impossible. Cohen and colleagues have convincingly argued that effort and funds have been misguided in the concentration on bioterrorist initiatives.48 What is really needed is a coherent, integrated operational plan, based on threat/risk assessments, to deal with all biological-toxin threats, be they natural or man-made.49 This will require sophisticated global surveillance, integrated (government–military–civilian) reaction/response policies and prospective logistical plans (medicines, equipment, etc.). NOTES AND REFERENCES * Dr Richard Sullivan is Head of Clinical Programmes at Cancer Research UK ([email protected]). Sebestyèn Gorka is Executive Director of the Centre for EuroAtlantic Integration and Democracy, Budapest, and a former policy analyst at the RAND Corporation ([email protected]). Both authors are founding members of the US Committee for Emerging National Security Affairs (CENSA), Washington. The authors would like to express their thanks to the referees for significant improvements to this article. 1 Swedish National Defence Research Establishment (FOA) briefing book on chemical weapons, June 2001; available at http://www.opcw.nl/chemhaz/toxins.htm. 2 Graham S. Pearson, ‘The Prohibition of Chemical and Biological Weapons’, in Malcolm R. Dando, Graham S. Pearson & Tibor Toth, eds, Verification of the Biological and Toxin Weapons Convention (Dordrecht: Kluwer Academic, 1998), pp. 1–5. 3 At the fourth review conference of the BTWC in 1996, the Final Declaration reaffirmed that Article 1 of the Convention included ‘all microbial and other biological agents or toxins, naturally or artificially created or altered, as well as their components, whatever their origin or method of production of types and in quantities that have no justification for prophylactic, protective or other peaceful purpose’. A comparable generalpurpose criterion for the CWC is embodied in the definition of chemical weapons in Article 2 as ‘toxic chemicals and their precursors, except where intended for purposes not prohibited under this Convention, as long as the types and quantities are consistent with such purposes’. 4 One the most serious limiting factors in state deployment of BWs would be the extensive problem of infecting one’s own troops; Ron Kupperman, ‘Countering High Technology Terrorism’, Scandinavian Journal of Development Alternatives and Area Studies, vol. 4, no. 3, September 1984, pp. 73–83. 5 Ricin was used in Virginia in 1980 to assassinate CIA agent Boris Korczak; also, in addition to the assassination of Bulgarian Georgi Markov, there was an unsuccessful assassination attempt against Bulgarian defector Vladimir Kostov in Paris by the Bulgarian



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Intelligence Services; Joseph D. Douglass & Neil C. Livingstone, America the Vulnerable: The Threat of Chemical and Biological Warfare (Lanham, MD: Lexington, 1987). A recent example of this is the reported use of various BW agents by Aum Shinrikyo. Although Aum Shinrikyo (now renamed as ‘Aleph’) and Aum leader Fumihiro Joyu admitted in their website that they had disseminated a ‘harmless’ strain of anthrax in 1993 from their building in Tokyo (Masaaki Sugishima, personal communication), there is no evidence to support the reports that they developed and/or attempted to deploy Q fever or tularaemia; Milton Leitenberg, ‘Aum SinriKyo’s Efforts to Produce Biological Weapons: A Case Study in the Serial Propagation of Misinformation’, Terrorism and Political Violence, vol. 11, no. 4, Winter1999, pp. 149–158. William Kucewicz, ‘Beyond “Yellow Rain”: The Threat of Soviet Genetic Engineering’, Wall Street Journal, April–May 1984, pp. 1–18. John van Courtland Moon, ‘Introduction’, in Erhard Geissler & John van Courtland Moon, eds, Biological and Toxin Weapons: Research, Development and Use from the Middle Ages to 1945, SIPRI Chemical & Biological Warfare Studies No. 18 (Oxford: Oxford University Press, 1999) pp. 5–7. Offensive and defensive research programmes into botulinum toxin were continued by both the Allies and Germany throughout the war. With regard to the USSR, it was not until 1984, some five years after the anthrax leak from Sverdlovsk, that US intelligence finally confirmed what many had suspected – there were ‘at least seven biological warfare centres in the USSR’ and these ‘have the highest security and are under the strictest military control’; Milton Leitenberg, ‘The Biological Weapons Program of the Former Soviet Union’, Biologicals, vol. 21, no. 3, September 1993, pp. 187–191. In the USA, Fort Detrick was by 1960 a major player in the BW programme. The USA also carried out vulnerability assessments by analysing dispersal through the release of non-lethal biological agents, such as Serratia marcescens and Bacillus globigii; John Mobley, ‘Biological Warfare in the Twentieth Century: Lessons from the Past, Challenges for the Future’, Military Medicine, vol. 160, no. 11, November 1995, pp. 547–553. Two human genome sequences were published at the same time. For the Celera sequence, see Science, vol. 291, no. 5507, 2001, pp. 1304–1351, and for the publicly funded sequence see Nature, vol. 409, no. 6817, February 2001, pp. 813–964. Although many toxins are prohibited under the present BTWC, Graham Pearson and colleagues consider these four toxins to have the appropriate characteristics for use as BWs; see ‘The Threat of Deliberate Disease in the 21st Century’, a 1998 report from the Henry L. Stimson Centre, available at http://www.brad.ac.uk/acad/sbtwc/other/ disease.htm. The US Army considers T-2 mycotoxins to be a greater threat than saxitoxin; see article on ‘Biological Toxins’, US Army Medical Field Manual; available at http://www.nbc-med.org/SiteContent/MedRef/OnlineRef/FieldManuals/medman/chap3.htm. Ali Khan, Stephen Morse & Scott Lillibridge, ‘Public-Health Preparedness for Biological Terrorism in the USA’, Lancet, vol. 356, no. 9236, September 2000, pp.1179–1182. There is a difference between biological lists for preparedness (i.e. defence) vis à vis prohibition/control. Legally defined lists of biological agents (including various toxins) have been created under the US Select Agent List (Section 511, Antiterrorism and Effective Death Penalty Act, Public Law 104-132, Section 511) and the Australia Group List, available at http://www.state.gov/www/global/arms/factsheets/wmd/bw/auslist.html.


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13 Streptolysin-O works by forming channels through cholesterol-rich areas. All toxins must interact with the plasma membrane in some form, either treating it as a final target (i.e. pore-forming) or in order to gain access to the cell interior; Clare Schmitt, Karen Meysich & Alison O’Brien, ‘Bacterial Toxins: Friends or Foes?’, Emerging Infectious Diseases, vol. 5, no. 2, March–April 1999, pp. 224–234. 14 Both these bacterial toxins target an essential secretory protein; Gianpietro Sciavo & Caesare Montecucco, ‘Neurotoxins Affecting Neuroexocytosis’, Toxicology Letters, vol. 80, no. 2, April 2000, pp. 717–766. 15 For the many examples of biomedical applications, see ‘Clinical Use of Botulinum Toxins’, National Institutes of Health Consensus Development Conference Statement, section 83, November 1990; available at http://text.nlm.nih.gov/nih/cdc/www/83txt.html. 16 Clostridial toxins target the multifunctional Rho family of proteins; Klaus Aktories, ‘Microbial Toxins and the Glycosylation of Rho Family GTPases’, Current Opinion on Structural Biology, vol. 10, no. 5, April 2000, pp. 528–535. 17 Abrin A and Ricin D isofroms have LD50s of 10ug/kg and 248 pg/kg, respectively (intraperitoneal route, mice). For a list of LD50s of BW-relevant toxins, see ‘Registry of Toxic Effects of Chemical Substances’, available at http://ftp.cdc.gov/niosh/rtecs.html. 18 There are a number of factors that relate to the stability and persistence of toxins, including the intrinsic biological nature of the toxin (stabile tertiary and quaternary structure), formulation (freeze-drying, specialized stabilizing fluid, liquid, etc.), delivery method and environmental parameters. Some toxins, such as botulinum, are not stable in chlorinated water, whereas ricin, T-2 mycotoxins and SEB are very stable; see Department of Defense, ‘Militarily Critical Technologies’, available at http:// www.dtic.mil/mctl/mctlp2.html. 19 Ricin has been used as a toxin case study in which details of the worldwide industry are described; see Jonathan Tucker, ‘Dilemmas of a Dual-Use Technology: Toxins in Medicine and Warfare’, Politics and the Life Sciences, vol. 13, no. 1, February 1994, pp. 51–62 20 Tetrodotoxin is similar in structure and action to saxitoxin, another marine toxin produced by blue-green algae. Both inhibit the activity of the voltage-sensitive sodium channel of the nervous system; further details available at http://fugu.hgmp.mrc.ac.uk. 21 There are a variety of specific peptide conotoxins. 22 The molecular toxicology of marine toxins and the epidemiology, diagnosis and management of paralytic shellfish (saxitoxin), tetrodotoxin, neurotoxic, diarrhoeic and amensic shellfish poisoning are covered in depth in Daniel Baden, Lara Fleming & Judy Bean, ‘Marine Toxins’, in F. A. de Wolff, ed., Intoxications of the Nervous System, Part II: Natural Toxins and Drugs, Handbook of Clinical Neurology vol. 65, no. 21 (Amsterdam: Elsevier, 1995) pp. 141–175. 23 A history of scientific research into maitotoxins is available at http://www.chbr.noaa.gov/ CoastalResearch/CTXMTXinfo.htm. 24 John Walter & Demitri Panaccione, ‘Host-Selective Toxins and Disease Specificity: Perspectives and Progress’, Annual Review of Phytopathology, vol. 31, no. 4, May 1993, pp. 275–303. The major classes of fungal toxins that are toxic to humans are cercosporin, HC-toxins, Ptr toxin, T-toxin, Victorin and Fuscicoccin; references and descriptions available at http://www.ca.uky.edu/agcollege/plantphysiology/ppa660/ppa660L27.htm.



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25 Mycotoxins can lead to infertility and enhance the pathogenicity of tuberculosis. 26 In small doses, aflotoxins are cumulative carcinogens and eventually lead to carcinoma of the liver. 27 There are at least ten different toxins produced by this snake alone. 28 The snakes that produce these toxins target a wide variety of proteins involved in blood-clotting; Kathyrn Senior, ‘Taking the Bite Out of Snake Venoms’, Lancet, vol. 353, no. 9168, June 1999, pp. 1946–1947. 29 Venom from Crotalus durissus terrificus and Bothrops jararaca have been found to be potent in vitro inhibitors in certain tumour cell lines. 30 David Franz, ‘International Biological Warfare Threat in CONUS’, Statement before the Joint Committee on Judiciary and Intelligence, US Senate, 4 March 1998, p. 5. 31 Some toxins are more toxic when inhaled (e.g. ricin, saxitoxin and T2 mycotoxins). 32 The difficulties associated with this approach effectively limit it to state-sponsored BW programmes; Seth Carus, ‘Biological Warfare Threat in Perspective’, Critical Reviews in Microbiology, vol. 24, no. 3, September 1998, pp. 149–155. 33 Novel functional toxins have been generated by transferring active sites onto new structural contexts to yield well-defined artificial proteins active against specific biological targets; Claudio Vita et al., ‘Novel Miniproteins Engineered by the Transfer of Active Sites to Small Natural Scaffolds’, Biopolymers, vol. 47, no. 1, February 1998, pp. 93–100. 34 The development of chimeric toxins has its origins in the attempt by the biomedical community to create ‘magic bullets’ that would target cancer cells; Carol Ezzell, ‘Magic Bullets Fly Again’, Scientific American, vol. 285, no. 4, October 2001, pp. 34–41. 35 These polymers can act as ‘carrier’ compounds for toxins that could not otherwise gain access to cells; Patrick Stayton, ‘Molecular Engineering of Proteins and Polymers for Targeting and Intracellular Delivery of Therapeutics’, Journal of Control Release, vol. 65, no. 1–2, March 2000, pp. 203–220. 36 For example, a fusion of the human IL-2 to the plant toxin ricin; Jonathan Cook, ‘Biologically Active IL-2 Ricin A Chain Fusion Proteins May Require Intracellular Proteolytic Cleavage to Exhibit a Cytotoxic Effect’, Bioconjugate Chemistry, vol. 4, no. 6, November 1993, pp. 440–447. 37 For instance, in the treatment of cancer either directly or through the use of aflotoxin to screen for chemicals that effectively kill this fungus, thus leading to a reduction in people exposed to aflotoxins. 38 The escalation is evident from the growth in size of the anti-WMD line item within the federal US anti-terrorism budget. In 1998, the USA spent $71.8 million on such programmes. By 2001, the budget had reached a projected $142.5 million. For full details, see ‘Federal Funding to Combat Terrorism, Including Defense Against Weapons of Mass Destruction, FY 1998–2001’; available at http://cns.miis.edu/research/cbw/ terfund.htm. 39 Corina Dennis, ‘The Bugs of War’, Nature, vol. 411 , no. 726, May 2001, pp. 232–235. 40 W. Seth Carus, ‘Unlawful Acquisition and Use of Biological Agents’, in Joshua Lederberg, ed., Biological Weapons: Limiting the Threat (Cambridge, MA: MIT Press, 1999), pp. 211–231. 41 W. Seth Carus, Bioterrorism and Biocrimes: The Illicit Use of Biological Agents in the 20th Century, rev. edn (Washington, DC: Center for Counterproliferation Research, July 1999), p. 13.


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42 The use of such weapons in the future by ‘lone misanthropes, hate groups, cults, or even minor states’ would lead humanity down a particularly undesirable route; biomedical science, the saviour and new ‘religion’ of modernity, would achieve pariah status. See Matthew Meselson, ‘Averting the Hostile Exploitation of Biotechnology’, CBW Conventions Bulletin, vol. 3, no. 48, June 2000, pp. 16–19. 43 Initiatives by biopharmaceutical firms to ‘speed up’ the transfer of new chemical entities into the clinic have been enabled by quantum leaps in the availability of raw data on structure (via X-ray crystallography, nuclear magnetic resonance [NMR], circular dichroism spectroscopy [CD], etc.) and data-handling by computational biology, with design focus through medicinal chemistry. These enabling technologies have only been with the R&D community since the mid-1990s; Roger Ulrich & Stephen Friend, ‘Toxicogenomics and Drug Discovery: Will New Technologies Help Us Produce Better Drugs?’, Nature Reviews Drug Discovery, vol. 1, no. 1, June 2002, pp. 84–88. 44 For example, PC-based software has been utilized to create an in silico chimeric, stabile, potent neurotoxin by transferring the active element of the curare-mimetic neurotoxin α to the scorpion scaffold charybdotoxin; Claudio Vita, ‘Engineering Novel Proteins by Transfer of Active Sites to Natural Scaffolds’, Current Opinion in Biotechnology, vol. 8, no. 44, August 1997, pp. 429–434. 45 One of the most compelling conclusions from Malcolm Dando’s review of the benefits and threats of developments in biotechnology and genetic engineering is the sheer diversity and complexity of the subject material and the inherent difficulties of predictive threat assessments in the area; see SIPRI Yearbook 1999: Armaments, Disarmament and International Security (Oxford: Oxford University Press, 1999), Appendix 13A, pp. 596–611. 46 Dry-powder formulations are considered easier to disperse. For live pathogens, however, this formulation is particularly sensitive to degradation. Many toxins – Staphylococcal Enterotoxin B, for example – can be very stable after freeze-drying. See ‘Observations on the Threat of Chemical and Biological Terrorism’, GAO/Y-NSAID-00-50 Testimony, US General Audit Office, October 1999. 47 The use of BWs by nation-states does not make rational sense, especially if BWs are deployed against an enemy with nuclear assets. The deterrent threat of retaliation only becomes irrelevant if one considers the non-rational, doomsday-type actor or fundamentalist/nihilistic terrorist groups; Sebestyèn Gorka, ‘2000AD: Boomtime in the Doom Market?’, Jane’s Intelligence Review, vol. 12, no. 1, January 2000, pp. 50–54 48 Hillel Cohen, Robert Gould & Victor Sidel, ‘Bioterrorism Initiatives: Public Health in Reverse?’, American Journal of Public Health, vol. 89, no. 11, November 1999, pp. 1629–1631. 49 According to the Centre for Non-Proliferation Studies, of the $2,000 million in funding for federal anti-terrorism activities (FY 2000), nearly three-quarters went on bioterrorism (see John Parachini, ‘Combating Terrorism: Assessing Threats, Risk Management, and Establishing Priorities’, available at http://cns.miis.edu/research/terror.htm). However, there has been no coherent policy guiding how the money has been spent on R&D projects; perhaps even worse, some have argued that the R&D supported is of poor scientific merit. Referring to the ‘unconventional pathogen countermeasures program’, an editorial in Science proclaimed ‘Too Radical for NIH? Try DARPA’; see Science, vol. 275, no. 5301, 1997, pp. 744–746.


Security Dialogue - CiteSeerX

Security Dialogue - CiteSeerX

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