The Body's Own Bioweapons

Abstract

The next biothreat could come from chemicals derived from the human body that can incapacitate and kill–and which skirt existing arms controls.

Bioregulators, a class of natural chemicals in the human body, control such vital functions as heart rate, respiration, temperature, sleep, mood, and the immune response. Examples of these molecules include angiotensin, which raises blood pressure; vasopres-sin, which regulates the body's water balance; Substance P, which transmits pain messages from peripheral receptors to the central nervous system; and bradykinin, which triggers inflammation in response to tissue injury. (Many bioregulators are peptides, or short protein fragments made up of fewer than 50 amino acid units.) The pharmaceutical industry is developing new drugs based on bioregulators to correct physiological imbalances caused by disease.

Despite their therapeutic promise, bioregulators have a dark side. Although essential in minute concentrations, they can be toxic when administered at high doses or when their molecular structure is modified to give them novel properties. 1 For example, a research paper published in 1999 by the Swedish Defence Research Establishment reported that inhaling an aerosol of Substance P caused acute toxicity in guinea pigs and speculated that “exposure to the substance at extremely low air concentrations may result in incapacitation in humans.” 2

Because peptide bioregulators may cause symptoms that are difficult to diagnose and for which antidotes or treatments do not exist, national security analysts worry that these compounds could provide the basis for a new generation of lethal or incapacitating agents. 3 The development of biochemical weapons based on natural body substances would broaden the scope of the bio warfare threat beyond microbial pathogens such as the anthrax bacterium and toxins such as botulinum. 4

In the past, experts discounted the risk that peptide bioregulators might be “weaponized” because such compounds are non-volatile and degrade rapidly when dispersed in the atmosphere, making them poorly suited for dissemination over large areas. But recent advances in drug delivery technology have changed this assessment. In particular, the development of systems for the delivery of insulin (a hormone made up of 51 amino acid units) as an inhalable aerosol has made it feasible to disseminate peptide bioregulators in the same manner. To prevent the misuse of these natural body chemicals for hostile purposes, scientists and national security analysts must understand the nature of the threat and develop appropriate policy responses.

Until its demise in 1991, the Soviet Union had a massive biological warfare program that, among other activities, explored the harmful potential of bioregulators. Beginning in 1978, under a top-secret project code-named “Factor,” Soviet military biologists incorporated short DNA sequences coding for the production of bioactive peptides into the genomes of bacteria and viruses. Their aim was to create genetically engineered microbes that would manufacture toxic substances and cause illness and death 5

For example, molecular biologists at the Soviet Academy of Sciences identified a natural body substance called my-elin basic protein. When present in excessive amounts, this protein triggers an allergic reaction that damages the my-elin sheaths insulating nerve fibers in the brain and spinal cord and impedes the transmission of nerve impulses. The Soviet scientists sent the gene for my-elin basic protein to the State Research Center for Applied Microbiology in Obo-lensk, where it was inserted into a bacterium called Legionella. When guinea pigs were infected with the engineered bacteria, the microbes multiplied in the host and released myelin basic protein, triggering an autoimmune reaction that caused death by paralysis in about two weeks. 6 According to Ken Alibek (aka Ka-natjan Alibekov), a former senior official in the Soviet biological warfare program, this experiment was considered a breakthrough: “For the first time, we would be capable of producing weapons based on chemical substances produced naturally by the human body. They could damage the nervous system, alter moods, trigger psychological changes, and even kill.” 7

Translating cutting-edge research on peptide bioregulators into effective and reliable calmatives or incapacitants would require overcoming a series ot technical hurdles related to manufacturing and delivery.

In other Project Factor experiments, Soviet scientists at the State Research Center for Virology and Biotechnology (known as Vector) near Novosibirsk engineered viruses by inserting genes coding for neuroactive peptides that affect brain function. Some of these experiments involved opiate-like neurotrans-mitters (substances that send messages between nerve cells) called enkephalins and endorphins, which in high doses can induce neurological and psychiatric disorders. 8 According to Sergei Popov, who worked at Vector from 1976 to 1986, neuroactive peptides are theoretically capable of altering human cognition, emotions, and behavior: “For example, you could make people more aggressive. Or you could create feelings of insomnia, where people wanted to sleep, but would never feel tired.” 9 Fortunately, the genetically engineered strains developed under Project Factor were never converted into actual biological weapons.

The Soviet Ministry of Health's Third Main Directorate also had an offensive research program, code-named “Flayta” (Flute), that involved a network of five biomedical research institutes in Moscow and the surrounding region. During the 1980s, Flute scientists developed psychotropic and neurotropic agents that caused lethal and nonlethal effects useful for KGB operations. 10 According to Alibek, the Soviet secret police was interested in employing bioregulators for covert assassination because these compounds could not be detected by pa-thologists, and the victim would appear to have died of natural causes. 11 Whether such weapons were ever used remains an open question.

Aside from the deliberate develop-ment of peptides as weapons, national security analysts are increasingly concerned about the potential misuse of research on bioregulators conducted for legitimate, peaceful purposes. Rapid scientific advances in understanding how bioregulators control vital body functions are stimulating the development of new drugs based on these natural compounds.

The neuropeptide oxytocin, for example, is known to mediate complex emotional and social behaviors, including attachment, social recognition, and aggression. In one experiment, the administration of oxytocin in humans was found to reduce anxiety and increase trust in interpersonal interactions. 12 In another study involving functional brain imaging of human volunteers, oxytocin strongly modulated the function of the amygdala, a region of the brain involved in generating fear. 13 A company called Vero Labs in Boca Raton, Florida, has even developed an oxytocin-based body spray called “Liquid Trust” that is designed to promote social bonding. 14 Although the company's claims are greatly exaggerated, some U.S. government agencies may well be experimenting with oxytocin to induce trust during interrogations.

In healthy humans, bioregulatory peptides exert their effects by attaching to receptor sites on the surface of cells. The activation of a receptor by a natural bio-regulator (or a synthetic drug that mimics its effects) triggers a cascade of molecular events inside the cell that leads to a change in its physiological activity. Conversely, a drug that selectively blocks a type of receptor inhibits the effects of the corresponding bioregulator.

In recent years, scientists have identified many families and subtypes of bioregulator receptors, making it possible to develop drugs that selectively stimulate or block a particular class of receptor. While this approach promises to yield medications with greater efficacy and fewer side effects, scientific insights into the action of bioregulators and their receptors could be misused to develop lethal or incapacitating agents that disrupt specific processes in the brain and the immune system. A 2006 report by the U.S. National Academies warned, “Burgeoning knowledge about the composition and regulation of homeostatic molecular circuits in the body's cells, tissues, and organs, and their dysregulation in disease, epitomizes the dual-use dilemma created by rapid advances in systems biology…. In this context, the concept of a ‘biothreat agent’ will expand beyond the current limited perspective of biothreats as being only ‘bugs’ (i.e., pathogenic organisms) to include an entirely new category of threats–the biological circuit disruptors.” 15

One powerful technique for identifying new peptide drug candidates, known as combinatorial biochemistry, could be used to develop novel warfare agents. This process involves the synthesis of peptides, one amino acid unit at a time, on resin beads enclosed in a mesh “tea bag.” The method allows for the parallel synthesis of many different peptides, each in its own tea bag. Moreover, by mixing the beads from different tea bags after each addition of an amino acid, researchers can generate a “library” of peptides with a diversity of amino-acid sequences. 16 A second technique called high-throughput screening then measures the physiological effects of the different peptide chains in a model biological system and identifies the most potent variants for further development. 17 This same process could identify substances that activate or block bioregulator receptors to produce lethal or incapacitating effects.

Of particular concern are drugs that affect the brain by interacting with receptor sites for peptide neurotrans-mitters or neuromodulators (chemicals released from secretory cells that act on a local region of the central nervous system to modulate the response of nerve cells to neurotransmitters). Given the vast and lucrative market for psycho-active drugs that relieve pain, depression, insomnia, and other mental ailments, pharmaceutical companies are intensively researching the functions of peptide neurotransmitters and neuromodulators in the brain. Exploiting this knowledge, bioregulator-based weapons that affect the brain could be designed to render subjects rapidly unconscious, to impair mental functioning, or to affect emotions or cognition.

A joint study published in October 2000 by researchers at the Applied Research Laboratory and the College of Medicine at Pennsylvania State University identified two bioregulatory peptides that could serve as the basis of “calmative” agents for law-enforcement and counterterrorism purposes. (The Applied Research Laboratory, a university-affiliated research center for the U.S. Navy, includes an Institute for Non-Lethal Defense Technologies.) The first bioregulator discussed in the Penn State report is corticotropin-releasing factor (CRF), a peptide made up of 41 amino acids that triggers the release of stress-related hormones. Concentrated in the hypothalamus of the brain, CRF binds to two classes of receptors that are closely linked to feelings of anxiety and stress. In principle, drugs that block CRF receptors in the brain could induce a tranquil behavioral state. 18

The second bioregulatory peptide discussed in the Penn State report is cholecystokinin (CCK). Although this substance was originally isolated as a 33-amino acid chain, it is present in the body in several biologically active forms. There are two classes of CCK receptors: CCK-A receptors are concentrated in the gastrointestinal tract and CCK-B receptors in the central nervous system. Drugs that stimulate CCK-B receptors trigger panic attacks, disruption of memory, and increased sensitivity to pain; drugs that block these receptors induce a tranquil state and could therefore serve as potential calmative agents. 19

Despite these discoveries, translating cutting-edge research on peptide bioregulators into effective and reliable calmatives or incapacitants would require overcoming a series of technical hurdles related to manufacturing and delivery. Producing peptides by chemical synthesis is considerably easier than it once was, and speciality chemical companies are now capable of manufacturing peptides in quantities up to hundreds of kilograms. For example, the U.S. Food and Drug Administration has licensed a synthetic conotoxin made up of 25 amino acids for the treatment of severe chronic pain. 20 Even so, the large-scale use of peptide incapacitants by police or military forces would probably require stockpiling such agents in multi-ton quantities, greatly in excess of current manufacturing capacities.

Moreover, much as a bullet is harmless without a cartridge, gun powder, and a rifle, a bioregulatory peptide could not serve as a weapon unless it was formulated and integrated with a container and an efficient delivery system. Although the limited stability and persistence of natural peptides make them poorly suited for aerosol dissemination over wide areas, recent advances in drug-delivery technologies could remove some of these technical obstacles. Advanced processing methods such as spray-drying can convert a drug in liquid form into a fine powder that is optimized for aerosolization. 21 In addition, the pharmaceutical companies Pfizer and Nektar Therapeutics developed a delivery system to dispense an aerosol of dry powdered insulin deep into the lungs, saving diabetic patients frequent needle injections. 22 Pfizer decided in October 2007 to withdraw this product from the market because of its low rate of adoption, but the feasibility of pulmonary drug delivery is now well established.

To enhance the stability of peptide bioregulators during aerosol delivery, it may be possible to coat the particles with a protective layer of a biodegradable organic material in a process called micro-encapsulation. Microcapsules could remain suspended in the atmosphere for hours and release their contents after being inhaled into the lungs. 23 Advances in nanotechnology, which involves engineering at the molecular scale, may also permit the design and production of microscopic particles that ferry peptide drugs through the bloodstream and deliver them to specific tissues. 24

Another factor constraining the delivery of neuroactive peptides is the “blood-brain barrier,” a specialized layer of cells surrounding blood vessels that restricts the ability of drugs to enter the spinal cord and brain. Most natural peptides cannot cross this barrier, but researchers have developed synthetic analogues that can. 25 These and other advances in drug-delivery technology have begun to remove the traditional obstacles to the weaponization of peptide bioregulators.

The expanding scientific and com-mercial interest in bioregulators has important implications for the global treaties that ban biological and chemical arms: the 1972 Biological and Toxin Weapons Convention (BWC) and the 1993 Chemical Weapons Convention (CWC). An important characteristic of the BWC is the comprehensive nature of its prohibitions. Rather than focusing on a specific list of biowarfare agents, the treaty bans the development, production, acquisition, and stockpiling of “micro-bial or other biological agents, or toxins whatever their origin or method of production, of types and in quantities that have no justification for prophylactic, protective or other peaceful purposes.” This broad formulation, known as the General Purpose Criterion, is designed to cover all microbial pathogens and toxins acquired or developed for hostile purposes, including those that might be discovered in the future. Because the BWC was negotiated at the height of the Cold War, however, it contains no provisions for on-site inspections of vaccine plants and other dual-use biological production facilities. Efforts over the intervening years to develop verification measures for the treaty have failed.

The status ot incapacitating agents under the Chemical Weapons Convention is unfortunately ambiguous, creating a legal gray area that states could exploit to create bioregulator-based chemical weapons designed to interfere with brain function.

Like the BWC, the prohibitions of the CWC are based on a General Purpose Criterion that bans the development, production, stockpiling, transfer, and use of toxic chemicals and their intermediates (“precursors”) except for non-prohibited purposes, provided that the types and quantities are consistent with such purposes. The treaty also defines a chemical weapon broadly as “any chemical which through its chemical action on life processes can cause death, temporary incapacitation or permanent harm to humans or animals.” 26

Unlike the BWC, the CWC has extensive verification measures that account for the bulk of its 46 pages and 126 pages of annexes. The Organization for the Prohibition of Chemical Weapons (OPCW), the treaty's governing body, conducts on-site inspections of chemical industry plants in member countries. Although the prohibitions of the CWC are comprehensive in scope, the routine verification activities carried out by the OPCW cover only part of the universe of toxic chemicals and precursors potentially suited for weaponization. The verified chemicals are listed on three schedules in an annex to the treaty that, together with quantitative production thresholds, determine which chemical industry facilities must be declared and opened to routine inspection.

The types of agents covered by the BWC and the CWC overlap in the middle of the “biochemical threat spectrum,” which extends from classical chemical warfare agents (e.g., mustard gas, sarin) and toxic industrial chemicals (e.g., chlorine, phosgene), through natural toxins and bioregulators, to classical microbial pathogens (e.g., anthrax bacteria, smallpox virus) and genetically modified pathogens. Whereas the CWC uniquely covers synthetic chemical agents and the BWC living microbial pathogens, both treaties capture the so-called “mid-spectrum agents”–toxins, bioregulators, and their analogues. Given the increasing crossover between the chemical and life sciences, the two regimes are likely to converge even further. 27

The General Purpose Criterion in the BWC and the CWC obligates member states to ensure that all bioregulators and toxins are utilized only for non-prohibited purposes. In addition, the CWC includes two toxins–the red-tide poison saxitoxin and the plant toxin ricin–on the lists of chemicals to be monitored. Facilities that produce these toxins for peaceful purposes are subject to the treaty's routine verification measures. In practice, though, verification of mid-spectrum agents under the CWC is spotty. Prior to the April 2003 Review Conference of the CWC, the OPCW Scientific Advisory Board proposed that the organization adopt special techniques for analyzing samples containing saxitoxin and ricin, but member states did not adopt this recommendation. 28 In addition, no bioregulators are currently subject to routine verification measures under the CWC.

The prospect that certain peptide bioregulators or their synthetic analogues could be developed into a new generation of powerful incapacitating agents is troubling from an arms-control perspective. Since the early 1960s, the United States, Russia, and other countries have researched “knockout drugs,” which aim to render a person temporarily unconscious. The Russian security service employed this type of agent during a hostage crisis in October 2002 at the Dubrovka Theater in Moscow. To end a three-day standoff with Chechen rebels who had taken hundreds of theatergoers captive, Russian commandos pumped a powerful incapacitating agent into the theater through the air-conditioning system. The mysterious agent, reportedly related to the opiate anesthetic fenta-nyl, knocked out the rebels holding the hostages and enabled the security forces to storm the theater and shoot the unconscious Chechens at point-blank range. Not only did the incapacitant facilitate the extrajudicial execution of the hostage-takers, but 129 of the hostages died from the toxic effects of the drug. Because the Russian security service refused to disclose the composition of the agent, antidotes could not be administered in time to save many lives.

The Dubrovka Theater incident exposed the notion of a nonlethal knockout drug as a myth. Drugs such as fentanyl have a wide range of effects depending on their concentration and the age and health of the exposed individuals. Children, the elderly, and the infirm are more susceptible to fentanyl than healthy adults, making it impossible during a tactical police operation to deliver a dose that can knock out terrorists or criminals yet does not cause serious harm or death to innocent bystanders or hostages. Moreover, the effects of fentanyl are far from instantaneous; the drug can take up to 20 minutes to induce unconsciousness.

The status of incapacitating agents under the CWC is unfortunately ambiguous, creating a legal gray area that states could exploit to create bioregula-tor-based chemical weapons designed to interfere with brain function. Although the treaty bans the development, production, and use of toxic chemicals for warfare purposes, it permits their use for “law enforcement including domestic riot control.” This provision allows member states to employ lethal injection for capital punishment and tear gases to quell domestic rioting, but it also creates some potential loopholes.

Whereas the CWC defines “riot-control agents” as chemicals that induce temporary irritation of the eyes and skin that diminishes rapidly when exposure ends, that definition does not capture powerful incapacitating drugs that act on the brain to induce a persistent state of sedation or unconsciousness. The CWC also does not specify whether the term “law enforcement” applies beyond national borders to cover overseas counterterrorism and peacekeeping operations. Taking advantage of these ambiguities, the U.S. Defense Department has sought to circumvent possible treaty restrictions on the development of nonlethal incapacitants by subcontracting the research and development of these types of weapons to federal law-enforcement agencies such as the National Institute of Justice. 29

Arms control experts worry that if a broad interpretation of the law-enforcement exemption in the CWC becomes accepted state practice, it would create pressures to develop novel incapacitating agents and specialized munitions to deliver them, eroding the basic prohibitions in the treaty. 30 Julian Perry Robinson of the University of Sussex in England warns that the “creeping legitimization” of incapacitants could lead to the development of a new generation of psychochemical weapons. “In the ability of [chemical and biological warfare] agents to target themselves on particular life processes, there is … growing scope to ‘tailor’ the nature or severity of agent effects to a particular combat objective,” Robinson writes. “In that such tailoring could also open the way to weapons suited to hugely malign purpose, an effective governance regime is essential.” 31

Alan Pearson of the Center for Arms Control and Non-Proliferation in Washington, D.C., also notes that powerful incapacitants developed and stockpiled for law-enforcement purposes might be diverted to the battlefield on grounds of “military necessity.” 32 Indeed, prior to the March 2003 invasion of Iraq, the Bush administration seriously considered the combat use of riot-control agents in densely populated urban areas. 33 Once novel incapacitants have been developed, there is no way to ensure that they will remain strictly in the hands of “responsible” countries.

Given the concerns over inca-pacitating agents, CWC member states should set limits on the types and quantities (if any) that may be employed for law-enforcement purposes, including domestic or foreign counterterrorism operations, along with rules of engagement for their use. Treaty members should also develop ways to monitor incapacitating agents. At present, these chemicals fall through the cracks in the CWC verification regime: They are not listed on the treaty's schedules and hence are not subject to routine declaration or inspection, nor do they meet the definition of riot-control agents, which must be declared. Because anesthetic drugs such as fentanyl are widely used in hospitals, requiring the verification of all facilities that possess such agents would be impractical. A more modest but still useful step would be for member states to declare any stocks of incapacitating agents and specialized delivery systems that have been developed and stockpiled for law-enforcement purposes.

Although nonlethal incapacitants have important implications for the future of the CWC, the issue is politically contentious and is likely to be excluded from the agenda of the second CWC Review Conference, scheduled for April 2008. To help provide a basis for future consensus, however, CWC member states should establish an advisory panel to explore the full range of scientific, medical, defense, counterterrorism, and legal issues related to nonlethal incapacitants and provide decision makers with a menu of policy options for regulating them.

Incapacitating drugs based on peptide bioregulators are at an early stage of development, so there is still time to develop reasonable policy solutions to the challenges posed by this class of chemicals. According to Lynn Klotz, a biotech consultant in Boston, acquiring various types of bioregulator-based incapacitants would entail overcoming distinct technical hurdles, resulting in different timelines. For knockout drugs, researchers do not know if peptide bioregula-tors would act more quickly and safely than synthetic opiates such as fentanyl. Klotz estimates that identifying suitable agents and stabilizing them for delivery would probably take about a decade. Developing bioregulator-based drugs that impair the mental functioning of a group of exposed individuals without inducing unconsciousness would be an easier task, but the main challenge here is aerosol delivery. Again, Klotz thinks that a state might need about 10 years to acquire an operational weapon.

Finally, developing bioregulator-based agents that alter the emotional state or cognition of a group in a predictable manner is likely to be quite difficult, as psychological processes involve the interaction of multiple neuroactive pep-tides and receptors in ways that are still poorly understood. Klotz estimates that such “mind-control agents” may be as much as 20 years off, although for captives under interrogation some altering of mental states is probably possible now. Other analysts believe that Klotz's 20-year estimate is too long. In any event, the OPCW's Scientific Advisory Board and interested countries should carefully monitor research and development on bioregulator-based drugs and delivery technologies, continually assess their dual-use potential, and begin to consider formal control mechanisms.

Because the BWC remains a weak instrument that lacks effective verification measures, the only alternative is to address the bioregulator issue within the CWC framework. Under the General Purpose Criterion, the basic prohibitions of the chemical treaty cover all bioregulators acquired or used for hostile purposes, yet such agents are excluded from the routine verification regime. Amending the CWC's lists of verified chemicals to include bioregulators or analogues of particular concern would not be practical, however. Not only is the number of bioactive pep-tides being synthesized and screened too large, but the amounts produced are too low to trigger the treaty's industry verification system. Moreover, adding certain bioregulators or their analogues to the list of putative chemical warfare agents on Schedule 1 would strictly limit the amounts that could be produced for peaceful purposes. Some countries also worry that amending the CWC schedules to include bioregulators might inadvertently call attention to their potential for misuse.

Another option would be to modify the provisions in the CWC Verification Annex that cover “other chemical production facilities,” which produce by synthesis more than 200 metric tons per year of organic chemicals not listed by name in the treaty. A subcatego-ry of these facilities covers plants that manufacture an unlisted organic chemical containing phosphorus, sulfur, or fluorine–elements that are common constituents of chemical warfare agents. Because such plants pose a higher risk of misuse for prohibited purposes, they must declare if they produce 30 metric tons or more of these chemicals per year. Conceivably, it might be possible to create another quantitative sub-threshold for declaring “other chemical production facilities” that manufacture peptides. To be acceptable politically, this subthreshold would have to be set high enough that it excludes university and small-scale industrial research facilities, but low enough that it captures commercial peptide production plants that could support a state-level biochemical weapons program. (The CWC was not designed to deal with the much smaller quantities that terrorists might manufacture.) A declaration subthreshold for peptide production facilities that meets these criteria would be on the order of 50 to 100 kilograms per year.

Introducing this measure would require making a technical amendment to the CWC Verification Annex, which would be considerably easier than amending the treaty itself. Still, the political hurdles are formidable. Despite the fact that the CWC must adapt to developments in science and technology if it is to remain effective and credible over the long term, many member states have preferred to limit the scope and burdens of treaty verification. The large majority of member states are also reluctant to confront Washington and Moscow by openly debating the status of nonlethal incapacitants. Yet another obstacle to monitoring bioactive peptides under the CWC is the resistance of the pharmaceutical industry to new reporting and inspection measures that might disclose valuable trade secrets. But as long as the proposed monitoring regime is reasonable and does not hamper research and development on bioregulator-based drugs, there is a chance of persuading the major pharmaceutical companies to play a constructive role.

Given the political challenges facing international efforts to incorporate peptide bioregulators into the CWC verification regime, the life sciences community should take independent steps to prevent the misuse of these natural body chemicals for hostile purposes. Neuro-biologists, pharmacologists, and physiologists in both academia and industry should raise awareness about the dual-use dilemmas associated with bioregulator research and emphasize the professional responsibility of scientists to prevent harmful applications.

Possible policy options include the development of educational modules on bioethics and biosecurity for bench scientists and graduate students, the adoption of professional codes of conduct, and the creation of mechanisms for the security review of dual-use research projects as a condition of federal government funding. 34 These and other measures will be needed to ensure that the future development of bioregulator-based drugs enhances human welfare and security rather than threatening it.

Our coverage continues online. Visit the www.thebulletin.org for an extended discussion of the growing range of biothreats.

Supplementary Material

Fact Sheet 4: What is a Chemical Weapon?

Supplementary Material

Note by the Director-General: Report of the Scientific Advisory Board on Developments in Science and Technology

Supplementary Material

Convention on the Prohibition of the Development, Production, and Stockpiling of Bacteriological (Biological) and Toxin Weapons and on Their Destruction

Supplementary Material

Convention on the Prohibition of the Development, Production, Stockpiling, and Use of Chemical Weapons and on Their Destruction