The convergence of biology and chemistry: Implications for arms control verification

Abstract

As biological and chemical production technologies grow increasingly interrelated, the implications of this convergence for preventing the spread of biological and chemical weapons are becoming more serious. The author writes that the routine verification regime of the Chemical Weapons Convention (CWC) does not cover biologically mediated production processes or the synthesis of most natural toxins by chemical means—gaps, he says, that are likely to expand as these technologies advance. To address the implications of convergence for biological and chemical disarmament, CWC member states should enhance the treaty’s verification measures. The author suggests that a panel of experts should examine the technical feasibility and cost-effectiveness of using biotechnological methods to produce classical chemical warfare agents; that CWC parties should increase the total number of inspections of declared chemical industry facilities that can be conducted per year in a member state; and that the scope of CWC verification should be broadened to cover production by chemical or biological means of natural peptides and structurally related molecules, some of which are highly toxic. Although efforts to update the CWC verification regime will face political resistance, he writes, it would be short-sighted to ignore this problem until determined cheaters start using undeclared biotechnology plants to manufacture chemical warfare agents, or exploit the chemical synthesis of bioactive peptides to develop a new generation of biochemical warfare agents.

The growing convergence of biological and chemical production methods has important implications for efforts to prevent the proliferation of biological and chemical weapons. In recent years, it has become possible to produce organic chemicals with biotechnological processes and to synthesize biological molecules by chemical means, including bioactive peptides (short protein chains) potentially suited for use as lethal or incapacitating agents. Although the convergence of biology and chemistry has been recognized for some time, yesterday’s bench-scale demonstrations are now becoming mainstream industrial processes in the pharmaceutical and chemical industries, posing new challenges to the biological and chemical disarmament regimes.

Because the 1972 Biological and Toxin Weapons Convention (BTWC) lacks formal verification measures, the onus for preventing the development and production of toxin warfare agents—poisonous chemicals of biological origin—rests with the 1993 Chemical Weapons Convention (CWC), which includes extensive provisions for the declaration and inspection of treaty-relevant industrial facilities. At present, however, the CWC’s routine verification regime covers neither biologically mediated production processes nor the synthesis of most natural toxins by chemical means, and these gaps are likely to expand as technology advances.

To address the implications of convergence for biological and chemical disarmament, CWC member states should take steps to enhance the treaty’s verification regime. First, a panel of experts should examine the technical feasibility and cost-effectiveness of using biotechnological methods to produce classical chemical warfare agents, such as blister and nerve agents. Second, CWC member states should increase the total number of inspections of chemical industry facilities that can be carried out per year in a member state. Finally, the scope of CWC verification should be broadened to cover production by chemical or biological means of natural peptides and structurally similar molecules, some of which are highly toxic.

Biologically mediated production of chemicals

Three biologically mediated methods of chemical production are currently in use or under development: biocatalysis, metabolic engineering, and biopharming. Each method is described briefly below.

Biocatalysis

The use of enzymes to catalyze chemical reactions has become increasingly practical and affordable in recent years. Enzymes offer several advantages over traditional inorganic catalysts, such as metals and metal oxides. For one thing, enzymes are highly specific, making it possible to modify complex molecules in precise ways. Second, enzymatic catalysis yields only products with a biologically active molecular structure, rather than a mixture of active and inactive structures, thereby improving the effectiveness of synthetic drugs. Third, enzymes function optimally at body temperature and thus require less energy than inorganic catalysts. Finally, enzymes are environmentally friendly because they use renewable feedstocks and produce fewer toxic waste products.

Because of these advantages, the chemical industry is expected to make greater use of biocatalysis in coming years, both for the high-volume manufacture of biofuels and other commodity chemicals and for the low-volume production of specialty chemicals and pharmaceutical ingredients (Schmid et al., 2001). For example, companies could harness enzymes called halogenases, derived from bacteria, to synthesize molecules containing halogens: non-metallic elements such as chlorine, bromine, fluorine, and iodine. About 15 percent of medicinal drugs, such as the antidepressant fluoxetine (Prozac) and the antibiotic ciprofloxacin (Cipro), include at least one fluorine atom (Murphy, 2003).

Despite the many benefits of biocatalysis, however, it has some potential for misuse. Industrial chemist George Parshall, the former head of research and development at DuPont, warned in 2002 that enzymes might be employed for the manufacture of chemical warfare agents or their precursors (Parshall, 2002). For example, the nerve agents sarin, soman, and cyclosarin all contain fluorine and might therefore be synthesized with the aid of a bacterial enzyme called fluorinase. Although it is unlikely at present that a proliferant state or terrorist group would invest the time, effort, and money needed to employ biocatalysis for the production of standard chemical warfare agents, that situation may change as biotechnological production methods become more widely available and less expensive. Moreover, the use of biologically mediated processes could make it easier to conceal the illicit manufacture of chemical weapons.

Metabolic engineering

In recent years, scientists have inserted clusters of plant or animal genes into bacteria or yeast to coax those microbes into producing medically useful compounds. The inserted genes code for a series of enzymes that catalyze the synthesis of a natural product, particularly a substance that is difficult and costly to extract from the natural source and whose molecular structure is too complex to synthesize chemically on an industrial scale. For example, the antimalarial drug artimisinin has long been purified from the sweet wormwood plant, an annual indigenous to China and Vietnam, yet by inserting the sweet wormwood genes that code for the biosynthetic pathway of artimisinin into E. coli bacteria, researchers at the University of California, Berkeley, hope to produce the drug more cheaply by bacterial fermentation than by obtaining it from the natural plant source (Ro et al., 2006). In a similar vein, start-up biotech companies in the United States have begun engineering bacteria to synthesize organic chemicals such as adipic acid, which is used to make nylon, and acrylic acid, an ingredient in the manufacture of paints and certain polymers (Voith, 2010). Metabolic engineering is also central to efforts by biotech firms to make ethanol from cellulosic material such as wood chips and cornstalks or to create diesel fuel from genetically modified algae.

Metabolic engineering has some potential for misuse. During the 1950s, the CIA obtained a stockpile of saxitoxin, a highly lethal toxin produced by a species of marine algae, for use in suicide pills for captured spies and possibly for covert assassination—although there is no record that it was ever employed for that purpose (US Senate, 1975). Gram quantities of pure saxitoxin were extracted at great effort and expense from tons of shellfish that had been contaminated by a harmful algal bloom known as a “red tide.” With today’s technology, however, it might be possible to isolate the algal genes that code for the enzymes responsible for the biosynthesis of saxitoxin and transplant this genetic material into bacterial cells, which could then be induced to mass-produce the toxin relatively cheaply for weapons purposes.

Biopharming

A third biologically mediated process, known as “biopharming,” involves the production of protein-based pharmaceuticals in transgenic plants and animals. Foreign genes coding for these proteins are inserted into crop plants such as corn and tomatoes, after which the crops are harvested and the desired products extracted. Although biopharming provides a cost-effective method for making vaccines, microbicides, and therapeutic antibodies, a 2006 report by the U.S. National Academies warned that “transgenic plants could also be engineered to produce large quantities of bioregulatory or otherwise toxic proteins, which could either be purified from plant cells or used directly as biological agents” (Institute of Medicine and National Research Council, 2006: 182).

Chemical synthesis of biological molecules

In parallel with the use of biotechnological processes to manufacture drugs and other specialty chemicals, companies are increasingly applying chemical methods to produce a variety of biological molecules from scratch. Thanks to the advent of high-throughput DNA synthesizers, for example, it is now possible to construct genes and even entire microbial genomes by stringing together the four chemical units of DNA in any desired sequence. Within the past decade, scientists have synthesized a number of pathogenic viruses, including poliovirus, a bat virus similar to the agent that causes SARS, and a virulent strain of influenza virus that caused a global pandemic in 1918–19. In May 2010, the J. Craig Venter Institute announced the chemical synthesis of a bacterial genome consisting of more than 1 million DNA units. When transplanted into a different species of bacterium, the artificial genome took charge of the cell’s metabolism and directed the production of new proteins (Gibson et al., 2010). A major goal of the emerging field of synthetic biology is to design and build artificial microbes capable of manufacturing useful products not found in nature. For example, a biotech startup near San Francisco called LS9 is using synthetic-biology techniques to develop “designer bacteria” that can mass-produce advanced biofuels.

Another area in which chemical methods are being used to produce biological molecules involves therapeutic peptides, including the anti-HIV drug Fuzeon and the potent painkiller Prialt (Bray, 2003). According to a recent survey, pharmaceutical companies are marketing about 40 peptide-based drugs worldwide, and hundreds more are in pre-clinical development or clinical testing (Peptide Resource Page, 2010). A promising source of new drugs is the large number of natural peptide toxins produced by poisonous snakes, spiders, insects, and marine invertebrates for defense or hunting prey. In addition, the human body produces a wide array of peptide bioregulators that control temperature, blood pressure, sleep, immunity, and other vital physiological functions but can be toxic when administered at high doses or if their molecular structure is modified (Kagan, 2001, 2006).

In 1999, for example, scientists at the Swedish Defense Research Establishment exposed guinea pigs to a nervous-system peptide called Substance P in the form of an aerosol: an airborne suspension of microscopic particles that can be inhaled and absorbed in the deep region of the lungs. The Swedish researchers found that the aerosolized peptide caused acute toxic effects, leading them to warn that Substance P was “a possible future warfare agent” (Koch et al., 1999). Indeed, gram for gram, the potency of many peptide bioregulators exceeds that of classical chemical warfare agents by several orders of magnitude (Phillips and Robinson, 2007). In principle, the same methods used to identify promising drug candidates, such as the rapid screening of large compound databases, could be exploited to identify structurally modified peptides with high toxicity and physical stability as potential chemical-warfare agents (Balali-Mood et al., 2008).

Once toxic peptides have been identified, they could be produced in large quantities by chemical means. Peptide synthesis is now a thriving commercial business involving some 80 companies worldwide that produce peptides to order according to customer specifications and in amounts ranging from a few milligrams for laboratory use to hundreds of kilograms for pharmaceutical applications (Andersson et al., 2000). The anti-HIV drug Fuzeon, for example, is manufactured in quantities exceeding 3,500 kilograms per year (Glaser, 2005).

Bioactive peptides tend to have low stability in aerosol form and a short half-life in the human body, limiting their potential utility as lethal or incapacitating chemical warfare agents. Nevertheless, structural analogues of these molecules might be developed that resist rapid degradation and can enter the brain from the bloodstream. In addition, advances in nanotechnology, such as engineered nanoparticles, may facilitate the delivery of bioactive peptides as an aerosol cloud. Recently, researchers at Washington University in St. Louis, seeking to develop a targeted treatment for cancer, attached molecules of the peptide toxin mellitin—the main component of bee venom—to nanoparticles that were each large enough to ferry thousands of toxin molecules yet small enough to bind to the surface of cancer cells and kill them in a selective manner (Ericson, 2009). It is not difficult to imagine the deliberate misuse of this technology for the targeted delivery of toxic agents that harm healthy tissues.

Convergence and the chemical and biological disarmament treaties

Given the emerging dual-use risks described above, it is important to assess the extent to which the biologically mediated production of toxic chemicals and the chemical synthesis of toxic peptides are covered by the verification provisions of the CWC.

Biologically mediated production of chemicals

Most of the routine verification measures of the CWC are keyed to three lists of chemicals called Schedules I, II, and III. Schedule I consists of known chemical-warfare agents and their immediate precursors, which have few if any peaceful uses, while Schedules II and III contain toxic chemicals and their precursors that have legitimate applications in small and large quantities, respectively, but could also be employed for the production of chemical weapons. Industry facilities that manufacture dual-use chemicals (listed on Schedules II and III) in quantities above specified annual thresholds must be declared and opened to routine international inspection. The verification annex of the CWC also sets out more generic criteria for monitoring “other chemical production facilities” (OCPFs) that produce by synthesis more than 200 metric tons per year of organic chemicals not listed on the Schedules. Such facilities are included in the CWC verification regime because they could potentially be diverted for the illicit production of scheduled chemicals. In addition, a subcategory of OCPFs called “PSF plants” manufacture chemicals containing the elements phosphorus, sulfur, or fluorine, which are common constituents of nerve and blister agents. Because these plants pose a greater risk of misuse, they must be declared if they produce more than 30 metric tons of PSF chemicals per year.

Nevertheless, the OCPF portion of the verification system has several weaknesses. First, CWC member states must declare only a minimal amount of information about these facilities, making it hard for international inspectors to identify the multi-purpose chemical plants that pose the greatest risk of diversion for warfare agent production. Second, the CWC verification annex limits the total number of inspections of Schedule III facilities and OCPFs in a given member state to a maximum of 20 per year. As a result, only a small fraction of the OCPFs in countries with large chemical industries, such as China, India, and the United States, can be inspected annually. Third, uncertainty persists over whether the OCPF verification regime covers only facilities that use traditional chemical production methods or if it also includes sites that employ biologically mediated processes such as biocatalysis.

Debate over the latter issue has dragged on for several years in various forums of the CWC secretariat, the Organization for the Prohibition of Chemical Weapons (OPCW) in The Hague. In 1999 the organization’s Scientific Advisory Board (SAB) concluded that it was no longer possible to make a clear distinction between chemical and biologically mediated production and that accordingly “the emphasis should be on the product and not the process” (OPCW SAB, 1999: paragraph 2.3). In response to the SAB proposal that facilities employing biological production methods be included in the OCPF verification regime, a group of experts from CWC member states met in February 2000 to consider this recommendation. The government experts ultimately decided that because it was not cost-effective to manufacture traditional chemical-warfare agents by biotechnological means, conducting routine inspections of OCPFs that used such processes would divert the attention of the international inspectorate away from more relevant chemical production facilities. Even so, the government experts urged that the convergence issue be kept under review (OPCW, 2003). As biotechnology continues to advance, the potential use of enzymes and other biologically mediated processes for the large-scale production of scheduled chemicals—either chemical-warfare agents or their precursors—may pose a growing risk to the CWC, eventually warranting the inclusion of such facilities in the verification regime.

Chemical synthesis of toxins and bioregulators

The current CWC verification system also fails to address the chemical synthesis of biological molecules, such as DNA and peptides. Chemical genome synthesis could potentially be misused to create artificial pathogens resistant to standard medical countermeasures. Yet because such organisms would produce their harmful effects by replicating in the host rather than through direct “chemical action on life processes,” the hostile use of synthetic biology would be banned by the BTWC rather than by the CWC. Both treaties, however, prohibit the development and production of weapons based on toxic chemicals of biological origin, such as toxins, bioregulators, and structurally related molecules (Aas, 2003). Unfortunately, as British chemical weapons expert Julian Perry Robinson (2008: 2) has observed, the overlap between the CWC and the BTWC “seems simply to have given people involved in implementing one of the two treaties the opportunity to relinquish, even deny, responsibility for anything also covered by the other treaty. The area of overlap thus risks becoming a gulf into which things disappear.”

Indeed, whereas the BTWC lacks formal verification measures of any kind, the CWC verification system provides very limited coverage of toxic natural products. Schedule I, which lists known chemical warfare agents and their immediate precursors, includes only two toxins: saxitoxin and ricin. Any facility that produces more than 100 grams per year of either toxin must be declared and opened to routine on-site inspection, and transfers of small quantities must be reported. Yet because no toxins or bioregulators other than saxitoxin and ricin are listed on the CWC Schedules, the verification regime provides little routine monitoring of legitimate activities involving this class of substances. Moreover, peptide toxins are typically produced in milligram to multi-kilogram quantities, which are far too low to be captured by the annual production thresholds in the OCPF verification regime (200 metric tons for ordinary chemicals and 30 metric tons for PSF chemicals), even though the extreme potency of some bioactive peptides could potentially make them militarily significant in kilogram amounts.

Given the growing capability for the large-scale chemical synthesis of bioactive peptides, it may be necessary to update the routine verification system of the CWC to address this emerging threat to the Convention. Managing the convergence issue within the treaty framework will be a challenge, however. Prior to the Second Review Conference of the CWC in April 2008, the Scientific Advisory Board observed, “While the further development of the OCPF verification regime, in principle, seems an appropriate direction in which to proceed, the differences between the design criteria underlying the regime and the characteristics of the facilities in industry and academia that are at the forefront of the cross-over between chemistry and biology need to be recognized” (OPCW, 2008: 3).

Recommendations for addressing convergence

Once most of the declared stockpiles of chemical weapons have been destroyed by 2012, it will be necessary to refocus the primary mission of the CWC from disarmament to nonproliferation, or preventing the misuse of chemistry for hostile purposes—a task that will continue in perpetuity. Because the convergence of chemical and biological production methods could eventually contribute to the risk of misuse, CWC member states should be made aware of this problem and the need to modify the treaty’s verification system to provide a reasonable assurance of compliance and to deter deviations. Steps that the member states might take to address the convergence issue include the following:

Request that the OPCW Scientific Advisory Board convene a panel of experts—ideally with the support of the International Union of Pure and Applied Chemistry (IUPAC)—to analyze the extent to which the compounds listed on Schedules I and II of the CWC, such as blister and nerve agents and their precursors, could be produced by biotechnological means. This working group would assess the various technical issues involved and prepare a report for CWC member states that sets out its findings in a clear, objective, and transparent manner.

Negotiate a higher cap on the total number of Schedule III and OCPF inspections that may be conducted per year in a given member state. If and when biologically mediated production processes, such as biocatalysis, start to be applied for the production of scheduled chemicals, the fraction of OCPF inspections devoted to plants that employ such technologies could be increased. By invoking the technical change provisions in Article XV of the CWC, it should be possible to raise the existing cap on the annual number of Schedule III and OCPF inspections without formally amending the Convention.

Employ the technical change procedure in the CWC to add a peptide bioregulator, such as Substance P, to the list of putative chemical warfare agents and precursors on Schedule I; this addition would then serve as a placeholder for all bioactive peptides that might be employed for hostile purposes. Modifying Schedule I in this way would then make it possible to cover other bioactive peptides under the OCPF verification regime, which is based on the aggregate production of unscheduled organic chemicals rather than the manufacture of specific listed chemicals. One way to expand the OCPF regime would be to create a new quantitative sub-threshold for declaring facilities that manufacture peptides, thereby opening these plants up to routine inspection. The declaration sub-threshold for peptide production should be set high enough to exclude university laboratories and small-scale industrial facilities, but low enough to capture dedicated peptide production plants that could potentially support a state-level biochemical weapons program. A peptide production figure that meets these criteria would be on the order of 50 to 100 kilograms per year (Tucker, 2008).

Establish a liaison office in the Verification Division of the OPCW Technical Secretariat for a representative from the BTWC’s Implementation Support Unit (ISU) in Geneva. This individual would monitor the growing convergence of the CWC and the BTWC, promote greater mutual engagement between the biological and chemical disarmament communities, and help coordinate approaches to national implementation in the areas of overlap between the treaties. Although the BTWC and the CWC have distinct legal obligations and lists of member states and therefore cannot be formally merged, it would make sense to harmonize these treaties more effectively, particularly with respect to “mid-spectrum agents” such as toxins and bioregulators. Before an ISU representative can be stationed in The Hague, however, it will first be necessary to expand the responsibilities and personnel of the Unit beyond those authorized under its current mandate. (This task might be undertaken at the upcoming BTWC Review Conference in 2011.)

At present, the risks posed by the convergence of chemical and biological production methods for the viability of the CWC are more potential than immediate. Given the rapid pace of technological development, however, it would be short-sighted to ignore this problem until determined cheaters start using undeclared biotechnology plants to manufacture chemical warfare agents, or exploit the chemical synthesis of bioactive peptides to develop a new generation of biochemical incapacitating agents. Unfortunately, efforts to update the CWC verification regime to address convergence issues will likely face strong political resistance from a number of member states including China, Cuba, India, Iran, and Pakistan. These countries object to increasing the scope of industry verification beyond the current “hierarchy of risk” represented by the three Schedules of Chemicals and OCPF inspections as stipulated in the Convention. According to the critics, expanding the CWC verification regime would raise the burden of inspections and associated implementation costs, such as the need for the OPCW Technical Secretariat to recruit and train a corps of inspectors with specialized skills in biochemistry or biotechnology. Objections from member states are likely to be seconded by representatives of the chemical, pharmaceutical, and biotechnology industries.

At least for the near term, facilities engaged in the biologically mediated production of organic chemicals and the large-scale chemical synthesis of peptides will be based almost exclusively in the advanced industrialized countries, which would bear the brunt of any increase in the scope of the routine CWC inspection regime. Only when convergent production technologies diffuse globally in the coming decades would relevant facilities in the developing world also become subject to declaration and inspection. This fact should reassure the most vocal critics of the proposed expansion. Finally, it might be possible to win political support from developing countries for enhanced CWC verification measures by linking them to an increase in the amount of money that the OPCW Technical Secretariat invests in cooperative programs under Article XI for promoting the peaceful uses of chemistry.