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Biomedicine

Putting Teeth in the Biological Weapons Ban

Pound for pound, microbes such as anthrax rival nuclear weapons in their ability to inflict mass casualties. But the enforcing the existing treaty banning biological weapons must not compromise the biotech industry’s valuable trade secrets.

It took 20 years, but in April a treaty finally went into effect banning chemical weapons. While the Chemical Weapons Convention is an important step toward a safer world, it may have the undesired effect of encouraging some countries to redouble their efforts to acquire biological weapons-disease-causing microbes and natural poisons such as anthrax, pneumonic plague, and botulinum toxin. Biological weapons are not only more potent than chemical weapons but they are easier to produce in small, clandestine facilities.

A biological attack could create an almost unimaginable catastrophe. According to an estimate by the U.S. Congress’s former Office of Technology Assessment, 100 kilograms of anthrax, released from a low-flying aircraft over a large city on a clear, calm night, could kill 1-3 million people. This figure is comparable to the casualties from a one-megaton hydrogen bomb. When disseminated as an aerosol, anthrax spores (analogous to microscopic seeds) are inhaled deep into the victim’s lungs and travel to the lymph nodes, where they germinate and multiply. The bacteria then secrete potent toxins, giving rise in about three days to a devastating illness. For the victims to have any chance at all of surviving, antibiotics must be administered intravenously before the onset of acute symptoms.

Because biological weapons are so potent yet much cheaper and easier to produce than nuclear weapons, they have been called “the poor man’s atomic bomb.” In addition to their potential use as strategic weapons of mass destruction, biological agents are well-suited for covert operations such as sabotage, terrorism, counter-insurgency warfare, and assassinations.

The threat of biological warfare is not just an academic concern. In October, the United Nations Special Commission (UNSCOM) monitoring the elimination of Iraq’s weapons of mass destruction concluded that Iraq was still trying to conceal the full scale and scope of its biological weapons program. Iraq acknowledged in 1995 that prior to the Gulf War, it had produced large quantities of anthrax spores, botulinum toxin, and a fungal poison called aflatoxin, filled them into at least 166 aerial bombs and Scud missile warheads, and stockpiled them ready for use. Although Iraq claimed to have destroyed its biological arsenal after the war, U.N. inspectors suspect that Iraq may still be hiding a cache of anthrax spores and germ filled warheads.
In November, Iraq barred U.S. experts from participating in UNSCOM weapons inspection teams, apparently because the Americans were hot on the trail of banned weapons activities. While the on-site inspections were on hold, the Iraqis moved equipment and tampered with surveillance cameras at ostensibly civilian facilities, such as vaccine plants, that could potentially be used for producing biological warfare agents as well. In a letter to the U.N. Security Council, UNSCOM Executive Chairman Richard Butler warned that without effective monitoring, the Iraqis could easily adapt laboratory or industrial equipment in “a matter of hours” to produce stocks of biological warfare agents.

Iraq is only the best-known example of several countries-among them China, Egypt, Iran, Iraq, Libya, North Korea, Sudan, Syria, and Taiwan-known or suspected to be pursuing a biological warfare capability. The U.S. government also believes that rogue elements within the Russian military may be continuing Soviet programs to develop biological weapons, despite President Boris Yeltsin’s 1992 order that such activities cease.

Particularly alarming is the possibility that domestic or international terrorist groups could acquire biological weapons and use them against civilian targets. The Japanese cult Aum Shinrikyo, which in 1995 carried out a deadly attack with a chemical nerve agent on the Tokyo subway, was found to have an advanced microbiological facility to produce anthrax and botulinum toxin. In 1994, cult members repeatedly released anthrax spores from the roof of a high-rise building in Tokyo in an attempt to inflict mass casualties. Fortunately, technical problems with the delivery system rendered these attacks ineffective.

In principle, production of biological weapons is already banned by the Biological Weapons Convention (BWC), a treaty that has been in force since 1975. But the BWC was born with a crippling defect: it lacks a formal mechanism for investigating alleged violations, and thus has come to be regarded as little more than a gentleman’s agreement. At the time the treaty was negotiated in the early 1970s, verification procedures were considered unnecessary because biological weapons were believed to have little military value. Shortly after the BWC took effect, however, the advent of recombinant-DNA technology raised the specter of engineering new pathogens that might be more controllable, lethal, or persistent, leading some defense analysts to reassess their utility as warfare agents.

The coming year will provide an opportunity for progress toward crafting an inspection regime to strengthen the BWC. A group of member-countries, known as the Ad Hoc Group, will meet in Geneva for a few weeks in January and then for three more negotiating sessions later in the year. Their goal: to develop monitoring mechanisms to check that member-countries are obeying the treaty’s prohibitions. This legally binding “compliance protocol” will specify how international inspectors from a future BWC monitoring organization will be allowed to enter and examine facilities suspected-or merely capable-of producing biological warfare agents.

Possible elements of a compliance protocol include:

requiring countries to declare the existence of all relevant biological facilities.
n routine on-site visits to check the accuracy of such declarations.occasional “challenge” inspections to pursue suspected treaty violations at declared or undeclared facilities.field investigations to pursue allegations of biological-weapons use and suspicious outbreaks of disease.

Whatever monitoring measures are agreed to will be equally binding in all participating states. Operating under a kind of “golden rule” for treaty negotiations, members of the Ad Hoc Group must be prepared to accept the same types of intrusive monitoring they wish to apply to others. Each nation must therefore find the right balance between a regime that is intrusive enough to ensure that other countries are following the rules and one that allows them to safeguard sensitive industrial and national-security information. U.S. pharmaceutical and biotechnology companies, for instance, have expressed concern that intrusive inspections could open the door to industrial espionage. Companies routinely invest millions of dollars to develop and test new medications, production microorganisms, and manufacturing processes. Any negotiated protocol must therefore specify compliance measures that safeguard proprietary information.

While most of the countries in the Ad Hoc Group agree that the compliance protocol should provide for short-notice inspections of suspect facilities, they have been unable to reach consensus on a mechanism for triggering them. Last summer, however, the group took an important step forward by deciding to prepare a draft treaty-a “rolling text,” in diplomatic parlance-in which non-agreed language is set off in brackets. Right now, the draft is still full of brackets.

Contending with Ambiguity

The negotiators have their work cut out for them. The equipment and facilities used to cultivate biological-warfare agents are essentially the same as those used for the commercial production of vaccines, antibiotics, vitamins, biopesticides, feed supplements-even beer and yogurt. The spread of these “dual-capable” technologies for industrial microbiology has given rise to a burgeoning global potential for biological warfare, since countries can easily cloak their acquisition of illicit agents under the guise of legitimate research and production. Moreover, it takes only an extremely small quantity of a microbial pathogen-on the order of a few kilograms-to produce a militarily effective weapon. A deadly arsenal could therefore be made over a period of weeks, eliminating the need for long-term stockpiling.

Cultivation of disease-causing microbes cannot be banned outright because the same organisms that can kill thousands of people also have legitimate medical and industrial uses. Pharmaceutical companies, in particular, routinely grow large quantities of dangerous pathogens for the production of vaccines. Similarly, potent toxins such as ricin and botulinum play an increasingly important role in the treatment of cancer and neurological diseases.

Recognizing these peaceful applications, the BWC specifically prohibits the development and production of biological and toxin agents only “in types and quantities that have no justification for prophylactic, protective, or other peaceful purposes.” As a practical matter, however, it is difficult to distinguish between offensive activities and benign ones. Merely looking at a fermentation tank reveals little about its contents. Only the analysis of an actual sample can tell which microbes are present, and that will require on-site inspections of dual-capable facilities such as vaccine plants. Inspectors of a suspicious facility might take samples from various steps in the production process, ranging from seed cultures to finished products. Samples might also be swabbed from the surface of production equipment, benches, walls, or floors, or collected from soil, water, air, plants, and animals outside the buildings. These samples would then be analyzed, using some combination of techniques now common in the biotechnology industry and medical diagnostics.

Three sophisticated analytical methods are routinely employed to identify disease-causing bacteria and viruses. In classical bioassay, scientists cultivate a sample to grow live microorganisms; these microbes can then be identified using a variety of chemical or physiological tests. Immunoassay techniques employ specific antibodies to detect unique molecular markers on the surface of target microorganisms, as well as protein toxins. Genetic analysis involves the use of “gene probes”-short strands of synthetic DNA that bind to complementary DNA sequences unique to each microbial species.

Gene probes are often employed in conjunction with a powerful technique called the polymerase chain reaction (PCR), which multiplies a given DNA sequence more than a million-fold. With the aid of PCR, scientists can identify a species of bacteria even if only a few dozen cells are present in the sample-avoiding the need to culture them into large colonies over a period of days or weeks.

In some cases, sampling and analysis can yield compelling evidence of illicit activities. When Japanese police raided the Aum Shinrikyo cult’s headquarters near Mount Fuji, they found an advanced microbiology lab producing anthrax bacteria and botulinum toxin, apparently intended for terror attacks.

Generally, however, the results of sampling and analysis are less clear. Analytical techniques occasionally produce “false positives” by appearing to recognize a biological-warfare agent that isn’t actually present. This problem may arise when the target DNA sequence or molecular marker is present in both a pathogenic agent and a harmless microorganism. To avoid false positives, inspectors should confirm a positive result obtained by one analytical technique with another method based on different scientific principles.

Samples may also be contaminated with pathogenic microbes naturally present in the environment. Anthrax spores, for example, are often found in sheep and cattle grazing areas in concentrations of 100 to 500 spores per 100 grams of soil. These levels, though well below the 10,000 or so spores that must be inhaled to cause infection, are easily detectable with PCR. The pharmaceutical industry therefore worries that anthrax spores naturally present in the environment might be tracked into a vaccine plant on the bottom of workers’ shoes and detected by international inspectors-raising suspicion of a BWC violation where none is warranted and damaging a firm’s hard-won reputation. “The release of erroneous information implying serious wrongdoing could cause irreparable harm to a company’s relationship with its shareholders and the general public,” observes William Muth, a scientist at Lilly Research Laboratories in Indianapolis.

Thus in the absence of a “smoking gun,” such as a rack of bombs or warheads filled with biological agents, sampling and analysis would not provide unequivocal proof of a treaty violation. Detecting anthrax would not necessarily be incriminating, for example, if the facility in question were culturing the agent for a legitimate purpose, such as the production of a protective vaccine, or if anthrax were endemic to the surrounding region. Moreover, highly sensitive detection technologies such as PCR could find minute traces of anthrax DNA, while revealing little about the total amount of agent produced at the site.

On the other side of the coin, since it is not possible to sample everywhere, inspectors may fail to detect actual violations of the BWC. Thus the inability to find an illicit biological-warfare agent at a suspected facility does not necessarily mean that the plant is treaty-compliant. A covert proliferator might exploit a series of negative findings to claim a clean bill of health. Because of the possibilility of false positives or false negatives, evidence of BWC violations obtained by sampling and analysis must be interpreted in the light of other types of information.

Protecting Trade Secrets

The pharmaceutical industry worries that sampling and analysis used during on-site inspections could jeopardize industrial trade secrets. The chemical industry initially had similar reservations about the intrusive inspections allowed by the Chemical Weapons Convention. For example, inspection of a chemical plant might reveal a proprietary manufacturing process that provides a small but significant competitive edge, such as lowering production costs of a commodity chemical by a few cents per ton. In the pharmaceutical and biotech fields, however, the financial stakes are much higher. Because drug development is so research-intensive, it costs a large pharmaceutical house between $350 million and $500 million to bring a new product to market. According to the Pharmaceutical Research and Manufacturers of America, an industry trade association based in Washington, U.S. pharmaceutical manufacturers spend 19.4 percent of sales on R&D, compared to an average across all industries of 3.8 percent. U.S. drug companies also lead the world in innovation, accounting for 36 percent of global pharmaceutical research and development.

Biotechnology-based medicines represent a major growth sector for the U.S. pharmaceutical industry. In 1995, U.S. firms and organizations were responsible for about 80 percent of patents for genetically engineered health-care and pharmaceutical products issued by the U.S. Patent Office. From 1989 to 1996, the number of biopharmaceuticals being developed by U.S. companies to treat diseases ranging from the common cold to cancer soared from 80 to 284. Over the same period, the number of U.S. companies developing new-generation biotechnology drugs more than doubled, from 45 to 113.

Biotech companies fear that foreign inspectors visiting their plants could gain insight into their production techniques or even obtain a covert sample of a genetically engineered microorganism, whose proprietary DNA sequences could then be determined. Such information can be worth vast sums. For example, the genetically engineered bacterium that produces human insulin is valued at more than $1 billion, according to Lilly’s Muth. With such huge investments at stake, the U.S. pharmaceutical industry is determined to protect its confidential proprietary information.

Most pharmaceutical industry representatives endorse the concept of “managed access,” an approach developed for on-site inspections under the Chemical Weapons Convention. In this procedure, the inspection team and the host country negotiate the amount of access to be provided to sensitive areas of the inspected site. For example, facility managers might turn off computers, lock up documents, place cloth shrouds over items of production equipment considered proprietary, and specify where and when samples may be taken. In return for such limits on access, the inspected party must make “every reasonable effort” to provide alternative means of addressing the inspectors’ compliance concerns. For example, the inspectors might ask the facility representative to lift the shroud covering a piece of equipment high enough to confirm that illegal materials are not hidden underneath, or to review the plant’s production records. Failure to cooperate with such requests might lead the inspectors to suspect the facility of concealing illicit activities.

Some arms-control analysts doubt that managed access will be effective in catching BWC violators because it assumes a large degree of good faith and cooperation on the part of the inspected party. “Managed-access negotiations could create delays that, unless overcome by technology or diplomacy, might allow proliferators to dispose of incriminating evidence,” contends Michael Moodie, president of the Chemical and Biological Arms Control Institute in Alexandria, Va. For example, a violator might use the managed-access negotiation as a pretext to stall the inspection long enough to eliminate most if not all traces of illicit biological agent production. Auditing of production records, critics say, would not resolve compliance concerns because such records can be falsified.

Critics of managed access have suggested alternatives that would protect corporate proprietary information while also increasing the likelihood of detecting illicit production. The inspected facility might, for example, provide escorts for the inspectors to keep them from touching equipment and taking covert samples. In addition, inspectors could be required to remove their street clothes and don disposable coveralls, booties, head coverings, and surgical masks, all of which would be destroyed after use. The inspectors would also shower after each inspection to make sure they do not remove proprietary microorganisms on their skin. Finally, the inspected facility would have the right to demand the removal of any inspector caught taking unauthorized samples.

As a further means of safeguarding proprietary production microorganisms, the Federation of American Scientists Working Group on Biological and Toxin Weapons Verification has proposed that personnel at an inspected facility could inactivate sampled microbes by heating them, and then partially digest the microbial genes with a special “restriction enzyme” to disrupt any confidential DNA sequences. Only then would the inspectors be allowed to verify the identity of the microbe or to screen for a list of biological-warfare agents with gene probes and immunoassays. In principle, the restriction enzyme would destroy proprietary information but leave enough characteristic DNA sequences to verify the identity of an illicit agent. This approach will need to be validated, however, both in the laboratory and in the field.

A number of government and commercial organizations are developing chip-based sensors containing an array of gene probes for detecting microbial pathogens and toxins of biological-warfare concern. Such devices might eventually be cheap enough to discard after use, like a disposable pregnancy-test kit. This approach would reassure the pharmaceutical industry, which fears that reusable analytical instruments accompanying an inspection team could, deliberately or inadvertently, remove samples containing proprietary microorganisms.

In crafting a set of on-site measures for monitoring BWC compliance, the Ad Hoc Group will need to balance costs and benefits. While technical and political constraints may circumscribe the use of sampling and analysis during on-site inspections, the mere possibility of sampling could deter potential violators by making illicit production more risky and expensive and by necessitating aggressive cleanup measures that would themselves arouse suspicion. At the same time, devising approaches to sampling and analysis that can safeguard legitimate industrial or national-security secrets remains a major challenge. Over the next few years, however, the development of accurate but inexpensive biosensors for the identification of microbial and toxin agents may make it easier for the Ad Hoc Group to find an acceptable tradeoff between these competing objectives.

The biotech and pharmaceutical industries have a huge stake in the outcome. So far, companies have mainly played the spoiler, complaining that proposed verification methods would intrude on their proprietary rights. They need to become more constructively involved. The biological weapons threat to international security has made it imperative to institute verification measures that will fortify the BWC, converting it from a gentleman’s agreement into enforceable international law. Companies that have the most to gain from biotech innovation-and the most to lose from unwanted disclosure of their trade secrets-need to help find suitable ways to allow international inspections of their production facilities without compromising the economic health of a leading U.S. industry.

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