Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
1 Introduction The great achievements of molecular biology and genetics over the last 50 years have produced advances in agriculture and industrial processes and have revolutionized the practice of medicine. The very technologies that fueled these benefits to society, however, pose a potential risk as well the possibility that these technologies could also be used to create the next generation of biological weapons. Biotechnol- ogy represents a "dual use" dilemma in which the same technologies can be used legitimately for human betterment and misused for bioterrorism. Events over the 1990s focused growing attention on this balance of risks and benefits, part of a larger concern about the proliferation of weapons of mass destruction (WMD) chemical, nuclear, or biological. In early 1992, President Yeltsin acknowledged that, despite being an original signatory and State party to the Biological and Toxin Weapons Convention (BWC), the Soviet Union had maintained a major clandestine biological weapons program into the early 1990s.1 Yeltsin ordered the program shut down, but concerns about other possible secret programs remained. Policymakers in the United States became increasingly concerned that so-called "rogue states" would turn to WMD to counter the overwhelming U.S. conventional military superiority. Secretary of Defense Les Aspin launched the "Defense Counterproliferation Initiative" in December 1993 to develop additional means to address these threats. Official statements continue to cite at least a dozen countries believed to have or to be pursuing a biological weapons capability.2 The terrorist attacks of September 11, 2001 and the subsequent anthrax letters accelerated already existing concerns that terrorists would seek WMD capabilities as well. President Bush, in a speech at West Point in 15
16 BIOTECHNOLOGY RESEARCH IN AN AGE OF TERRORISM 2002, said: "The gravest danger to freedom lies at the perilous crossroads of radicalism and technology. When the spread of chemical and biological and nuclear weapons, along with ballistic missile technology when that oc- curs, even weak states and small groups could attain a catastrophic power to strike great nations."3 States, groups, and individuals are pursuing a biological weapons capability and the means for them to do so are widely available. U.S. and British concerns about Iraq's reported biological and other WMD programs in early 2003 were a primary reason for launching preemptive military action to find and destroy these weapons capabilities.4 Biological weapons have long been stigmatized as "indiscriminant agents of unnecessary suffering, [whose] use ... contradicts the univer- sal principles of war."5 As discussed below, since November 1969 the U.S. programs linked to biological weapons have been restricted to re- search and development on defensive measures only. Thus few biologists in the United States today have knowledge of our country's past offensive weapons programs or of the concerns of the national security branches of government. In this respect the life sciences community is in a different situation from that of the physics community, which in large part has been continuously involved in government-sponsored weapons research programs since at least World War II. The scientific community and the government jointly face a double challenge: (1) to establish a working re- lationship with the national security branches of government, and (2) to help craft a system that will minimize the risk of wrongful use of biologi- cal agents or technology without damaging the scientific infrastructure that has made biological research so vital to the health of the nation. THE LIFE SCIENCES TODAY The biological sciences have experienced enormous growth over the last century, fueled by a stream of discoveries such as the principles of genetics, the structure of DNA, and the discovery of gene-splicing tech- nologies. These have opened new fields of inquiry and provided the basis for myriad applications in industry, agriculture, and medicine. Among the technological breakthroughs in the life sciences, genetic engineering plays a particularly significant role. Genetic engineering is a technique that permits the artificial modifica- tion and transfer of genetic material from one organism to another and from one species to another. This technology is used throughout the world to alter the protein produced by a gene and to design organisms with desirable traits for applications ranging from basic research and develop- ment activities to pharmaceutical and industrial uses. During the last 30 years, these recombinant techniques have spawned a vibrant biotechnol- ogy industry focused largely on the development of new pharmaceuticals
INTRODUCTION 17 to fight disease.6 By 2000 the annual investment in the biotechnology in- dustry peaked at nearly $29 billion, while employment in the biotechnol- ogy industry reached 191,000 by 2001.7 In response to the opportunities presented by these developments, the resources devoted to the life sciences have increased dramatically, making further discoveries possible. The government has funded biologi- cal research generously through the National Institutes of Health and Na- tional Science Foundation budgets, with few strings attached; private foundations and the pharmaceutical industry have also made major con- tributions. The number of PhDs awarded each year in the biological and agricultural sciences has increased steadily; 6,526 were awarded in 2001.8 This ever-expanding research activity has resulted in numerous new biopharmaceutical products that are transforming medicine. Examples include human recombinant insulin for the treatment of diabetes, a vac- cine against hepatitis B. and medicines for diabetes, cancer therapy, ar- thritis, multiple sclerosis, cystic fibrosis, heart attacks, hemophilia, and sepsis. As knowledge of the human genome increases, it may even be- come possible to tailor pharmaceutical products not only to specific dis- eases but also to specific individuals. Throughout this process, the time between new discoveries and their applications has grown ever shorter. One example is the very short time it took the scientific community to identify the coronavirus as the causal agent of the newly emerging hu- man disease, severe acute respiratory syndrome (SARS). Biotechnology research is now a truly global enterprise. While indus- trialized countries such as the United States, the United Kingdom, Ger- many, Israel, and lapan may be the first to develop advanced research and technologies, other countries have a skill base that will enable broad domestic utilization of biological technologies.9 For example: China has an aggressive program in plant biotechnology, and as of 2002 plans to increase funding by 400 percent by 2005. This energetic invest- ment also exists in the Chinese private sector, and the national scientific establishment is attempting to lure foreign-trained scientists to return with lucrative financial packages. India is in the process of tripling fund- ing to its national biotech center, and is promoting the development and use of genetically modified crops throughout Asia. Singapore has for many years made a practice of recruiting foreign scientists. Taiwan is investing large amounts in biotechnology and is seeking citizens to re- turn home to build up biotechnology in academia and industry. A Brazil- ian coalition recently demonstrated sophisticated domestic use of bio- logical technologies by successfully sequencing the plant pathogen X[ylella]fastidiosa in 2000.~° In addition to the dispersed research enterprise, publications and per- sonnel are also widely spread. Well over 10,000 journals in the life sci-
18 BIOTECHNOLOGY RESEARCH IN AN AGE OF TERRORISM ences are published worldwide. Biological Abstracts, an international da- tabase on biology, clinical and experimental medicine, biochemistry, and biotechnology, provides coverage of over 6,000 active international jour- nals and 14,000 archival titles from over 100 countries; Medline, the online service of the National Institutes of Health, provides abstract information for more than 4,600 biomedical journals published in the United States and 70 other countries; and PubMed currently provides full-text web ac- cess to 4,058 journals. According to Medline, the total number of scientific articles published in the peer-reviewed biomedical literature increased from 449,109 in 1998 to 491,620 in 2001. Given the global nature of the biotechnology research and development enterprise, it is unrealistic to think that biological technologies and the knowledge base upon which they rest can somehow be isolated within the borders of a few countries. The rapid advance of scientific knowledge and applications owes much to a research culture in which knowledge and biological materials are shared among scientists and people move freely between universities, government agencies, and private industry. Large numbers of foreign graduate students and postdoctoral associates have been an essential in- gredient in the success of the biological research enterprise. The scientific workforce is increasingly international; at the National Institutes of Health, for example, approximately 50 percent of the technical staff are non-U.S. citizens. Research results have been widely disseminated, so that even high school students now routinely perform experiments involving recombinant DNA techniques. In short, a dynamic national and interna- tional research enterprise has evolved, with an extraordinary record of achievement at multiple centers of excellence. These are values that should be preserved in any sensible policy for minimizing the risks associated with the misapplication of the fruits of the biotechnology enterprise. THE DUAL USE DILEMMA The regulation of dual use biotechnology research is a highly conten- tious technical, political, and societal issue. In the language of arms con- trol and disarmament, dual use refers to technologies intended for civil- ian application that can also be used for military purposes. Technology involves more than just products; it also encompasses a means to produce and use products in such a way as to solve a problem. Thus, technology comprises "the ability to recognize technical problems, the ability to de- velop new concepts and tangible solutions to technical problems, the con- cepts and tangibles developed to solve technical problems, and the ability to exploit the concepts and tangibles in an effective way." The "general purpose clause" of the BWC prohibits the development, production, and stockpiling of biological weapons, but permits States that
INTRODUCTION 19 are parties to the treaty to conduct research activities for peaceful pur- poses or in order to defend or protect against BW agents. Useful distinc- tions between permitted and prohibited activities at the level of basic re- search are difficult to make because biotechnology presents a classic example of the dual use dilemma. In the life sciences, for example, the same techniques used to gain insight and understanding regarding the fundamental life processes for the benefit of human health and welfare may also be used to create a new generation of BW agents by hostile gov- ernments and individuals. For the scientists and technicians involved in cutting-edge research and development in biology, biotechnology, medi- cine, and agriculture, this duality creates both uncertainties and ethical dilemmas. The duality between the purposes permitted and prohibited under the BWC is at the heart of this Committee's activities.~3 Current research programs in universities, government laboratories, and pharmaceutical companies include experiments directed toward such goals as discovering vaccines for major diseases such as influenza, AIDS, and cancer; new antibiotics for both bacterial and fungal diseases; new sources of genes to protect crops against pests and diseases; and treat- ments for diabetes, stroke, and Alzheimer's disease. These research activi- ties also include an intense effort to discover vaccines, antibiotics, and detection systems that would provide the defense against each of the se- lect agents. But many of the same methods for developing attenuated live vaccines against viral diseases can have offensive applications as well.~4 The key issue is whether the risks associated with misuse can be reduced while still enabling critical research to go forward. A BRIEF HISTORY OF MODERN BIOLOGICAL WARFARE Of thousands of species of potentially pathogenic microorganisms, very few have been developed and deployed as biological weapons. As a society, we tend to think that biological and chemical warfare are re- cent threats to individuals and populations, but in reality, the offensive use of chemical and biological agents has its origins in antiquity (see Annex to this chapter). It has only been within the last century, how- ever, that infectious disease agents have been seriously considered, on a continuing basis, as tools of war. Based on scientific discoveries during the late nineteenth and early twentieth centuries, biologists were able for the first time to identify, isolate, and culture disease-causing mi- crobes under controlled conditions and use them to intentionally induce disease in a "naive" host. "The foundations of microbiology pioneered by Louis Pasteur and Robert Koch offered new prospects for those inter- ested in biological weapons because it allowed agents to be chosen and designed on a rational basis."~5
20 BIOTECHNOLOGY RESEARCH IN AN AGE OF TERRORISM Germany was accused of using disease-causing germs during World War I by infecting horses and mules with "landers a highly infectious animal disease and cattle with anthrax. German spies were caught in 1917 allegedly trying to spread anthrax bacteria among reindeer herds in the far northern portion of Norway, near the border with Russia. These charges were confirmed when anthrax-laced sugar cubes obtained from a Swedish-German-Finnish aristocrat arrested as a German agent in 1917 were found to be still viable after being stored in the archives of a Norwegian museum for the last 80 years.~7 Over the past 60 years pathogens have been identified and per- fected as strategic and tactical weapons. Every major combatant dur- ing World War II including the United States, Great Britain, Canada, France, the former Soviet Union, Germany, and Japan had some type of biological weapons program. During the Sino-Japanese War (1937- 1945), Japan repeatedly attacked China with the plague-causing bacte- ria Yersinia Testis, targeting some eleven cities. At least 700 Chinese reportedly died from plague alone,~9 although the number of Chinese civilians killed between 1933 and 1945 by Japanese germ warfare may be much higher.20 lapan's secret biological warfare program, Unit 731,2~ officially re- ferred to as the Army Anti-Epidemic Prevention and Water Supply Unit, was located in a remote, high-security area in lapanese-occupied Man- churia, first in Harbin and then in Ping Fan. The Japanese perfected cul- ture and dispersal techniques for a large number of biological agents. Af- ter the war the Japanese commander of Unit 731, General Shiro Ishii, traded research data, at the suggestion of his debriefers with the Ameri- can occupation government in Japan, in exchange for a grant of immunity from war crimes prosecution. Information obtained from General Ishii later found its way to Camp Detrick, and is still held in the National Ar- chives in the United States.22 The United States' offensive biological weapons program also had its origins in World War II. Begun in 1942 within the Chemical Warfare Ser- vice at Camp Detrick in Frederick, Maryland, the program's primary mis- sion during World War II was biological warfare research on the caus- ative agents of anthrax and botulism.23 The main element for carrying out this program, the Special Projects Division of the Army Chemical Warfare Service, had at its peak 3,900 personnel, of which 2,800 were Army, nearly 1,000 Navy, and the remaining 100 civilian. The work was carried out at four installations. Camp Detrick was the parent research and pilot plant center. Field testing facilities were established in 1943 and 1944 in Missis- sippi and Utah, respectively, and a production plant was constructed in Indiana in 1944. All work, which was coordinated with Great Britain and Canada, was conducted under strictest secrecy.24
INTRODUCTION 21 From the end of World War II until the U.S. decision to renounce its biological weapons program in 1969, this program developed and per- fected offensive weapons capabilities for the Air Force, Navy, and the Central Intelligence Agency (CIA), utilizing a variety of human, animal, and plant pathogens.25 "Between 1941 [sic] and 1969, the policy of the United States regarding biological warfare was first (to) deter its use against the United States and its forces, and secondly to retaliate if deter- rence failed."26 The largest biological weapons complex ever created was in the former Soviet Union. Two main groups of facilities were involved in the research and development, production, and testing of biological weap- ons: a military-controlled system, which started in the 1920s, and Biopreparat, a top-secret program operating under civilian cover from 1972 until at least 1992,27 despite the fact that the Soviet Union was an original signatory to and repository for the Biological Weapons Conven- tion. As a result, the Soviet program not only caught up with but sur- passed the U.S. program to become the most sophisticated biological weapons program in the world. Its size and scope were enormous; by the early 1990s more than 60,000 people were involved in the research, devel- opment, and production of biological weapons as well as the stockpiling of hundreds of tons of anthrax spores and tens of tons of other pathogens, including smallpox and plague.28 In addition, it is now known that other state programs were involved in aspects of this effort including those of the Ministry of Health, Ministry of Agriculture, Ministry of Defense, KGB, and the Soviet Academy of Sciences. U.S. POLICY AND THE CREATION OF THE BIOLOGICAL AND TOXIN WEAPONS CONVENTION After intensive debate in the United Nations and domestic inter- agency review, President Richard Nixon on November 25, 1969 renounced the first use of lethal and incapacitating chemicals and stated that he would seek ratification of the Geneva Protocol by the U.S. Senate. (The Geneva Protocol of 1925 prohibits the use of chemical or biological mate- rials in war, although it does not proscribe their acquisition or posses- sion.) President Nixon also renounced the use of lethal bacteriological (biological) agents and weapons as well as all other methods of biological warfare, and directed the Defense Department to make recommendations for the disposal of existing BW stockpiles. He further stated that the United States would confine its biological agent and toxin research to de- fensive measures, such as immunization and safety. On February 14, 1970, this policy was extended to biological toxins regardless of their means of production.29
22 BIOTECHNOLOGY RESEARCH IN AN AGE OF TERRORISM The United States decided to abandon its offensive biological weap- ons program, destroy its existing stockpiles of biological and toxin weap- ons, and convert the production facilities to other purposes because it was recognized that: · Biological weapons could be as great a threat to large populations as nuclear weapons and that no reliable defense is likely; · Biological weapons could be much simpler and less expensive than nuclear weapons to develop and produce; proliferation of biological weapons would therefore greatly increase the number of nations to which the populations of the United States and its allies [could] be held hostage; · Our biological weapons program was pioneering an easily dupli- cated technology and was likely to inspire others to follow suit.30 The United States concluded that its biological weapons program was a substantial threat to its own national security and that one of the best ways to reduce this threat was not only to renounce biological weapons in this country but also to strengthen the international barriers to their pro- liferation.3~ The United States, the United Kingdom, and the former So- viet Union together were responsible for the effort to sponsor the Biologi- cal and Toxin Weapons Convention (BWC) of 1972 the first arms control agreement to ban outright an entire class of weapons.32 The U.S. Senate ratified the BWC in 1975. To date, 162 countries have signed and 148 coun- tries have ratified the BWC. THE NEW THREAT The revolution in biotechnology was just beginning when the BWC went into force in 1975. With the advent of the biotechnology revolu- tion and the apparent proliferation of countries desiring to have a bio- logical weapons capability, its signatories must reexamine the efficacy of the Convention in governing the use of disease as a method to spread terror. The acquisition of biotechnology and biological weapons capability is considerably easier than was the case in the 1940s and 1950s. The explo- sion in biotechnologies and genetic engineering technologies all of which have legitimate civilian applications could empower a hostile agent. Gordon Oehler, director of the Non-Proliferation Center at the Cen- tral Intelligence Agency, testified before the Senate Armed Services Com- mittee on March 27, 1996, and stated that there was "a continuing pursuit by many countries to acquire chemical and biological weapons and that The chilling reality is that these materials and technologies are more ac- cessible now than at any other time in history."33
INTRODUCTION 23 The information to conduct genetic engineering research is easily ac- cessible on the Internet. Moreover, the equipment and expertise to use this information to create novel agents are available globally. The interna- tional diffusion of knowledge and capabilities in biotechnology means that the capacity to carry out beneficial as well as harmful research activi- ties is widely accessible, both to nations and to terrorist groups. In this situation it is futile to imagine that access to dangerous patho- gens and destructive biotechnologies can be physically restricted, as is the case for nuclear weapons and fissionable materials.34 The nature of the biotechnology problem indeed the nature of the biological research en- terprise is vastly different from that of theoretical and applied nuclear physics in the late 1930s. The contrast between what is a legitimate, per- haps compelling subject for research and what might justifiably be pro- hibited or tightly controlled cannot be made a priori, stated in categorical terms, nor confirmed by remote observation. Matthew Meselson, a leading molecular biologist, gave a stark warn- ing of the potential dangers posed by the destructive applications of bio- technology in May 2000: Every major technology metallurgy, explosives, internal combustion, aviation, electronics, nuclear energy has been intensively exploited, not only for peaceful purposes but also for hostile ones. Must this also hap- pen with biotechnology, certain to be a dominant technology of the com- ing century? During the century just begun, as our ability to modify fun- damental life processes continues its rapid advance, we will be able not only to devise additional ways to destroy life but ... also ... to manipu- late it including the processes of cognition, development, reproduction, and inheritance. A world in which these capabilities are widely employed for hostile purposes would be a world in which the very nature of con- flict has radically changed. Therein could lie unprecedented opportuni- ties for violence, coercion, repression, or subjugation.35 These dangers cannot be eliminated entirely since the fundamental knowledge from which they emerge is available around the world and the potential benefits of biotechnology for health promotion and national defense are too great to contemplate efforts to prohibit or reverse such research. But the potential adverse effects associated with the malicious exploitation of these technological advances cannot be ignored. Because of widespread moral repugnance against the production and use of chemi- cal and biological weapons (CBW), the involvement of scientists and en- gineers in CBW research, development, and production is widely con- demned.36 History demonstrates, however, that without any military application in mind, research in biology may still contribute to the pro- duction of biological weapons.37 As discussed earlier, the discovery and elaboration of the "germ theory of disease" in the nineteenth century led
24 BIOTECHNOLOGY RESEARCH IN AN AGE OF TERRORISM not only to better sanitation and hygiene practices but also to the inten- tional development of disease as a weapon in the twentieth century. In discussing modifications of microorganisms that might have sig- nificance for bioweapons, Nixdorff and Bender38 identified four classes of microbial manipulations that have been the subject of intense debate within and outside the scientific community: 1. The transfer of antibiotic resistance to microorganisms, 2. Modification of the antigenic properties of microorganisms, 3. Modification of the stability of microorganisms to the environment, and 4. The transfer of pathogenic properties to microorganisms. Regarding these manipulations, they observed that: All four kinds of manipulations are possible and are being carried out daily in research laboratories. Some of the most intensive research con- cerns the elucidation of the mechanisms of pathogenesis. This work is essential for combating infectious diseases. It is hoped that the produc- tion of more effective vaccines with [fewer] side effects, better diagnos- tics and new therapeutic drugs will result from this research. At the same time, it is feared that the advances in biotechnology can be misused to develop and produce biological weapons.39 The National Institutes of Health's (NIH's) recently released research priorities for countering bioterrorism identified several categories of re- search activities in immunology and genomics that would be considered "provocative" if conducted by a hostile or rogue government. These in- clude efforts to "identify pathogen-induced immunoregulatory and immu- nosuppressive effects" as well as to "analyze gene expression of agents of bioterrorism."40 John Cannon, former chairman of the National Intelligence Council and a former deputy director for intelligence at the CIA, observed that "the continuing revolution in science and technology will accentuate the dual use problem related to biotech breakthroughs in biomedical engi- neering, genomic profiling, genetic modification, and drug development.... Responsible scientists will have an extraordinary opportunity to improve the quality of human life across the planet. At the same time, terrorists and other evildoers may develop a powerful capability to destroy that life."4 RECENT EXAMPLES OF "CONTENTIOUS RESEARCH" IN THE LIFE SCIENCES Biological weapons differ from other weapons systems in a number of important respects. They generally are based on naturally occurring patho- gens that have convolved along with their hosts to possess features such as
INTRODUCTION 25 high infectivity, ease of transmission, and virulence. As a corollary, how- ever, the effects of naturally occurring pathogens are limited by the evolu- tionary advantage gained by not eliminating their hosts. Among the many implications of the anticipated progress in biotechnology is the presump- tion that it may be feasible to create novel biological agents that are far more predictable and dangerous than any of the naturally occurring pathogens that have been developed as biological weapons in the past.42 It may be difficult to engineer a more successful pathogen than those already present in nature that have been perfected by evolution for their niche in life. How- ever, application of the new genetic technologies makes the creation of "de- signer diseases" and pathogens with increased military utility more likely.43 There have been several recent examples of what Gerald Epstein of the Defense Threat Reduction Agency refers to as "contentious re- search"44 experiments that resulted in the creation of organisms or knowledge with "dual use" potential. The Australian ectromelia virus (mousepox) experiment; total synthesis of the poliovirus genome and re- covery of infectious virus, and the comparison of the immune response to a host defense function from vaccinia and smallpox have all attracted the attention of the scientific community, the media, the defense community, and policy analysts. Each is elaborated below. The Mousepox Virus: A Case Study in Preconsideration The mousepax virus: a case study in preconsideration. Probably the most celebrated recent case involving the dissemination of research with the potential for bioterrorist uses was the report of an unexpected effect of the bioengineering of a strain of ectromelia virus (mousepox) that was in- tended to help eradicate mice in Australia. The authors of the papery had originally set out to make an infectious immunocontraceptive for wild mice by incorporating an ovary specific antigen, the mouse zone pellu- cida 3 (ZP3) glycoproteina gene into the genome of ectromelia virus. The authors subsequently sought to alter the ectromelia by adding an immunomodulator with the hope that this would increase the immune response of the infected mice to their fertilized eggs and thus make them permanently infertile. They drew upon previous published work by oth- ers with recombinant vaccinia virus in mice in which it had been shown that incorporating the gene for the immunomodulatory cytokine IL-4 into the viral genome and thus overexpressing it in vivo enhanced the viru- lence of vaccinia virus in mice. The increased virulence is probably due to suppression of the antiviral immune response mediated through compet- ing cytokines like IL-2, IL-12, and interferon gamma, which work by stimulating immune effecter cells to kill virus-infected cells and thus con- trol the virus infection.
26 BIOTECHNOLOGY RESEARCH IN AN AGE OF TERRORISM The authors of this study used standard and quite simple procedures for incorporating the IL-4 gene into the mousepox genome. They then demonstrated that this engineered mousepox virus was more virulent than the parent virus and killed 60 percent of infected mice, even if the mice were from a genetically resistant strain. Even more unexpected was their observation that mice that had been vaccinated and were completely resistant to the parent virus, and even to a more virulent strain of mouse- pox, were now killed by the IL-4 gene-expressing virus. Some have felt that the publication of this paper provides a blueprint or road map for terrorists to engineer a more virulent strain of smallpox that could overwhelm the human immune system in even well-vaccinated individuals. The methods section of the paper illustrates how easy it is to make an IL-4 expressing orthopox virus. It has been suggested that either the paper should not have been published, or at the very least the "mate- rials and methods" section of the manuscript should have been altered or omitted entirely from the published article. The authors were sensitive to these issues and consulted with their peers in the Pest Animal Control Cooperative Research Center at the Australian National University in Canberra about whether the paper should be submitted for publication. The manuscript was submitted in fuly 2000 to the Journal of Virology. The reviewers and editors expressed no concerns about potential misuse of any information in the manuscript and the article was published in Febru- ary 2001. A retrospective review by the editor-in-chief following con- cerns raised after the article was published concluded that the journal was correct in its decision to publish. This example illustrates the difficulty of attempting to censor either the initiation of research or the publication of results. The initial goals of the mousepox research were directed to control the population densities of a rodent pest in Australia. The studies were done on mice, and the virus itself, while related to smallpox, is not of any danger to humans. Thus, these studies had desirable scientific and societal goals and there was no obvious reason not to undertake them. Even in retrospect, the decision by informed scientists who had no vested interest in the work to approve publication seems appropriate. There were numerous examples in the published literature demonstrating the effects of cytokines like IL-4 on immune modulation. The authors of this study, therefore, were build- ing upon an established literature in this field that is filled with similar findings on the effects of the decreased or increased levels of IL-4 and other immunomodulatory factors on the virulence of other viruses and many microorganisms. As previously noted, the design of the mousepox study built upon previously published studies in which vaccinia virus en- gineered to express IL-4 was studied in mice. There is also a relevant pre- existing literature in the field of oncology in which the increased expres-
INTRODUCTION 27 sion of various cytokines incorporated into the fowlpox genomes and other orthopox viruses along with tumor antigens has been used to in- crease the immune response to tumors and decrease the immunogenicity of the viruses. The technique for incorporating new genes into the poxvi- rus genome had been published in many places. Thus there is little techni- cal information that was not already abundantly available in the literature and well known to the scientific community. The observation that even vaccinated mice were killed by the IL-4 expressing mousepox was a somewhat surprising finding that is of po- tential concern. However, since the ability of immunomodulatory factors to increase the virulence of this virus could have been predicted and the means to make such a virus were readily available, it was important to publicize that this strategy could overcome vaccination because it alerted the scientific community to such a possibility occurring either intention- ally or spontaneously. First, knowledge of these experiments allows the scientific community to explore how to overcome such engineered vi- ruses. It informs us of the fact that we should monitor cytokine levels in the blood of the initial cases of a highly virulent virus that is used in an attack. Second, it suggests that we should be prepared to treat infections caused by such an engineered virus with antibodies that inactivate the relevant cytokine, with gamma interferon that would counter the effect of IL-4, or with both. Finally, it is worth noting that this work was done outside the United States and could have been published in an Austra- lian or European journal, illustrating the limits of national policies to ad- dress dual use concerns and, in this case specifically, the need to have international guidelines for the publication of manuscripts containing "sensitive" information. Total Synthesis of the Poliovirus Genome and Recovery of Infectious Titus Wimmer and colleagues46 reported that they had reconstructed po- liovirus from chemically synthesized oligonucleotides that were linked together and then transfected into cells. This report attracted considerable attention in the news media and concern in some segments of the public. The media treatment of the work suggested that this experiment proved that one could synthesize any virus from chemical reagents that can be purchased on the open market. This implication raised the public concern about bioterrorism because it suggested that the Wimmer experiment pro- vided a recipe for terrorists to manufacture the virus. In response to the publication of this article in Science, in the 107th Congress, Representative Dave Weldon (R-FL) introduced H.Res. 514, which criticized the publica- tion of this research because of its implications for compromising the na-
28 BIOTECHNOLOGY RESEARCH IN AN AGE OF TERRORISM tional security interests of the nation. The Weldon resolution, which did not pass, went on to state the concern of the House of Representatives regarding the potential of the poliovirus paper to enable terrorists to syn- thetically create a human pathogen to release on the people of this coun- try and further called upon the publishers and editors of scientific publi- cations and the scientific community to establish ethical standards and exercise restraint in the dissemination of information of potential use to terrorists in the development of bioterrorism agents. The Weldon resolu- tion also called upon the Executive Branch to "examine all policies, in- cluding national security directives, relevant to the classification or publi- cation of federally-funded research to ensure that, although the free exchange of information is encouraged, information that could be useful in the development of chemical, biological, or nuclear weapons is not made accessible to terrorists or countries of proliferation concern."47 Many scientists concluded that the Wimmer experiment was neither a novel discovery nor a potential threat. The general principle that one could make live poliovirus from a DNA template was already known in 1981, when Baltimore and colleagues48 reported that a DNA copy of the positive strand RNA genome of poliovirus could be taken up into living cells under appropriate conditions and result in the generation of encap- sulated, infectious virus. These studies led to the ability to manipulate DNA copies of RNA viral genomes to generate preselected genetic changes. This technology bypasses the technical problems of working with RNA molecules and allows subsequent recovery of infectious virus. Sub- sequent research has succeeded in extending this technology to RNA vi- ruses with larger positive strand genomes, negative polarity RNA, or seg- mented genomes. Several points should be emphasized, however. Like the mousepox IL-4 experiment discussed above, the technology for producing and ma- nipulating the genome of RNA viruses has been available in the literature for a long time. The ability to synthesize a poliovirus genome and recover infectious virus was regarded as a foregone conclusion. The Wimmer ap- proach offers no technical advantage to a terrorist. And more importantly, in fact it is a very laborious and difficult way to accomplish this synthesis. The interesting scientific results from the Wimmer experiment were not its highly touted potential for bioterrorism, but rather the fact that the virus synthesized had significantly weakened pathogenicity as compared to wild- type strains of poliovirus. The decreased virulence is likely due to third- base and noncoding changes inserted as supposedly neutral markers.
INTRODUCTION Comparison of the Immune Response to a Virulence Gene from Vaccinia and Smallpox 29 Variola major virus causes smallpox, which has a 30-40 percent mor- tality rate, whereas vaccinia virus, which is used to vaccinate humans against smallpox, causes no disease in immunocompetent humans. In a paper that appeared in the Proceedings of the National Academy of Sciences, Rosengard and colleagues49 investigated a possible basis for the differ- ence in the putative virulence factor between the virus that causes human disease and the one used to vaccinate against the disease. Both viruses have an inhibitor of immune response enzymes vaccinia virus comple- ment control protein (VCP) and smallpox inhibitor of complement en- zymes (SPICE). The authors focused on a comparison of the genes encod- ing this inhibitor. As live variola is not available for study, they used standard techniques to synthesize the variola SPICE gene. They found that variola SPICE has a greater degree of specificity for human complement and is nearly a hundredfold more active than VCP at inactivating this component of the human immune system (human complement compo- nent C3b). The authors suggested that the difference between VCP and SPICE could explain the difference in virulence between the two viruses and the restriction of variola's host range to humans. Some might argue that the Rosengard study is of greater concern than the previous two examples because it provides information on how to increase the virulence of vaccinia virus, and thus on how to convert a readily available agent that has minimal virulence into a virulent virus. A commentary written on this paper pointed out that it is very unlikely that vaccinia virus carrying SPICE in place of VCP would approach the patho- genicity of variola.50 Furthermore, publication of the article alerted the community of scientists to this mechanism for virulence. This information should stimulate scientists in both the public and private sectors to iden- tify compounds or immunization procedures that disable SPICE. These could form the basis for new treatments or vaccines both to immunize against the naturally occurring smallpox virus and to counteract the ge- netically engineered variety. THE RESPONSE OF THE LIFE SCIENCES COMMUNITY TO PREVIOUS CHALLENGES As the preceding examples make abundantly clear, there is an increas- ing awareness within and outside the scientific community of the dangers posed by the proliferation of biological weapons capabilities. This height- ened awareness has also increased the collective concerns of this Commit- tee and the scientific community about preventing the destructive appli-
30 BIOTECHNOLOGY RESEARCH IN AN AGE OF TERRORISM cations of biotechnology research. This is not a completely new issue. When gene splicing technology was first reported, the scientific commu- nity at the time raised concerns that the technology might deliberately or inadvertently be used to create organisms with increased virulence or novel characteristics.5~ These possibilities eventually led to the 1975 Asilomar Conference, where scientists gathered to discuss the safety of manipulating DNA from different species.52 The meeting resulted in the issuance by NIH of Guidelines for Research Involving rDNA Molecules (hereafter called the NIH Guidelines) in 1976 that regulated the conduct of NIH-sponsored recombinant DNA research and established a mecha- nism for reviewing proposed experiments in this field. lust as the life sciences community with the Asilomar Conference stepped up to the challenge of responding to concerns that biology could set back rather than advance human welfare, so too the Human Genome Project created the ethical, legal, and social implications program to ex- plore how advances in genetics intended to improve human health could proceed without undermining other dimensions of human well-being. National commissions and Congress continue to debate whether certain advances in biology should be pursued and published.53 The initial fears about the inadvertent creation of virulent microbes by gene splicing techniques have abated because of overwhelming scien- tific evidence to the contrary. There have been no reported cases of dis- ease caused by recombinant microorganisms despite the widespread use of gene splicing techniques in academic laboratories and in the produc- tion of pharmaceuticals. In view of this experience, and the prospects for understanding the etiology of complex diseases and finding cures for them, the NIH has revised its Guidelines several times, with the net result being the elimination of the earlier prohibitions and the exemption from the Guidelines of essentially all recombinant DNA experiments except those that involve the molecular manipulation of human and restricted animal and plant pathogens. COMMITTEE CHARGE AND PROCESS Current policy at both the national and international levels may not be adequate to cope with the dangers inherent in the use and applications of genetic engineering. As discussed in greater detail in the following chapters, the United States has enacted legislation to provide for the physi- cal security of select agents and screening of personnel. The Committee's proposed system for reviewing research projects and publications would complement and strengthen this statutory regime. Internationally, however, protection against misuse of biotechnol- ogy is very uneven. The Biological and Toxin Weapons Convention, the
INTRODUCTION 31 centerpiece of biological weapons arms control, lacks effective verifica- tion and compliance measures. Moreover, it addresses only the actions of states and was never intended to guard against the development of a BW capability by individuals or nonstate actors (although national implementing legislation required by Article IV of the Convention could constrain the actions of individuals and groups within the state). In November 2001 the draft text for an international protocol covering compliance and verification measures was rejected by the United States. New, informal measures to strengthen the BWC being explored by ex- pert groups and States parties are scheduled to continue over a period of three years (the first meetings were held in Geneva in August 2003~. The measures include enactment of national criminal legislation supple- mented by an enhanced extradition regime; security standards for pathogenic organisms; genetic engineering oversight; and international adoption of professional codes of conduct.54 The hope is that these dis- cussions will translate into coordinated action by the States parties, but at present only a few states have instituted security measures to protect against diversion and misuse of biotechnology. The most elaborate treaty-based inspection procedures could not achieve effective restrictions at the level of basic research without severely restricting research in general. The inevitable diffusion of knowledge and capabilities has already demonstrated that the capacity to do harm is be- coming globally available, both to state and nonstate actors. At the same time, developments in biotechnology are also capable of yielding great benefits, such as new treatments for many diseases. The distinction be- tween the great opportunities and great dangers of biotechnology turns on assessing whether the risks associated with the benefits of funda- mental research outweigh the potential for misuse. The challenge to the scientific community, therefore, is to develop formal and informal pro- cesses and procedures to mitigate or minimize the destructive applica- tions of advanced biotechnology without unduly restricting legitimate biotechnology research activities. Beginning the process of addressing these challenges is the purpose of this study. Specifically, the Committee was charged to: 1. Review the current rules, regulations, and institutional arrange- ments and processes in the United States that provide oversight of re- search on pathogens and potentially dangerous biotechnology research, within government laboratories, universities and other research institu- tions, and industry. The review would focus on how choices are made about which research is and is not appropriate, and how information about relevant ongoing research is collected and shared. 2. Use the review to assess the adequacy of current U.S. rules, regula-
32 BIOTECHNOLOGY RESEARCH IN AN AGE OF TERRORISM lions, and institutional arrangements and processes to prevent the destruc- tive application of biotechnology research. 3. Recommend changes in those practices that could improve U.S. capacity to prevent the destructive application of biotechnology research while still enabling legitimate research to be conducted. This report is part of a larger body of work that The National Acad- emies have undertaken in recent decades on science and security issues, beginning with Scientific Communication and National Security in 1982 and continuing into the 1990s with the publication of Chemical and Biological Terrorism: Research and Development to Improve Civilian Medical Response (1999) and Firepower in the Lab: Automation in the Fight Against Infectious Diseases and Bioterrorism (2001~. In response to the events of September lath, the Academies undertook a comprehensive survey of the contribu- tions that science and technology could make to countering terrorism; Making the Nation Safer: The Role of Science and Technology in Countering Terrorism was published in 2002. The report of its panel on bioterrorism, Countering Bioterrorism: The Role of Science and Technology, was published separately. In addition, the Institute of Medicine's Forum on Emerging Infections convened a 3-day workshop on Biological Threats and Terrorism: Assessing the Science and Response Capabilities, which was released as a workshop summary late in 2002. The 2002 report on Countering Agricul- tural Bioterrorism, a study already in progress prior to September 11th, en- abled the Committee to focus its primary efforts on threats to human health. In the area of potential controls on information and data, the re- port on Sharing Publication-Related Data and Materials: Responsibility of Au- thorship in the Life Sciences (2003) is particularly relevant to the continuing concerns for ensuring the wide availability of the results of scientific re- search.55 Information about current projects may be found on the Acad- emies website http://www.nas.edu. Committee Process In creating the Ad hoc Committee on Research Standards and Practices to Prevent the Destructive Application of Biotechnology, the National Re- search Council (the operating arm of The National Academies) selected committee members representing a broad spectrum of backgrounds, exper- tise, and interests. Areas of expertise included molecular and cellular biol- ogy, virology, medicine, laboratory safety, international and regulatory law, bioethics, and defense policy (see Appendix B for biographical information on the members of the Committee). In addition, the Committee relied on the expertise and advice of representatives from the Executive Office of the President, governmental and nongovernmental technical and policy ex-
INTRODUCTION 33 perts, as well as educators and private consultants. Information available from the open literature and materials submitted by experts were reviewed and considered during the Committee's deliberations (see Appendix C). Even though the Statement of Task did not require the Committee to consider information control regimes for dissemination of information in the life sciences that could be exploited for nefarious purposes, the Committee concluded that this issue was implicit in the larger task before it and needed to be considered along with the regulatory environment for biotechnology research. An additional impetus for the Committee's consideration of infor- mation control regimes for unclassified research in the life sciences was the announcement by the White House shortly before the Committee's first meet- ing of its renewed interest in the application of "sensitive but unclassified information" control regimes for managing the dissemination of unclassified research that is financed by the federal government.56 Report Road Map Chapter 2 reviews the current domestic and international rules, regulations, and institutional arrangements and processes that provide oversight of research on pathogens and potentially dangerous biotechnol- ogy research within government laboratories, universities and other re- search institutions, and industry. Chapter 3 reviews the existing and emerging regulatory environment governing the control of information related to biological research. Chapter 4 presents the Committee's conclu- sions and recommendations about the ways in which the current regula- tory environment for genetic engineering research might be enhanced while allowing the scientific enterprise to continue its essential activities. ANNEX: BIOLOGICAL WARFARE IN HISTORY People figured out how to intentionally spread illnesses long before naturalists came up with the discovery that germs cause disease. Among the older military techniques that can be claimed as biological warfare is the use of corpses of humans or animals to befoul wells or other sources of drinking water.57 While the principal objective was thought to be the de- nial of clean water to the enemy, a secondary effect was to spread disease among people and animals that consumed the contaminated water.58 One of the earliest recorded instances of biological warfare occurred in 600 BC, when the Athenian leader Solon poisoned the water supply in the city of Kirrha with the noxious roots of the Helleborus plant a primitive but ef- fective biological toxin of plant origin. The Greeks and Romans may have used human and animal corpses to poison drinking water wells.
34 BIOTECHNOLOGY RESEARCH IN AN AGE OF TERRORISM Alexander the Great is thought to have catapulted the bodies of dead men over the walls of besieged cities, possibly as a means of spreading disease and inciting terror among their inhabitants.59 A related technique, used in the Middle Ages, was to deliberately leave dead human or animal corpses behind in areas that would be occu- pied shortly by invading troops; catapults were used as well.60 In 1346, invading Tartars intent on controlling the Silk Road trade attacked the Black Sea port of Caffa at the time occupied by the Genoese. The Tartar army, already exposed to the Black Death, hurled plague-infested cadav- ers over the impregnable walls of Caffa to infect the enemy population. It is usually reported62 that the fleeing Genoese brought the Black Death with them via plague-infested rodents, along shipping routes to Sicily, Sardinia, Corsica, and Genoa and from there it spread overland through- out Italy and Europe. It is considered equally likely, however, that the entry of plague into Europe from the Crimea occurred independent of this event.63 Over a four-year period, the plague eventually caused 25 million deaths one-third of Europe's population at the time. Population losses were probably much higher in the French Mediterranean coastlands and in northern Italy.64 During the seventeenth and eighteenth centuries, French and British soldiers and civilians are alleged to have deliberately infected North American Indian populations with European diseases. "(T)he use of small- pox as a weapon may have been widely entertained by British military commanders and may have been employed without scruple when oppor- tunity offered, possibly on a number of occasions."65 During the French and Indian Wars, for example, Sir leffrey Amherst, commander-in-chief of the British forces, was concerned that his troops west of the Allegheny Mountains were in danger of being overrun by Indians. He wrote to the commander of the garrison at Fort Pitt on the Pennsylvania frontier and urged that smallpox be spread among the disaffected tribes.66 In tune 1763, Captain Ecuyer of the Royal Americans met with two Indian chiefs under a pretense of friendship and gave them blankets that had been taken from a smallpox hospital. During the following months, according to his- torians of the episode, many Indians suffered and died as "smallpox raged among the tribes of the Ohio."67 During the 1800s, U.S. government agents were alleged to have deliberately infected the Plains Indians by giving them trading blankets infected with the deadly disease, decimating the population.68 NOTES ~ Interview with President Boris Yeltsin, Rossiskiye Vesti, May 27, 1992. In Foreign Broadcast Information Service. Central Intelligence Agency. Washington, D.C.: FBIS-SOV-92-103.
INTRODUCTION 35 2 John Holum, then director of the Arms Control and Disarmament Agency, listed a dozen unspecified countries in 1996 as possessing or pursuing BW capabilities, commenting that this was twice as many as in 1975 when the BWC entered into force. Remarks to the Fourth Review Conference of the Biological Weapons Con- vention in Geneva, Switzerland, November 26,1996. In May 2002 Under Secretary of State John Bolton named Iran, Iraq, North Korea, Libya, Syria, and Cuba as states the United States was certain possessed or were actively seeking BW. "Be- yond the Axis of Evil: Additional Threats from Weapons of Mass Destruction," remarks to the Heritage Foundation, Washington, D.C. 3 President George W. Bush. June 1, 2002. Remarks at the Graduation Exercise of the United States Military Academy. Available at http://www.whitehouse.gov/ news/releases/2002/06/20020601-3.html. 4 Intelligence estimates prior to the war concluded that Iraq had stocks of biologi- cal weapons. "We judge that Iraq has continued its weapons of mass destruction (WMD) programs in defiance of UN resolutions and restrictions. Baghdad has chemical and biological weapons as well as missiles with ranges in excess of UN restrictions; if left unchecked, it probably will have a nuclear weapon during this decade." National Intelligence Estimate, "Iraq's Continuing Programs for Weap- ons of Mass Destruction," October 2002. Available at http://www.ceip.org/files/ projects/npp/pdf/Iraq/declassifiedintellreport.pdf. An "interim progress report" on the search for banned weapons of mass destruction in Iraq released on October 2, 2003 revealed no stockpiles of such weapons, though it did cite "rudimentary" traces of weapons programs, concealed equipment, and so forth. A copy of the unclassified statement, presented by David Kay and made available by the CIA, may be found at: http://www.fas.org/irp/cia/product/dkaylO0203.html. 5 Zanders, l.P. 2002. Introduction in "Ethics and Reason in Chemical and Biologi- cal Weapons Research," Minerva (special Issue); 40:5. 6 For purposes of this report, biotechnology is broadly defined to include "any technique that uses living organisms (or parts of organisms) to make or modify products, to improve plants or animals, or to develop microorganisms for specific use." Although the fields of biotechnology have expanded greatly in the last three decades, the term is more suitable for this study than biology or life science. Office of Technology Assessment (1988~: New Developments in Biotechnology: Field-Testing Engineered Organisms: Genetic and Ecological Issues, May. NTIS Order #PB88-214101. 7 See U.S. Biotech Employment Chart, available at http://www.bio.org/inves- tor/signs/200210emp.asp. ~ "Doctorates awarded by field of study and year of doctorate, 1999-2001," Science and Engineering Doctorate Awards: 2001. National Science Foundation, October 2002, p.5. 9 Carlson, R. 2003. The Pace and Proliferation of Biological Technologies, Biosecurity and Bioterrorism: Biodefense Strategy, Practice and Science. 1 (3~:203-215. lo Ibid. ii Autio., E., and T. Laamanen.1995. "Measurement and evaluation of technology transfer: Review of technology transfer mechanisms and indicators." International Journal of Technology Management. 10~7/8~: 647 as cited in P. Zanders, op. cit., p. 6.
36 BIOTECHNOLOGY RESEARCH IN AN AGE OF TERRORISM i2 United Nations. 1972. Convention on the Prohibition of the Development, Pro- duction and Stockpiling of Bacteriological (Biological) and Toxin Weapons and on Their Destruction. United Nations General Assembly Resolution 2826 (XXVI) (New York: United Nations). The BWC recognizes that the equipment and materi- als used to produce BW agents are almost entirely dual use, having legitimate commercial as well as military applications. For this reason, the treaty specifically prohibits only those activities involving pathogens that "cannot be justified for prophylactic, protective, and other peaceful purposes." i3 Under the general purpose criterion, it is not the objects themselves but rather the purposes for which they may be applied that are prohibited. In this way, it is not necessary to ban dual use technologies that have legitimate purposes but that can also be applied to develop or produce BW. By using the general purpose crite- rion, the scope of the prohibition is comprehensive, because Art. 1 of the BWC lists the purposes that are not prohibited. Nixdorff, K., and W. Bender. 2002. "Ethics of University Research, Biotechnology and Potential Military Spin-Off," Minerva (special Issue):40, fn. 2, p. 15 and fn. 18, p. 19. i4 Huxoll, D. 1989. "Biological weapons proliferation and the new genetics," Tes- timony before the Senate Committee on Governmental Affairs and its Permanent Subcommittee on Oversight and Investigations. May 17. Senate Hearing, 101-744; 101St Congress, 1St session. i5 Frischknecht, F. 2003. "The history of biological warfare: Human experimenta- tion, modern nightmares, and lone men in the twentieth century," EMBO Reports 4 (special issue): S47. i6 Wheelis, M. 1999. "Biological sabotage in world war I," in Geissler E. and l.E. van Courtland Moon, eds., "Biological and Toxin Weapons: Research, Develop- ment and Use from the Middle Ages to 1945," SIPRI, 18 (London: Oxford Univer- sity Press), p. 52. i7 Redmond, C., et al. 1998. "Deadly relic of the great war," Nature, 393:747-748. i~ Geissler, E., and l.E. van Courtland Moon, eds. 1999. "Biological and Toxin Weapons: Research, Development and Use from the Middle Ages to 1945," SIPRI, 18 (London: Oxford University Press). i9 Williams, P., and D. Wallace. 1989. Unit 731: The fapanese Army's Secret of Secrets. (London: Hodder and Stoughton), pp. 280-281; and Harris, S.H. 1994. Factories of Death: fapanese Biological Warfare, 1932-45, and the American Cover-Up (London: Routledge). 20 "Chinese Civilians Sue Over WWI-Era lapanese Biological Weapons Activities" CBW Chronicle III (3~:December 2001. "http://www.stimson.org/cbw/?sn= cb20020112244" http: / /www.stimson.org/cbw/?sn=cb20020112244. 2i There were at least four operational units of the lapanese secret biological war- fare complex: Unit 731, located in Ping Fan, Unit 100 in Changchun, Unit 9420 in Singapore, and Unit Ei 1644 in Nanking. There is also some evidence that the lapanese had an epidemic prevention center a euphemism for BW research on tropical diseases in Rangoon, Burma. Each unit had 10-15 individual facilities located within and outside mainland China. See Williams, P. and D. Wallace, 1989, Unit 731: The fapanese Army's Secret of Secrets. (London: Hodder and Stoughton), p. 280-281; and Harris, S.H. 1994, Factories of Death: fapanese Biological Warfare, 1932- 45, and the American Cover-Up (London: Routledge).
INTRODUCTION 22 Ibid. 37 23 Bernstein, B.1988. "America's biological warfare program in the Second World War," Journal of Strategic Studies 11 (September):292-317, especially p.304 and 308- 310. In addition to Bacillus anthracis and Clostridium botulinum, pathogens studied at Camp Detrick included the causative agents of: "landers; brucellosis; tularemia; melioidosis; plague; psittacosis; coccidiomycosis; a variety of plant pathogens in- cluding the causative agents for rice blast; rice brown spot disease; late blight of potato; and cereal stem rust. Animal and avian pathogens studied included rinder- pest virus, Newcastle disease virus, and fowl plague virus. The Problem of Chemical and Biological Warfare, SIPRI, I (London: Oxford University Press), 1971, p.122. See also Cochrane, R.C. 1947. "Biological Warfare Research in the United States" in History of the Chemical Warfare Service in World War II (1 July 1940 - 15 August 1945), Vol. II (declassified). Historical Section, Office of Chief, Chemical Corps. 24U.S. Department of the Army.1977. U.S. Army Activity in the U.S. Biological War- fare Programs I; (unclassified) February 24, p. 1-3. 25 Ibid. 26 Ibid., p. iii. 27Alibek, K., and S. Handelman. 1999. Biohazard: The Chilling True Story of the Larg- est Covert Biological Weapons Program in the World - Toldfrom the Inside by the Man Who Ran It (New York: Random House). 28 For personnel numbers, see Leitenberg, M.1993, "The Conversion of Biological Warfare Research and Development Facilities to Peaceful Uses," in Control of Dual- Threat Agents: The Vaccines for Peace Programme, SIPRI Chemical and Biological Warfare Series, 15 (London: Oxford University Press). For the environmental im- pacts associated with biological weapons field testing see Choffnes, E. 2001, "Germs on the loose," The Bulletin of the Atomic Scientists 57 (March/April): 57-61. 29 U,S, Department of the Army. 1977. U.S. Army Activity in the U.S. Biological Warfare Programs, Vol. 1; Feb. 24, p. 7-1. 30 Meselson, M. 1989. Testimony to the U.S. Senate Committee on Governmental Affairs and its Permanent Subcommittee, Hearings on Global Spread of Chemical and Biological Weapons." May 17 (Washington, D.C.: U.S. Government Printing Of- fice, 1990), pp. 498-511. See also National Security Council, 1969. "U.S. Policy on Chemical and Biological Warfare Agents," report submitted by the Interdepart- mental Political-Military Group in response to NSSM 59, November 10. Available at http://www.gwu.edu/~nsarchiv/NSAEBB/NSAEBB58/#docs. 31 Ibid. 32 Unlike the Nuclear Non-Proliferation Treaty and the Chemical Weapons Con- vention, however, the BWC does not have formal mechanisms to monitor or en- force compliance. The BWC also has no international secretariat or inspectorate to oversee or verify its implementation. Thus, although the treaty enshrines a norm of international behavior, it lacks the capacity to enforce these prohibitions. 33 Biotechnology and Genetic Engineering: Implications for the Development of New Warfare Agents-1996; Executive Summary available at http:// www.acq.osd.mil/cp/biotech96/xsum.pdf. 34 This is not recognized by some of those concerned about the proliferation of biological weapons or bioterrorism resulting from the diffusion of advanced bio- technology research. The Counterterrorism Act of 2000, for example, which passed
38 BIOTECHNOLOGY RESEARCH IN AN AGE OF TERRORISM the Senate but not the House in the 106~ Congress, cited the recommendation of the National Commission on Terrorism that "the standards for the storage, trans- port, and handling of biological pathogens should be as rigorous as the current standards for the physical protection of critical nuclear materials." Congress, Sen- ate. Counterterrorism Act of 2000, 106~ Congress, 2n~ session, S. 3205. 35 Meselson, M. 2000. "The Problem of Biological Weapons," remarks at the Sym- posium on Biological Weapons and Bioterrorism, National Academy of Sciences, May2. 36 Nixdorff, K., and W. Bender. 2002. "Biotechnology, Ethics of Research, and Po- tential Spin-off," INESAP Information Bulletin, 19 (March): p. 19-22. 37 Ibid. 38 Ibid. 39 Ibid. 40 Fauci, A. 2002. "Defining 'Sensitive' Information in the Life Sciences," oral pre- sentation to the committee, September 9. 4i Gannon, l.C. 2001. "Viewing Mass Destruction Through A Microscope," New York Times, Section E, p. 10, October 11. 42 Developers of BW agents would strive for the greatest possible degree of predict- ability in infectiousness, virulence, and other militarily relevant characteristics. 43 Speaking at the conference on the future of weaponry, Professor Kathryn Nixdorff, of the University of Darmstadt, said that dangerous microorganisms had already been produced inadvertently during attempts to modify vaccines and viruses. In the past 30 years biotechnology has been revolutionized by molecular biology and genetic engineering. These techniques, used to control infectious dis- eases, can also be used to create more effective biological weapons. See Hearst, D. 2003. "Smart big-weapons are now possible," The Guardian. May 20. Available at http: / /www.guardian.co.uk/uk_news/story/0,3604,959473,00.html. 44 Epstein, G.L. 2001. "Controlling biological warfare threats: Resolving potential tensions among the research community, industry, and the national security com- munity," Critical Reviews in Microbiology, 27~4~:321-354. Epstein defines "conten- tious research" as "fundamental biological or biomedical investigations that pro- duce organisms or knowledge that could have immediate weapons implications, and that therefore raise questions concerning whether and how that research should be conducted and disseminated." 45 Jackson, R.~ ., Ad. Ramsay, C .D. Christensen, S. Beaton, D. F. Hall, and I.A. Ramshaw. 2001. "Expression of mouse interleukin-4 by a recombinant ectromelia virus suppresses cytolytic lymphocyte responses and overcomes genetic resistance to mousepox," Journal of Virology 75:1205-1210. 46 Cello, l., A.V. Paul, and E. Wimmer. 2002. "Chemical synthesis of poliovirus cDNA: Generation of infectious virus in the absence of natural template," Science Online, July 11. Available at http://www.sciencemag.org/cgi/ontent/full/297/ 5583/1016. 47 Shea, D. 2003. "Balancing Scientific Publication and National Security Concerns: Issues for Congress." (Washington, D.C.: Congressional Research Service, Report Number RL31695), January 10. 48 Racaniello, V.R., and D. Baltimore. 1981. "Cloned Poliovirus Complementary DNA Is Infectious in Mammalian Cells," Science 214:916-19.
INTRODUCTION 39 49 Rosengard, A.M., Y. Liu, Y.Z. Nie, and R. limenez.2002. "Variola virus immune evasion design: Expression of a highly efficient inhibitor of human complement," Proceedings of the National Academy of Sciences, 99: 8808-8813. 50 Lachmann, A. 2002. "Microbial subversion of the immune response," Proceed- ings of the National Academy of Sciences 99: 8461-8462. 5i Wade, N. 1980. "Biological Weapons and Recombinant DNA," Science 208:271; S. Budianski.1982. "US Looks to Biological Weapons. Military Takes New Interest in DNA Devices," Nature 297: 615-616. 52 It should be noted that the Asilomar Conference addressed only the accidental creation of recombinant microorganisms with increased virulence and other dan- gerous properties. It did not address the deliberate creation of such organisms for offensive applications in warfare and terrorism. 53 Kennedy, D. 2003. "Two Cultures" and "Statement on Scientific Publica- tion and Security," Science 299 (5610~:1148-1150. Available at http://www. sciencemag.org/content/vol299/issue5610/index.shtml. 54 U.S. Department of State. 2001. "New Ways to Strengthen the International Regime Against Biological Weapons," Fact Sheet, Bureau of Arms Control, Wash- ington, D.C., October 19. Available at http://www.state.gov/t/ac/bw/fs/2001/ 7909.html. 55 All of these reports are published by The National Academies Press. Information about these and other reports may be found at http://www.nap.edu, which may be searched by subject matter and by report title. 56 Card, A.H. Jr. 2002. "Action to Safeguard Information Regarding Weapons of Mass Destruction and Other Sensitive Documents Related to Homeland Security," March 19. Avaliable at http://www.fas.org/sgp/bush/whO31902.html. 57 Stockholm International Peace Research Institute. 1971. "Instances and allega- tions of CBW, 1914 -1970," SIPRI, The Problem of Chemical and Biological War- fare, p. 214 in Vol. 1: The Rise of CB Weapons (Almqvist & Wiksell: Stockholm). 58 Ibid., p. 215. 59 Glenn, l. 1989. "Biological weapons proliferation and the new genetics," Chairman's Opening Statement; Senate Committee on Governmental Affairs and its Permanent Subcommittee on Oversight and Investigations. May 17. Senate Hearing, 101-744; 101St Congress, 1St session. 60 SIPRI, op. cit., p. 215 6i According to one account the plague in Caffa "might have spread naturally because of unhygienic conditions in the beleaguered city." Frischknecht, F. 2003. "The history of biological warfare: Human experimentation, modern nightmares, and lone madmen in the twentieth century," EMBO Reports 4 (special issue): S47. 62 Wheelis, M.2002. "Biological warfare at the 1346 siege of Caffa." Emerging Infec- tious Diseases 8~9~:1971. Available athttp://www.cdc.gov/ncidod/EID/vol8no9/ pdf/01-0536.pdf. See also Wheelis, M. 1999. "Biological Warfare Before 1914," in E. Geissler and l.E. van Courtland Moon, eds, "Biological and Toxin Weapons: Research, Development and Use from the Middle Ages to 1945," SIPRI, 18 (Lon- don: Oxford University Press). 63 Ibid.; see also, Frischknecht, F.2003. "The history of biological warfare: Human
40 BIOTECHNOLOGY RESEARCH IN AN AGE OF TERRORISM experimentation, modern nightmares, and lone madmen in the twentieth cen- tury," EMBO Reports. 4 (special issue): S47. 64Italian records are potentially very rich but have only begun to be carefully studied. Cf. Bowsky, W.M. 1964. "The impact of the Black Death upon Sienese government and society," Speculum, 39:1-34. D. Herlihy.1966. "Population, plague and social change in rural Pistola, 1201-1430." 0, 18:225-244. Some French towns also have abundant notarial records that can yield data on plague losses. Cf. Em- ery, R.W. 1967. "The black death of 1348 in Perpignan." Speculum, 42: 611-623. Emery estimated a die-off of 58-68 percent among the notaries of Perpignan from the plague. As cited in, McNeill, W.H. 1976. Plagues and Peoples, (Garden City, New York: Anchor Press). See also, Wheelis, M. 2002. "Biological warfare at the 1346 siege of caffa." Emerging Infectious Diseases 8~9~:1971. Available at http:// www.cdc.gov/ncidod/EID/vol8no9/pdf/01-0536.pdf. "The claim that biological warfare was used at Caffa is plausible and provides the best explanation of the entry of plague into the city. This theory is consistent with the technology of the times and with contemporary notions of disease causation; however, the entry of plague into Europefrom the Crimea likely occurred independent of this event." (empha- sis added). 65 Fenn, E. 2000. "Biological warfare in eighteenth century America: Beyond lef- frey Amherst." Journal of American History 86:1552-1558, and Fenn, E.A. 2001. Pox Americana: The Great Smallpox Epidemic of 1775-1782. (New York: Hill & Wang Pub- lishers). 66 op. cit., Fenn, E.A. 2001, and E.W. Steam and A.E. Steam. 1945. The Effect of Smallpox on the Destiny of the Amerindian. (Boston: Bruce Humphries Publishers), pp. 45-55. 67 It is also possible that by the time of this intentional introduction of smallpox among the tribes of the Ohio that there was a concurrent outbreak of smallpox among these tribes. On the topic of smallpox blankets and Native Americans, see Wheelis, M. 1999. "Biological Warfare Before 1914," in Geissler, E. and l.E. van Courtland Moon, eds., "Biological and Toxin Weapons: Research, Development and Use from the Middle Ages to 1945," SIPRI, 18 (London: Oxford University Press). Also Fenn, 2000, op. cit. 68 See Wheelis, M. 1999. "Biological Warfare Before 1914," in Geissler, E. and l.E. van Courtland Moon, eds., "Biological and Toxin Weapons: Research, Develop- ment and Use from the Middle Ages to 1945" SIPRI, 18 (London: Oxford Univer- sity Press). Also Fenn, 2000, op. cit.