Globalization, Biosecurity, and the Future of the Life Sciences (2006) / Chapter Skim
Currently Skimming:
1 Framing the Issue
1 Framing the Issue
Pages 15-78
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From page 15... ...
This rapid pace of technological growth in the life sciences research enterprise reflects a revolutionary change in the way people interact with biological systems and a growing capacity to manipulate such systems. Such advancing technologies offer great promise for improving the quality of human life: promoting health, preventing disease, and ensuring adequate food and even the possibility of new energy sources.
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COMMITTEE CHARGE AND PROCESS As discussed above and in more detail throughout the report, life sciences knowledge, materials, and technologies are advancing with tremendous speed, making it possible to identify and manipulate features of living systems in ways never before possible. On a daily basis and in laboratories around the world, biomedical researchers are using sophisticated technologies to manipulate microorganisms in an effort to understand how microbes cause disease and to develop better preventative and therapeutic measures against infectious disease.
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statements continue to cite around a dozen countries that are believed to have or to be pursuing biological weapons capabilities.4 The threat of bioterrorism, coupled with the global spread of expertise in biotechnology and biological manufacturing processes, raises concerns about how this advancing technological prowess could enable the creation and production of new biological weapons and agents of biological terrorism possessing unique and dangerous but largely unpredictable characteristics. The Committee on Advances in Technology and the Prevention of Their Application to Next Generation Biowarfare Threats, an ad hoc committee of the National Research Council and the Institute of Medicine, was constituted to examine current trends and future objectives of research in the life sciences, as well as technologies convergent with the life sciences enterprise from other disciplines, such as materials science and nanotechnology, that may enable the development of a new generation of biological threats over the next five to ten years, with the aim of identifying ways to anticipate, identify, and mitigate these dangers.
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2. Evaluate the potential for hostile uses of research advances in genetic engineering and biotechnology that will make biological agents more potent or damaging.
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EMERGING TECHNOLOGIES IN THE LIFE SCIENCES Heralded by Science magazine as the 2002 "Breakthrough of the Year,"5 RNA interference (RNAi) has emerged as a promising therapeutic approach for the treatment of a wide range of diseases, including cancer.6 Yet just a year before it earned its breakthrough title, RNAi was met with doubt and criticism.7 RNAi therapy involves using small interfering RNA molecules (siRNAs)
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-- that can guide the construction of novel, synthetic proteins and direct cells to perform assigned tasks.11 By assembling genes into circuits that direct cells to perform assigned tasks, synthetic biologists have taken genetic engineering to a level so profoundly different from recombinant technology that, in an October 2004 Nature news article, the latter was referred to as "old hat."12 DNA synthesis applications are now largely limited to places like the MIT's Independent Activities Period (IAP) course, where students design DNA circuitry, send their designs via the Internet to Blue Heron Biotechnology, Inc.
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For example, in January 2005, in a paper published in Physical Review Letters, researchers from the University of California, Los Angeles, described a nanoscale mechanism for externally controlling protein function, a technological advance that could ultimately lead to a generation of targeted "smart" drugs that are active only when certain DNA is present or a certain gene is expressed.21 In February 2005, in a paper published in the Proceedings of the National Academy of Sciences, Northwestern University researchers described a nanoparticle-based assay for detecting the onset of Alzheimer's disease.22 Also in February 2005, an Illinois-based company, Nanosphere, Inc., announced plans to expand and market the application of the same assay to a variety of other diseases, including cancer.23 While new tools, like RNAi therapeutics and nano-based drug delivery are emerging, already proven tools such as the polymerase chain reaction (PCR) and DNA sequencing, are becoming more versatile, more affordable, and faster.
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and that consist of a protein with "infectious" capacity to initiate misfolding of similar proteins.27 This series of events in the development of PCR recapitulates a theme in the life sciences: the sudden arrival of a new technique, followed by its technological exploitation, further refinement, and subsequent extension to other related fields. Similar scenarios have accompanied the discovery of restriction endonucleases and the development of recombinant DNA, and are unfolding now with RNAi technology or recently described multiplex DNA synthesis capabilities.
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assembly cost about $10 to $12 per base pair. By the beginning of 2005, the cost had dropped to about $2 per base pair (e.g., Blue Heron offers a special price of $1.60 for new customers33 )
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It is not unreasonable to expect that, before long, scientists will develop and have access to computer programs that simulate in detail the molecular processes in cells, so that the interaction of cells with pathogenic microbes and molecules can be fully anticipated and understood. Notable Features of Technological Growth in the Life Sciences Technological growth in the life sciences is characterized by several notable features.
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As discussed in greater detail in Chapter 2 of this report and in an earlier workshop summary report from this committee, a number of countries around the world are investing heavily in life sciences technologies.39 Indeed, several countries that are not commonly viewed as being technologically sophisticated, or that have not been considered technologically savvy in the past, are making remarkable progress in biotechnology and are wellpositioned to become regional or global leaders in the near future. Importantly, the rapid global dispersion of life sciences materials, knowledge, and technologies is not limited to technologies with proven therapeutic and market value.
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This stands in sharp contrast to the still relatively small number of nuclear materials that could potentially be used for malign intent. This is evident in the increasing pace of research activity in the life sciences, as reflected in the number of biotech drug approvals (i.e., as opposed to large pharma drug approvals)
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These sciences include, for example, branches of mathematics and computational science, as these are now being applied in efforts to effectively model a wide variety of biological systems, or materials science, as it is applied to the manipulation of biological systems. Here "associated technology" refers to the development and application of tools, machines, materials, and processes based on knowledge derived within or applied to the life sciences: genetic engineering, synthetic biology, aerosol technology, combinatorial chemistry, and nanotechnology are just a few of these technologies.
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However, it is not necessary for a biological agent to be specifically "weaponized" for it to be used as a weapon, as, for example, a routine culture of a bacterial pathogen might simply be added to food or drinking water. The term "dual-use" refers to the capacity or potential for biological agents, information, materials and supplies, or technologies to be used for either harmful or peaceful purposes.
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With plans to screen more than 100,000 small-molecule compounds within its first year of operation, one of the goals of the Chemical Genomics Center network is to explore the areas of the human genome for which small molecule chemical probes have yet to be identified. Data generated by the network will be deposited in a comprehensive database of chemical structures (and their biological activities)
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Sales of ornamental fishes are not federally regulated. The Food and Drug Administration asserts jurisdiction over genetically modified animals using the New Animal Drug Application process.d After a brief internal review and interagency consultation, the FDA's Center for Veterinary Medicine determined that "because tropical aquarium fish are not used for food purposes, they pose no threat to the food supply.
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Despite this, Yorktown Tech nologies is considering other markets, including parts of Asia and Latin America. Extensive information requirements suggest that GloFishTM will not be marketed in Canada or the European Union in the near future.
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The term "bioterrorist" refers to individuals or groups, usually nonstate actors, that develop and/or use biological agents with the intent to cause harm. On the other hand, "biological warfare" refers to the intentional use of such weapons by state actors, regardless of whether they are deployed against civilian or military targets, or on either a large or small scale.
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56 Japan's secret biological warfare program, Imperial Unit 731 (hereinafter Unit 731) , which was officially known as the Army Anti-Epidemic Prevention and Water Supply Unit, studied, cultured, and developed a large number of biological agents, including B
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of Biopreparat, defected to the United Kingdom62 and the United States in the late 1980s and early 1990s.63 Biopreparat, an ostensibly state-owned pharmaceutical organization was, in reality, carrying out a secret offensive and defensive biological weapons program that operated from 1972 until at least 1992.64 It was the most sophisticated biological weapons program in the world, and its size and scope were enormous. By the early 1990s, more than 60,000 people were involved in the research, development, and production of biological agents for use in weapons, and the complex had the capability to stockpile hundreds of tons of material containing anthrax spores and dozens of tons of material containing other pathogens, including smallpox and plague agents.65 Many state programs were involved in various aspects of this effort.
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At the time of the project, research conducted in the national interest was considered the most important research in the country.68 As recommended by the international community, the South African government has attempted to keep many experts in this area employed under its watch rather than have them take their expertise elsewhere.69 Beating Nature: Is It Possible to Engineer a "Better" Pathogen? The rapid, unpredictable, and widespread growth of the life sciences and biotechnology has raised concerns that, while such growth benefits national development and enriches the quality of life for millions of people worldwide, it also creates new opportunities for inappropriate or malicious use.
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Rather, injury or "disease" occurs as an incidental effect of mechanisms evolved by the infectious agent to promote its multiplication and long-term survival. To illustrate the devastation that natural biological agents can cause, Table 1-1 provides a snapshot of cases and deaths of emerging infectious diseases in the past and present.
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However, influenza virus does this in an ongoing fashion and at a dizzying pace, at times making fantastic genetic leaps. Many scientists consider an
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Less often, a more dramatic change in the antigenic structure of the virus takes place through a process of reassortment of its segmented genome. This occurs through mixing of gene segments from different influenza viruses co-infecting the same host, producing a new influenza strain with a different complement of gene segments.
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Given the clear capability of at least some microbes and viruses to evolve quickly, acquire new genes, and alter their behavior, it might seem reasonable that over hundreds of thousands of years all conceivable biological agents have been "built" and "tested" and that the agents seen today are the most "successful" of these. Thus, is there any reason to think that it might be possible to artifically create a more successful biological agent?
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The Evolution of Pathogenicity: What Does It Take to Cause Disease? Early views of pathogenicity and virulence were based on the assumption that these characteristics were intrinsic properties of microorganisms, although it was recognized that pathogenicity was neither invariant nor absolute.80 Over the course of the last century, as increasing numbers of viral and microbial pathogens were identified and the pathogenesis of multiple infectious diseases was characterized, the complexity and individuality of host-pathogen relationships became evident, while the general definitions of pathogenicity and virulence became increasingly qualified and cumbersome.
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However, there are often no direct positive benefits derived by the microbe per se in causing disease or killing its host.88 Of the several thousand species estimated to inhabit the body, only a handful are capable of causing disease on a routine basis, while only a modest additional number are capable of causing disease when host defenses become impaired. Those that regularly cause disease in unimpaired hosts employ a strategy for replication and survival that involves colonization of a highly protected anatomic site that is usually off-limits to microbes; the strategy includes mechanisms for resisting or subverting host defenses.
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microbe that more often assumes the role of commensal or symbiont.90 Recent research indicates that viral as well as bacterial pathogens that infect or colonize animals share broadly common strategies with those that infect plants.91 Both can express proteins that mimic, suppress, or modulate host cell-signaling pathways and enhance pathogen fitness, and both are recognized by similarly sophisticated host surveillance systems. Striking architectural similarities between surface appendages of plant and animal pathogenic bacteria suggest common mechanisms of infection, while structural differences -- most notably the presence versus absence of a cell wall -- reflect the profound differences between plant and animal cells.
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Most successful pathogens maintain an evolutionary middle ground with respect to the amount of damage they exact on their host; to survive in the privileged anatomic niche they have chosen and to be transmitted to a new susceptible host, they may need to inflict some degree of injury but not so much that they hinder the fitness of their host as an optimal partner in attaining these goals: pathogen survival, persistence, and transmission. An interesting and potentially serious anomaly is provided by those infectious agents, such as some arthropod-borne viruses like West Nile virus, that infect humans "accidentally." For such pathogens, human infection is not a necessary part of its essential life cycle, as for example West Nile virus usually cycles between avian and mosquito species with only occasional forays into mammals such as humans.
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Some pathogens occasionally increase their virulence to overcome a different type of disadvantage they face in the environment, such as poor vector competence.98 Thus, the setting and conditions under which nature judges the "success" of a pathogen may limit our appreciation for the kinds of virulence properties that might be possible in a biological agent and cause us to arrive at false conclusions concerning our ability to create new pathogenic agents. The overall survival strategy of a pathogen may involve adaptation to an external environment and transmission among hosts over thousands of years; the result is often attenuation of virulence for the human host.99 Nature rewards long-term survival of an organism whereas, longterm survival is not an important requirement for an organism to be capable of causing disease and disrupting human populations in the shortterm (e.g., months, years)
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Irrespective of whether caused by a virus or bacterium, infectious diseases typically result either from direct tissue injury caused by an infectious agent or from the host's response to it. How, then, does the host differentiate between pathogenic and benign microbes?
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might not necessarily be traditional "threat agents."105 Advancing Technologies Will Alter the Future Threat Spectrum Although this report is concerned with the evolution of science and technology capabilities over the next 5 to 10 years with implications for next-generation threats, it is clear that today's capabilities in the life sciences and related technologies may have already changed the nature of the biothreat "space." In a 1996 Department of Defense (DOD) report, it was argued that advances in biotechnology and genetic engineering had provided the means to modify agents in very specific ways and had consequently facilitated the development of a new generation of biological warfare agents that could potentially be more dangerous than classical
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This timeline depicts the relative threat level presented by traditional Genetically Modified Traditional Agents/ Biochemical Agents FIGURE 1-3 Timeline describing impact of biotechnology on biological warfare threat. Reprinted with permission from BioSecurity and Bioterrorism: Biodefense Strategy, Practice, and Science 1(3)
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.108 Although not possible until recently with negative-strand RNA viruses, in October 2004 researchers at the University of Wisconsin used reverse genetic engineering techniques to partially reconstruct the highly virulent strain of influenza responsible for the 1918-1919 pandemic;109 and the following year the complete sequence and characterization of the 1918-1919 influenza A virus was reconstructed.110 Although the knowledge, facilities, and ingenuity to carry out this sort of experiment are beyond the abilities of most non-experts at this time, this situation is likely to change over the next 5 to 10 years.111 Some experts argue that bioregulators, which are small, biologically active organic compounds, may pose a more serious dual-use risk than had been previously perceived, particularly as improved targeted delivery technologies have made the potential dissemination of these compounds much more feasible than in the past. This shift in the perceived magnitude of the risk posed by bioregulators highlights the fact that the materials, equipment, and technology necessary for disseminating and delivering biological agents to their intended recipient(s)
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may start developing new bioweapons programs, either secretly or under the cover of biodefense research programs. Likewise, the technologies and tools required to develop bioweapons capabilities are becoming increasingly accessible and affordable to individuals.
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The data presented below exclude accidental releases, such as happened in Sverdlovsk, USSR, in April 1979, resulting in the documented deaths of 67 people from inhalational anthrax as well as purposeful, experimental releases, such as the TABLE 1-2 Authenticated Acts of Biological Warfare or Terrorism Directed Against People, 1940 to 2004 Details of Key Date Location Episode Information Sources 1940-1941 China: Hangzhou Japanese aircraft drop Recent testimony in a and Nanjing packages containing Tokyo court by one of fleas infected with the aircraft pilots. Yersinia pestis.
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1990-1993 Japan: Tokyo Aum Shinrikyo cultists, Confessions and other prior to their 1994-1995 information contained sarin attacks, had sprayed in leaked police biological agents, including reports. anthrax bacteria, against several U.S.
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Moreover, there is no question that from a political and strategic point of view these weapons are often strongly coupled, for example, in the connection between biological or chemical weapons and state doctrines regarding "no first use" of nuclear weapons. Of note, one striking similarity between nuclear technology and biotechnology is their dual-use nature.
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Although there are lessons to be learned from the history of and our experience with nuclear weapons technology, many of the differences between the nuclear and biological realms are too great to adopt a similar mix of nonproliferation, deterrence, and defense. Effective strategies for anticipating, identifying, and mitigating the dangers associated with advancing and emerging life sciences technologies demand a clear understanding of the varied and unique nature of the biological threat spectrum.
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, intended to prevent the diversion of fissile material from civilian use to weapons programs. The regime employs inspections, audits, and surveillance cameras and instrumentation, monitoring some 1,100 facilities and installations worldwide.
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Despite its challenges, including difficulties created by uncooperative nations that may possess capable delivery systems, the nuclear nonproliferation regime has been reasonably successful in part because the production of nuclear weapons-usable plutonium or uranium has substantial technical requirements (reactors or enrichment plants, respectively) that create conspicuous bottlenecks for any would-be weapons program.
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For example, while the maintenance of inventories of critical materials is of considerable use in monitoring the proliferation of nuclear weapons and, while less so, still of use in monitoring the proliferation of chemical weapons, there is little basis for such efforts in monitoring or preventing the proliferation of biological weapons. Due to the inherent replicative properties of bacteria and viruses, large stocks of biological agents can readily be produced from very small quantities of stolen agent, so small that their absence would not be missed from even the most carefully inventoried collections.
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For example, the Australia Group adopts consensus national export controls to impede the transfer of biological agents and technology where possible. Nevertheless, the biological nonproliferation regime faces intrinsically greater challenges than does its nuclear or even chemical counterpart, because many of the relevant materials, technologies, and knowledge are far more widespread in the biological case.
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This aspect of these weapons has no good analog in the realm of nuclear weapons and only partial ones in the realm of chemical weapons. Many of the same tools that address natural disease threats will be needed to respond to an attack using biological weapons, or to prevent such an attack from succeeding, and this is likely to remain true even in a future case involving a genetically engineered pathogen.
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That is, protective measures are in a race with the malevolent application of potentially beneficial basic research, rather than primarily against technologies being developed in weapons programs of other countries.129 However, there is a legitimate concern that defensive research undertaken in one country's program could be misperceived as offensive, or potentially offensive, in character and drive other nations to pursue offensive research as well. For example, would it be legal and wise to have classified biodefense research activities produce modified pathogens that no adversaries are believed to have yet created in order to ostensibly understand and more robustly defend against them?
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A more detailed discussion of these benefits, particularly for the developing world, may be found in an earlier workshop summary report from this committee, An International Perspective on Advancing Technologies and Strategies for Managing Dual-Use Risks: A Workshop Report.131 There is no question that many populations have benefited greatly from advances in biotechnology and applications of related technologies (e.g., nanotechnology and informatics) to biomedicine and agriculture.
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identified the ten biotechnology-related developments that are likely to improve human health in developing countries within the next five to ten years:132 molecular diagnostics, recombinant vaccines, drug and vaccine delivery systems, bioremediation, sequencing pathogen genomes, female-controlled STI protection, bioinformatics, enriched genetically modified crops, recombinant drugs, and combinatorial chemistry. In addition to improved health, world agriculture stands to benefit greatly from new discoveries in the life sciences and growing technological capabilities.
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The Fink report summarized the details and implications of three recent examples of "contentious research" in the life sciences -- experiments that resulted in the creation of new infectious agents or knowledge with dual-use potential: the 2001 ectromelia virus (mousepox) experiment, in which Australian researchers engineered a recombinant virus that expressed the mouse interleukin-4 (IL-4)
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host cells, immune-response evasion and antibiotic resistance, from which to pick and choose the most lethal combinations."138 · A method for the construction of "fusion toxins," derived from two distinct toxins, for the purpose of killing cancer cells.139 This technique might be redirected to develop novel toxins that could target the normal cells of almost any tissue when introduced into a human host.
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Nanodevices that may be used to unplug blocked arteries could instead be employed to interfere with circulatory function. Advanced drug delivery technologies and pharmacogenomics knowledge could be used to develop and deliver
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. REPORT ROADMAP Chapter 2 of this report reviews the current global dispersion of tools and technologies used in the life sciences enterprise both domestically
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Chapter 3 provides an overview and perspective on the breadth and types of technologies that will -- directly or indirectly -- have an impact on how the life sciences enterprise will evolve in the near-term future. Finally, Chapter 4 presents the committee's conclusions and recommendations about the ways in which the adoption of a "web of prevention" approach might enhance our collective abilities to mitigate or minimize the negative consequences of inadvertent, inappropriate or purposeful malevolent applications of any of these technologies in the decades to come.
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2005. Six opportunities in nano-enabled drug delivery systems.
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2004. Accurate multiplex gene synthesis from programmable DNA microchips.
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2005. An International Perspective on Advancing Technologies and Strategies for Managing Dual-Use Risks.
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. 50One of the earliest recorded instances of biological warfare occurred in 600 BC, when the Athenian leader Solon used the noxious roots of the Helleborus plant to poison the water supply in the city of Kirrha.
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in Control of Dual-Use Threat Agents: The Vaccines for Peace Programme, SIPRI Chemical and Biological Warfare Series, 15 London, Oxford University Press. For the environmental impacts associated with biological weapons field testing, see Choffnes, E
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2001. The Rollback of South Africa's Chemical and Biological Warfare Program.
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Lancet Infectious Diseases 2(10) :62835; Casadevall, A
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Journal of Infectious Diseases 191(11)
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The list was initiated in 1997, when the Antiterrorism and Effective Death Penalty Act of 1996 required the Secretary of HHS to establish and enforce safety procedures for the transfer of listed biological agents (select agents) , including measures to ensure proper training and appropriate skills to handle such agents, and proper laboratory facilities to contain and dispose of such agents.
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2004. Nuclear, biological, and chemical weapons and missiles: Status and trends.
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347-348. This analysis was extended in a presentation given to the Committee on June 23, 2004 titled "Sensitive Information in the Life Sciences." A presentation very similar to that one, and available online, was delivered at the International Forum on Biosecurity in Lake Como on March 21, 2005 and can be found online at www7.nationalacademies.org/biso/Biosecurity_Epstein_2.0.ppt [accessed January 4, 2006]
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2005. Characterization of the 1918 influenza virus polymerase genes.
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