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2 The Pace of Developments in the Life Sciences A s the range of presentations covered at the workshop illustrates, the meeting surveyed developments in the life sciences broadly. Although it was not able to cover all possible topics in depth, the committee sought to identify major themes and trends and then to consider ways in which these scientific developments might relate to the Biological and Toxin Weapons Convention (BWC). The committee’s dis - cussions were guided by the three major trends identified in Chapter 1: • The pace of relevant advances in science and technology (S&T) and in related, enabling technologies; • The diffusion of S&T research and its applications; and • The breadth of fields now engaged in the “life sciences.” This chapter examines the first of these trends. 2.1 ADVANCES IN SCIENCE AND TECHNOLOGY 2.1.1 Developments Since 2006 As the message from United Nations Secretary General Ban Ki-moon to the BWC States Parties in 2010 (see Chapter 1) illustrates, one of the important trends that potentially affects the future of the BWC is the rapid pace of advances in S&T. The 2010 workshop provided the international scientific community with an opportunity to review major developments in S&T since the 2006 meeting organized by IAP, the International Council 25

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26 TRENDS RELEVANT TO THE BIOLOGICAL WEAPONS CONVENTION for Science, and the Royal Society. Many of the subject areas discussed in 2010 echoed those that were highlighted in 2006, including the “omics” fields,1 synthetic biology, delivery technology, and vaccine and counter- measures development. The workshop reviewed not only the potential to apply areas of S&T to the creation or delivery of biological agents that could be employed as weapons, but also to prevention, defense, and response against the misuse of biological agents, and to the promotion of beneficial uses of biology. Progress continues to be made in many of the research areas discussed in 2006 and 2010. Examples of key developments in advancing areas of life sciences are highlighted below. Particularly rapid developments have also occurred in enabling technologies and are discussed in more detail in Section 2.2. 2.1.2 Genomics, Systems Biology, and Synthetic Biology Developments Since the draft sequence of the human genome was published in 2001 and the completed sequence announced in 2003 (HHS and DOE, 2003; International Human Genome Sequencing Consortium, 2004), the sequencing of additional human genomes has proceeded rapidly. A vari- ety of large-scale collaborative genome sequencing initiatives have been undertaken, such as the international 1000 Genomes Project to catalogue human genetic variation as a resource for future biomedical research, which was mentioned at the workshop (The 1000 Genomes Project Con - sortium, 2010). A recent article on worldwide human genome sequenc- ing efforts notes, “although far from comprehensive, the tally indicates that at least 2,700 human genomes will have been completed by the end of this month [October 2010], and that the total will rise to more than 30,000 by the end of 2011” (Nature, 2010). A significant proportion of this increased sequencing capacity is expected to come from China, where BGI (formerly the Beijing Genomics Institute) is now one of the 1 “Omics” fields in the life sciences generally refer to the holistic analysis of a set of bio - logical information, in order to achieve a comprehensive understanding of its structure, function, interactions, and other properties. Omics fields include genomics, the study of the complete DNA sequence of an organism; metagenomics, the identification and analysis of the genomes of a community of organisms without first culturing and separating them; transcriptomics, the analysis of the set of RNA transcripts expressed by a cell, tissue, or organism; proteomics, the study of the set of expressed proteins that result from these transcripts; interactomics, the analysis of interactions among the molecules in a cell; me - tabolomics, the study of the cellular metabolites produced by the cell, tissue, or organism; and many others.

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27 THE PACE OF DEVELOPMENTS IN THE LIFE SCIENCES world’s largest sequencing centers2 and reportedly predicted in 2010 that it would complete 10,000 to 20,000 human genomes by the end of 2011 (Nature, 2010). Beyond human genome sequencing, international col - laborations are under way to sequence 1,000 plants and animals of eco - nomic and scientific importance (Fox and Kling, 2010) and to characterize the earth’s microbial communities from the soil, air, and water through the Earth Microbiome Project. The project, launched in 2010, plans to “analyze 200,000 samples from these communities using metagenomics, metatranscriptomics and amplicon sequencing to produce a global Gene Atlas describing protein space, environmental metabolic models for each biome, approximately 500,000 reconstructed microbial genomes, a global metabolic model, and a data-analysis portal for visualization of all infor- mation” (http://www.earthmicrobiome.org/; accessed June 1, 2011). 3 As several workshop presenters explained, additional omics fields con- tinue to advance steadily and build on the understanding gained through genomics, providing researchers with functional information to annotate the more static genomic data (de Villiers, 2010; Dhar, 2010; Pitt, 2010a,b). The field of systems biology seeks to integrate these multiple levels of bio - logical knowledge into descriptive, and ultimately predictive, mathemati - cal models, combining experimental knowledge with computational tools in order to study the interactions between the components that make up a particular biological system. As a result, a primary goal of systems biology is to understand how the system being studied functions, what its proper- ties are that arise from the interactions of its individual components (also referred to as emergent properties), and the design principles on which it operates (Bruggeman and Westerhoff, 2007; Ferrell, 2009). The field of synthetic biology seeks to use the knowledge gained through these other biological disciplines in order to design new path- ways4 having defined functions. Perhaps of all the S&T areas examined during the workshop, synthetic biology has received the greatest public and policy attention, both for its potential contributions to health, the economy, and the environment and for the security risks that misuse of 2 Second generation sequencers at BGI include 137 HiSeq 2000 systems from Illumina and 27 SOLiD 4 systems from Applied Biosystems, along with multiple, earlier generation capillary electrophoresis (“Sanger method”) sequencers (http://www.genomics.cn/en/). BGI has locations in China, the United States, and Europe. 3 Descriptions of genomic sequencing projects are derived from articles current at the time of committee discussions. With rapid development in research and sequencing capacity, the state of these projects and the numbers of genomes sequenced also change rapidly. 4 “A biological pathway is a series of actions among molecules in a cell that leads to a certain product or a change in a cell. Such a pathway can trigger the assembly of new mol - ecules, such as a fat or protein. Pathways can also turn genes on and off, or spur a cell to move” (U.S. National Human Genome Research Institute, Fact Sheets: Biological Pathways, http://www.genome.gov/27530687, accessed August 29, 2011).

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28 TRENDS RELEVANT TO THE BIOLOGICAL WEAPONS CONVENTION its discoveries could pose.5 Given this, the committee addressed synthetic biology in the context of all three major trends it identified, and discus - sions of aspects of synthetic biology are found in Chapters 3 and 4 as well as here. Synthetic biology has now resulted in the successful creation of indi - vidual components or elements that can be used as building blocks within a larger genetic network or pathway (Khalil and Collins, 2010; Purnick and Weiss, 2009),6 bringing ever closer the promise of practical appli- cations based on synthetic biology principles. Examples of successful engineering of specific cellular pathways derived from existing genetic sequences have already been reported, notably the design of a terpe- noid biosynthesis pathway in yeast to produce the plant-derived antima- larial drug precursor artemisinic acid (Ro et al., 2006). Terpenoids are a very large class of molecules with diverse functions, many of which may have potential pharmaceutical uses (statin drugs, for example, inhibit an enzyme in a terpenoid synthesis pathway resulting in decreased down- stream production of cholesterol). Understanding and manipulating ter- penoid pathways, the enzymes involved in those pathways, and pathway regulation also hold promise for the development of novel antimicrobial drugs (Muntendam et al., 2009). In 2010, yet another milestone in synthetic biology was reported—the design and synthesis of a functioning bacterial genome and its insertion into a cell from which the natural genetic material had been removed (Gibson et al., 2010). This advance was notable because it represented the creation of a fully synthetic genome able to successfully direct the range of activities needed for the bacterial cell to survive, grow, and reproduce 5 For example, SYNBIOSAFE, a project supported by the European Commission, examines issues of safety, security, and ethics in synthetic biology (http://www.synbiosafe.eu/). Ethi- cal and security issues in synthetic biology have also been addressed in reports from the U.S. Presidential Commission for the Study of Bioethical Issues (2010) and the U.S. National Science Advisory Board for Biosecurity (2010). The Implementation Support Unit (ISU) of the BWC has co-hosted workshops on synthetic biology in partnership with the United Nations Interregional Crime and Justice Research Institute (UNICRI) and with the Geneva Forum, as well as delivered presentations on biosecurity issues at synthetic biology confer- ences (reports of the activities of the ISU are available at http://www.unog.ch/bwc/isu). 6 These include, for example, various promoters and regulators to influence gene expres - sion. Building on roots in both molecular biology and traditional engineering disciplines, synthetic biologists frequently conceive of cellular systems through the framework of elec - tronic circuit design. As a result, biological modules may be viewed as functioning like switches, oscillators, logic-gates, and other electronic components; the framework is used as an aid in trying to design and conceptualize biological systems similar to the manner in which engineers design machines. Synthetic biologists have also borrowed terminology from the computational sciences, referring to the ability of genetic material to operate as the “software” of living systems and to “boot up” the operations of a cell (which can analo - gously be thought of as the hardware).

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29 THE PACE OF DEVELOPMENTS IN THE LIFE SCIENCES itself. It also represented progress along the pathway toward “synthetic life,” although the study itself did not create a fully synthetic organism from scratch (i.e., from a pool of chemical precursors to create not only the genetic information but also the cell membrane and necessary cellular machinery), an achievement that still remains out of reach. Discussion and Implications The combination of enabling tools, particularly high throughput mea- surement techniques (see Section 2.2), and the number of omics projects being undertaken results in the creation of vast amounts of biological data to be analyzed and converted into information that will be useful to systems and synthetic biologists. Based on the workshop discussions, the committee emphasizes, however, that the complexity of biological systems remains a significant obstacle to the ability to construct accurate mathematical models, even at the level of a single signaling pathway. For example, Dr. Andrew Pitt of the University of Glasgow in the United Kingdom7 noted at the workshop that solving a mathematical model of the epidermal growth factor receptor pathway requires equations for 322 components and the 211 reactions in which they are involved (Oda et al., 2005). As a result, truly rational systems design in biology remains a goal of the field (Pitt, 2010a). As a recent review of developments in synthetic biology notes, Whereas traditional engineering practices typically rely on the stan- dardization of parts, the uncertain and intricate nature of biology makes standardization in the synthetic biology field difficult. Beyond typical circuit design issues, synthetic biologists must also account for cell death, crosstalk, mutations, intracellular, intercellular and extracellular condi - tions, noise and other biological phenomena. A further difficult task is to correctly match suitable components in a designed system. As the number of system components grows, it becomes increasingly difficult to coordinate component inputs and outputs to produce the overall desired behavior. (Purnick and Weiss, 2009) Nevertheless, advances in omics, systems, and synthetic biology have potential implications for the BWC in several overarching areas. On a fundamental level, these fields continue to advance the understanding of biological systems—including human, animal, plant, and microbial physi- ology. These fields provide information on how systems function, on net - works of interactions (for example, between receptors, ligands that bind to them, and resulting cascades of signaling molecules), and on points at 7 Dr. Pitt is currently affiliated with Aston University.

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30 TRENDS RELEVANT TO THE BIOLOGICAL WEAPONS CONVENTION which such systems might be modified or acted upon to cause specified biological effects. In addition to the goal of improving the understanding of existing systems, scientists are exploring how to control these systems in ways that we currently cannot and to enable the design of completely new systems. The knowledge that results from these discoveries might eventually be used to explore new targets and mechanisms of action of biological agents, or new agents themselves, with implications for both protective and prophylactic purposes or for bioweapons. For example, understanding of immune pathways gained through systems biology approaches can be applied to the development of new vaccines (Oberg et al., 2011), while studies of drugs and their networks of interactions in the body can aid in the identification of new drug targets (Chua and Roth, 2011). Laboratories in synthetic biology are already working toward designing and synthesizing new microorganisms by manipulating meta - bolic and biosynthetic pathways, work that is being conducted for socially beneficial ends such as biofuel production (Alper and Stephanopoulos, 2009; Keasling, 2010). However, advances in synthetic biology may also enable the synthetic re-creation of known pathogens, the combination of sequences from several microorganisms to create new chimeric patho - gens, or even the design and synthesis of novel pathogens (NRC, 2010b; Tucker and Zilinskas, 2006).8 2.1.3 Immunology The workshop surveyed the state of life sciences research broadly and considered both whether S&T developments might have the potential to be misused and how advances in science could help provide solutions to BWC concerns. Developments in understanding the immune system have potential relevance to both of these themes. Developments Advances in molecular biology, high throughput techniques, and bioinformatics tools for data analysis are moving the field from empiri- 8 Discussion continues about the relative risks and extent to which advances in areas such as DNA synthesis and synthetic biology enable the construction of novel viral or bacterial pathogens. Design issues arising from the complex nature of biological systems are noted above (Purnick and Weiss, 2009), suggesting that creating a novel genome that yields specifi - cally desired pathogen functions and virulence, either by de novo design or by combining sequences derived from existing microorganisms in new ways, would continue to take sig- nificant time and effort. To create a functional pathogen also requires additional, nontrivial steps beyond the construction of a nucleic acid genome. These include packaging the genome into a viral capsid or a bacterium, replication and production of larger quantities of the pathogen, and possibly steps to protect the pathogen from environmental degradation and render it more suitable for delivery (Tucker, 2011a). Further discussion about tacit and explicit knowledge required to conduct complex scientific experiments may be found in Section 5.1.2.

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31 THE PACE OF DEVELOPMENTS IN THE LIFE SCIENCES cal, trial-and-error design of vaccines and drugs toward rational design (Adams et al., 2011; Bagnoli et al., 2011; Bowick and Barrett, 2010; Connell, 2010; Plotkin, 2009). To accomplish this goal, scientists characterize the pathogens, their hosts,9 and systems of pathogen-host interactions that occur during infection and subsequent immune responses. For example, by comparing the genomic sequences of multiple strains of a pathogen, researchers may identify genetic alterations that correlate with greater or lesser virulence. In fact, increasing virulence of a pathogen is a use - ful experimental approach to understanding pathogenic mechanisms (Shimono et al., 2003). Yet such manipulations of even mildly virulent organisms could lead to the creation of novel pathogens, which could result in some States Parties questioning whether the project could be a possible violation of Article I. By using high throughput microarrays, scientists can also identify the patterns and changes of gene and pro- tein expression that occur in the pathogen and the host. All of these techniques are directed toward determining the specific molecules and signaling pathways involved in host responses to a pathogen and the ways that pathogens disrupt effective host immune reactions in both plant and animal species,10 ultimately enabling scientists to move toward a systems-level understanding of the infection process. This expanded base of knowledge is used to identify proteins, nucleic acids, or attenu - ated pathogen strains for testing as vaccine candidates, to design vaccines and countermeasures that will stimulate aspects of the host immune response that are predicted to be effective in eliminating the pathogen, or to disrupt the mechanisms that a pathogen uses to bypass an effective host response. The increased DNA sequencing and characterization of individual genomic data and the correlation of different genetic variations with different responses to a pathogen or to a vaccine are also moving the field toward “personalized vaccinology” (Connell, 2010). Researchers developing vaccines and countermeasures are actively studying new expression and delivery systems (see Section 2.1.6), along 9 Because potential biothreat agents could be used not only to cause human disease but also to act against veterinary or agricultural targets, the relevant “host” for a pathogen could be a human, a nonhuman animal, or a plant. 10 Many pathogens employ strategies designed to diminish the effectiveness of a host’s immune response against them. For example, almost all human cells display Major Histo - compatibility Complex (MHC) class II molecules on their surfaces, and certain cells also display MCH class I molecules. These molecules present antigens derived from infecting pathogens to the immune system. Some pathogens decrease MHC I or II expression on cell surfaces, diminishing the resulting immune response. Other pathogens directly target and kill frontline immune sentinel cells such as macrophages and dendritic cells. Plant pathogens also employ strategies to decrease the effectiveness of plant immune responses directed against pathogen-associated molecular patterns and virulence factors. Although plants lack some types of immune responses exhibited by mammals, they employ similar types of “in - nate” immune responses (Jones and Dangl, 2006).

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32 TRENDS RELEVANT TO THE BIOLOGICAL WEAPONS CONVENTION with options to enable more rapid development and manufacturing (Bagnoli et al., 2011; Plotkin, 2009). One example mentioned during the workshop is the use of nonpathogenic latent viruses as transgene vaccine delivery systems (Connell, 2010). Such viruses result in an ongoing but nonsymptomatic and nondisease-causing infection and so can provide a more long-lived boost to the immune system through continued pro- duction of immunogens. For example, altered strains of Herpes Simplex Virus-1 (HSV-1) are being developed to deliver foreign antigens (i.e., immunogenic proteins for protection against infection by bacteria and non-Herpes viruses) (Manservigi et al., 2010; Marconi et al., 2009). An added advantage of this approach is that HSV-1–based vaccines are capa- ble of eliciting a strong cellular immune response.11 DNA-based vaccines are another option, particularly when combined with adjuvants or as the first (prime) immunization in a two-pronged prime and boost strategy (Liu, 2011). The DNA that encodes pathogen proteins against which an immune response is desired can be delivered to cells using viruses or bacteria as vectors or using lipid or polymer-based nonviral particles, as discussed in Section 2.1.6. The immunoprotective proteins encoded by the DNA are subsequently produced within host cells and expressed as anti - gens on host cell surfaces, generating immune responses (Ledgerwood and Graham, 2009; Plotkin, 2009). There is also significant interest in the development of new human and veterinary adjuvants, which work in conjunction with vaccines to boost immune responses (Heegaard et al., 2011; Reed et al., 2009). All adjuvants appear to act by stimulating components of the innate immune system, thereby affecting the outcome of adaptive immunity. Thus as more is learned about innate immunity, adjuvants can be designed in ways that direct the efficacy of a given vaccine toward a specific outcome. These studies will greatly enhance vaccine development in the future. New vaccine platforms are another major focus of countermeasures research. Platforms are flexible systems of vectors (whether viruses, bac- teria, or particles) that deliver genes for the pathogen-associated proteins against which immunity is desired, are adaptable so that genes of interest can be swapped in and out of the base platform system, and are optimized for rapid production (Drew, 2007; Ledgerwood and Graham, 2009). Finally, 11 The mammalian immune system includes innate immune responses (which are rapid in response and are frequently directed against conserved pathogen signals such as bacte - rial lipopolysaccharides) and adaptive immune responses. The adaptive immune system includes two broad pathways—one that results in the generation of circulating antibodies directed against an extracellular pathogen or toxin (“humoral immunity”), and one that di - rects the immune system to kill cells that have been infected with an intracellular pathogen such as a virus (“cellular immunity”). The nature and extent of immune system responses are influenced by many factors, including the type and location of immune cells that first encounter the pathogen and by chemical signals such as cytokines that preferentially direct the immune response toward one or the other pathway.

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33 THE PACE OF DEVELOPMENTS IN THE LIFE SCIENCES the global prevalence of antimicrobial resistance remains a significant and growing concern, including the spread of multidrug resistant strains, and new antibiotic and antiviral countermeasures are clearly needed. Although the introduction of high throughput screening has greatly reduced cost and increased efficiency of drug discovery and the search for new antibiot- ics, the length of time, regulatory hurdles, and costs of bringing new com- pounds into the clinic remain high (Hamad, 2010; IDSA, 2011; IOM, 2010). Discussion and Implications Advances in vaccine design and production, in particular those associated with rapid manufacturing methodologies, will have obvi - ous benefits for global health and for preparedness for and response to the potential use of bioweapons or bioterrorism, as well as serving an important public health function. Advances in understanding plant immune systems and plant defenses against infection similarly have rel- evance to the protection of crops against both natural disease outbreaks and potential intentionally introduced pathogens. Article X of the BWC, which addresses cooperation in the prevention of disease, promotes the sharing of materials and knowledge in the development of infectious disease therapeutics. However, advanced understanding of the immune system has potential dual use implications because it could be misap - plied to create pathogens with increased virulence or to decrease the effectiveness of a human, animal, or plant immune response. A concern has been raised, for example, that as synthetic biology continues to advance it could be used to design novel pathogens for these functions. Effectively modulating and controlling the immune system whether for beneficial or harmful purposes remains a challenge because of the complexity of the immune system itself and because of the complexity of immune system interactions with other physiological systems like the endocrine and nervous systems. Biological systems exist in an “exquisite balance” (Connell, 2010), and although scientific knowledge continues to expand, it is still not possible to predict with certitude the downstream effects of disrupting these biological control systems (Connell, 2010; Nixdorff, 2010). The well-known mousepox case study represents one example in which immune modification provoked unintentional negative effects, creating a lethal vaccine (Jackson et al., 2001).12 12 Researchers seeking to create a contraceptive vaccine used a nonpathogenic strain of the Ectromelia virus, which causes mousepox, to deliver DNA encoding a mouse egg protein to mice. The goal was to induce an immune response against the egg protein, preventing fertil- ity. In order to boost the effectiveness of their vaccine, researchers also co-delivered DNA for the cytokine IL-4, which modulates the immune system. By influencing the immune system in such a way that it mounted a less effective response to the vaccine virus, the researchers unintentionally created a mousepox virus that was lethal to the mice.

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34 TRENDS RELEVANT TO THE BIOLOGICAL WEAPONS CONVENTION Other significant challenges are associated with the development of new vaccines and countermeasures against infectious diseases. Sophisticated laboratory containment systems are required to safely handle certain patho- gens, particularly ones of concern as potential bioweapons and as new emerging diseases. Developing and testing vaccines against these patho- gens often requires the use of animal models because of ethical consider- ations that prevent experimental infection in humans and make conducting clinical trials problematic. In many cases, suitable animal models may not currently exist or the specific types and levels of immune responses that correlate with protection in humans are not well known (Matheny et al., 2007; NRC, 2006b). There are also few significant commercial markets for vaccines, and this fact coupled with the regulatory requirements necessary to develop a licensed product result in low commercial interest. As a result, incentives and government and philanthropic investments have been used to drive the creation of new vaccines and medical countermeasures. Many pathogens of concern as bioweapons and as emerging infec- tious diseases are zoonoses (e.g., Bacillus anthracis (anthrax), Yersinia pes- tis (plague), Rift Valley fever virus (Rift Valley fever), Coxiella burnetii (Q fever), Burkholderia mallei (glanders), equine encephalitis viruses (East- ern, Western, and Venezuelan equine encephalitis), Ebola virus (Ebola hemorrhagic fever), influenza viruses such as H5N1 (avian influenza), and others).13 This fact highlights the fundamental importance of coop- eration among human, animal, and plant health research communities to support new medicine and vaccine development efforts and global disease surveillance; natural partners include the World Health Organi- zation (WHO), the World Organisation for Animal Health (OIE), and the United Nations’ Food and Agriculture Organization (FAO). The creation of appropriate animal models to support the development and testing of new licensed human products against pathogens of concern is an obvious area for collaboration. The committee noted that contact already exists between the BWC, WHO, FAO, OIE, and other potential partners.14 Fur- ther descriptions of this engagement may be found in Chapter 3 as part of a broader discussion of international collaboration on public health. 2.1.4 Neuroscience The ability to target and deliver substances to the brain and central nervous system brings great promise to the treatment of diseases like brain cancer. Delivery of therapeutics to influence mood and cognition 13 A zoonotic disease is one that can be transmitted between wild or domesticated animals and humans. 14 Reports of the activities of the BWC ISU reference relevant meetings with a variety of intergovernmental and nongovernmental organizations and are available at http://www. unog.ch/bwc/isu.

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35 THE PACE OF DEVELOPMENTS IN THE LIFE SCIENCES also play roles in treating a range of neurological disorders like depres - sion, attention deficit disorder, and many others. Developments Neuroscience research is providing new insights into gene expression, variability, and phenotypic plasticity at the level of individual nervous system cells, knowledge that is helpful to understanding the functions of cells in the nervous system as well as exploring improved options for drug screening platforms (Eberwine, 2010). It is also helping scientists to better understand processes in disease development and pathology, for example in elucidating the role of genetics and molecular interactions in Alzheimer’s disease (Holtzman et al., 2011). Advances in delivery meth - ods and formulations intersect with neuroscience research in, for example, developing improved therapeutics to cross the blood brain barrier (BBB).15 Finally, research continues to actively explore the brain-machine interface, which could have positive applications for the replacement of motor or sensory system functions lost due to injury and the creation of functional prosthetics. Signals captured from neurons in the brain can be processed computationally, for example, to allow a subject to move a cursor on a screen or to move a robotic hand (Leuthardt et al., 2009; Warwick, 2011). This area has received significant civilian and military attention and some overstatement of current levels of development. Commercial games using noninvasive methods to capture neural output (for example, by wearing a helmet that monitors brain electrical signals) have been on the market for several years (Li, 2010). Small numbers of patients have received initial prototypes of invasive or noninvasive neural interfaces, several com- panies are actively developing neural systems (e.g., BrainGate, http:// www.braingate.com/), and clinical trials are ongoing (e.g., the U.S. study “Microelectrode Brain-Machine Interface for Individuals with Tetraple - gia,” http://www.clinicaltrials.gov, accessed August 18, 2011). A variety of scientific and technical hurdles remain to be overcome, however, in cre- ating more sophisticated and accurate medical devices (Lega et al., 2011). Advances in the delivery of molecules to the brain also raise the possibility of delivering substances that could influence brain and body pathways as bioregulators and that could either enhance or degrade aspects of cognition, performance, and mood. Oxytocin, for example, is a 9 amino acid peptide found naturally at high levels in women following 15 The blood brain barrier inhibits the movement of most molecules from the body’s bloodstream into the brain and central nervous system, although small molecules such as dissolved oxygen can pass, and some molecules, such as glucose needed by brain cells, are actively transported across. The barrier consists largely of tight junctions between the endothelial cells that line the capillaries.

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48 TRENDS RELEVANT TO THE BIOLOGICAL WEAPONS CONVENTION government influences. The enormous amounts of data and information being generated from research in omics technologies and fields such as immunology, neuroscience, and systems biology are providing scien- tists with information to better understand processes within biological systems. Research in these fields is helping to support a more complete understanding of human, animal, and plant variability and its relation - ship to disease and is also identifying and characterizing new microbes and their roles in multiple environments. Scientists are actively seeking to integrate information at multiple biological levels (from genes, to pro - teins, to networks of intra- and inter-cellular interactions, to community dynamics) in order to improve biological understanding and to support rational engineering and design. As a result, advances in S&T are increas- ing the overall understanding of biological systems. Important milestones have been achieved in molecular biology and synthetic biology, and very active research in these areas is expected to continue worldwide. The extraordinary complexity of biological sys - tems and the challenges this complexity presents to the effective under- standing and design of biological systems remain significant barriers even as applications building on these research fields draw closer to fruition. This complexity is likely to remain a defining feature of biologi- cal systems for the foreseeable future. As a result of this complexity, for example, ab initio design of biological organisms will likely be unachiev- able for a number of years to come. Well-funded and well-organized research programs are making significant steps toward this goal, but their efforts remain far from commonplace. Although genetic modifica- tions of organisms are already possible and relatively straightforward today, the complexity and stochastic nature of many biological interac - tions can also render the outcome of novel modifications unpredictable. Understandings reached by the Sixth Review Conference of the BWC include “that all naturally or artificially created or altered microbial and other biological agents and toxins, as well as their components, regardless of their origin and method of production and whether they affect humans, animals or plants, of types and in quantities that have no justification for prophylactic, protective or other peaceful purposes, are unequivocally covered by Article I” (BWC, 2006). This suggests that any forms of artificial biological systems (such as might be created by synthetic biology), or synthetic chemical analogs of biological molecules, would be covered under the prohibitions enshrined in Article 1. How - ever, as science continues to advance rapidly new research develop - ments may provide additional opportunities for further clarification and understandings to be reached. Developments in S&T in areas such as transgenic animal expres - sion systems, production of proteins in plants through “pharming,” availability and sophistication of small-scale bioreactors, and chemical

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49 THE PACE OF DEVELOPMENTS IN THE LIFE SCIENCES synthetic methods to produce biological molecules also affect the ways in which biological materials are produced or reduce the time, space, or cost requirements needed to produce them. These advances raise the possibility that molecules that have previously been very difficult or expensive to obtain may be more readily produced in larger amounts (for example, extraction in the 1960s of several grams of the neurotoxin saxitoxin reportedly required processing tons of affected clams [Tucker, 2011b]). The changing nature of biological production systems thus expands the understanding of potentially relevant production capabili - ties beyond the traditional model of fixed, industrial-scale, cell culture fermentation tanks. Advances also continue in the development of effective injectable, implantable, and inhalable delivery systems for molecules such as genes and drugs. The medical industry is a primary driver of this development, and the most notable advances are being made at the level of individual- use systems (for example, the delivery of nanoparticles encapsulating chemotherapeutic agents to a cancer patient or the implantation of mate - rials able to release insulin in a diabetic patient in response to glucose levels). In the context of the BWC, questions on the potential for advanced or targeted delivery systems to be scaled up and delivered to multiple people, such as through environmental aerosol dispersal, are particularly relevant. The committee interpreted the obligations contained in Article 1(b) as covering advanced forms of delivery systems, should such systems be used to deliver biological agents in violation of the other provisions of the BWC, but noted that delivery systems developed for medical (vet - erinary, pest control, etc.) purposes may be relevant to the overall assess- ment of risks posed to the objectives of the BWC by new technological advances. Detailed discussions on these questions were beyond the scope of the Beijing workshop and current report, but may be areas for further discussions and monitoring. Biosensors and detectors are another area that has seen significant interest since 2006. The biological and engineering advances that under- pin the development of these sensors continue to move forward, although there are still limitations in what can be achieved, and sensor develop- ment balances factors such as specificity, sensitivity, range of target mol - ecules analyzed, and type of use (for example, sampling environmental components such as a building’s air supply or sampling fluids such as blood from a single individual for diagnostic purposes). Biosensors are also only one tool and are used with information provided by other sci- entific and policy tools in order to make decisions. Finally, the committee noted that multiple, parallel S&T fields are developing and advancing. As key advances are achieved in one field, they may be combined with developments in others to achieve new opportunities and new applications.

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50 TRENDS RELEVANT TO THE BIOLOGICAL WEAPONS CONVENTION 2.2 ENABLING TECHNOLOGIES Some of the most notable developments since 2006 can be found in the enabling technologies that underlie and support significant advances in life sciences research, particularly the availability of high throughput systems and powerful computational resources. Access to these resources and the availability of large amounts of data storage capacity underpin many of the developments in the omics fields and in systems and syn- thetic biology (see Section 2.1.1). Increasing global access to computational and data resources is also cited in the Chapter 3 discussion on diffusion of research capacity and applications. These enabling technologies have general implications relevant to the BWC because they are helping to push the overall life sciences research enterprise forward at an ever more rapid pace. Unlike in the previous section, specific implications for the BWC are not drawn out within each subsection; rather a broader discus - sion of the potential implications of enabling technologies is provided in Section 2.2.4. 2.2.1 High Throughput Systems Significant research and development are taking place in new tech- nologies for high throughput sample analysis. High throughput systems generally rely on robotics, computer-based control systems, and detector technologies to automate sample handling and analysis, emphasizing the multidisciplinary nature of modern life sciences research. Although an initial investment in such systems can be significant, they have the abil - ity to greatly increase speed and capacity by analyzing multiple samples in parallel. DNA sequencing technology is one area that has experienced particu- larly rapid advances (de Villiers, 2010; Dhar, 2010; Pitt, 2010a,b; Taylor, 2010).23 Next or “second generation” DNA sequencing systems, such as the Illumina HiSeq 2000 released in 2010, have significantly increased DNA throughput capacity. The HiSeq 2000, for example, can reportedly read up to 25 billion bases of DNA per day in 100 base pair read lengths using a modified method of sequencing during synthesis (Illumina.com, http://www.illumina.com/documents/products/datasheets/datasheet_ hiseq2000.pdf). Second generation sequencing technology such as the 23 “First generation” DNA sequencing was based on a method initially developed by Frederick Sanger in the 1970s and on the fact that double-stranded DNA is synthesized using its complementary strand as a template. As this synthesis is conducted, regular deoxynucle - otide triphosphates (the building blocks of DNA) are mixed with labeled dideoxynucleotides that will terminate an extending DNA chain. The result is a series of DNA molecules that each differ by one nucleotide in length; these are separated by capillary electrophoresis and the terminal nucleotide identified, allowing the DNA sequence to be read.

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51 THE PACE OF DEVELOPMENTS IN THE LIFE SCIENCES HiSeq generates relatively short lengths of DNA sequence, which are aligned and assembled into the complete sequence using software and computer systems. This process is made significantly easier when a pre - viously sequenced reference genome is available to help guide the align- ment, such as the reference human genome sequenced in 2003. A variety of new (“third” or “fourth” generation) DNA sequencing technologies are also on the horizon, some of which might produce longer DNA sequence lengths and higher accuracy than the current technology or might further increase speed and decrease costs (Niedringhaus et al., 2011; Shendure and Ji, 2008). In some cases, these technologies streamline steps in the sequencing process so that each nucleotide is directly read as it is incor- porated into a single molecular DNA chain (e.g., Pacific Biosciences) (Niedringhaus et al., 2011). In other cases, very different technical pro- cesses are being explored for sequencing, such as the detection of altera - tions in current as individual bases of a DNA molecule pass through a nanopore (e.g., Oxford Nanopore) (Niedringhaus et al., 2011). Along with the increase in speed has come a dramatic decrease in DNA sequencing costs. Figure 2.1 analyzes data from the U.S. National Human Genome Research Institute (NHGRI). Since 2008, costs have decreased even more rapidly than would be predicted by Moore’s Law,24 reflecting the use of second generation sequencing systems combined with the availability of the existing human genome reference (Wetterstrand, 2011). As a result, human genome sequencing can now be accomplished for approximately $0.10 per million bases of DNA or less than $10,000 per human whole genome, with costs dependent on factors like the sequenc- ing coverage and error rates, as well as which specific costs are factored into the calculation. In 2010, the company Complete Genomics announced that it had sequenced a genome for a cost of approximately $4,400 in consumables such as reagents (Drmanac et al., 2010). Science may be approaching the $1,000 genome in the not too distant future, a price that may in turn bring the concept of personalized medicine closer to reality (Pitt, 2010b; Venter, 2010). High throughput systems are also available to analyze gene and protein expression. For example, gene microarrays consist of small pieces of DNA attached to a solid surface to act as probes. Pieces of nucleic acid from a biological sample will hybridize with the fixed probes if they have a complementary sequence, and through this pro - cess researchers identify those genes that are expressed (turned into messenger RNA) in a particular cell and their relative expression levels. 24 “Moore’s Law” is the observation by Gordon Moore, the founder of Intel Corporation, that the number of transistors on a computer chip roughly doubles every two years. The comparison has frequently been drawn between this exponential growth and a comparable growth in DNA sequencing and synthesis capabilities.

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52 TRENDS RELEVANT TO THE BIOLOGICAL WEAPONS CONVENTION FIGURE 2.1 Decreasing costs of DNA sequencing. NOTE: Based on “production cost” data from the Large-Scale Genome Sequencing Program of the U.S. National Human Genome Research Institute. Costs include labor, reagents and consumables, DNA preparation, amortization of instrument costs, and initial data processing, but not expenses such as technology and bioin - formatics development and subsequent data analysis and interpretation. SOURCE: Wetterstrand (2011). Similarly, a variety of protein microarrays exist to identify and quantify the proteins found in a biological sample (Chandra et al., 2011). The use of mass spectrometry (MS), which ionizes proteins and measures the mass-to-charge ratio of the intact protein molecules and fragment ions, has also become a powerful and widely used tool to characterize the proteins and peptides in biological samples and to support proteomics research (Domon and Aebersold, 2006). Improvements in techniques to generate ions from biological molecules, including matrix assisted laser desorption/ionization (MALDI), have enabled improvements in analysis methods that can provide more detailed structural informa - tion about peptides. Examples include time-of-flight (TOF) analysis, in which the mass-to-charge ratio of ions is determined by measuring the time it takes the ion to travel through a vacuum after being accel - erated by an electric field, and tandem mass spectrometry (MS/MS), which makes use of multiple stages of MS analysis. These techniques

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53 THE PACE OF DEVELOPMENTS IN THE LIFE SCIENCES can enable the rapid and sensitive identification of microorganisms as well as their toxins; MS can also be applied to detect a microorganism’s nucleic acids amplified through techniques such as polymerase chain reaction (PCR), which may be useful in cases in which a microorganism cannot be cultured (Boyer et al., 2011; Ho and Reddy, 2011). As a result, these advances can contribute to areas relevant to the BWC including monitoring, diagnostics, and bioforensics. These types of high throughput systems all function as tools to help support active research in many of the areas discussed at the workshop, including genomics, proteomics, systems biology, and synthetic biol - ogy (de Villiers, 2010; Dhar, 2010; Pitt, 2010a). The characterization of changes in gene and protein expression during the progress of different diseases helps researchers identify new targets for the development of diagnostics and therapeutics, while the ability to analyze gene and pro - tein expression in individuals helps advance the concept of personalized medicine. 2.2.2 Computational Technologies and Data Resources Increasingly powerful stand-alone supercomputers are being con- structed, including specialized computers to investigate computationally intensive problems in the life sciences. For example, Anton, constructed by D.E. Shaw Research in 2008, is a massively parallel machine designed specifically to enable atomic-level simulations to be conducted of biologi - cal molecules up to millisecond-length time scales and up to 100 times faster than previously possible (Shaw et al., 2008; http://www.deshaw - research.com/). These molecular dynamics simulations can be used to investigate the folding and interactions of proteins and nucleic acids, for example to examine predicted interactions between cellular receptors and drug candidates in efforts to advance biological understanding and improve therapeutics development. Supercomputing resources are also now available in regions beyond the United States and Europe. Until June 2011, the world’s fastest stand-alone supercomputer, Tianhe-1A, was located at the National Supercomputing Center in Tianjin, China, surpassing the U.S.-developed supercomputer, Jaguar, in the November 2010 rankings published by the Top500 Project. In June, a computer at the RIKEN Advanced Institute for Computational Science in Japan bumped Tianhe-1A to number two on the list and four of the top five fastest super- computers are now located in Asia.25 25 Supercomputer rankings by the Top500 project are released twice a year based on the use of a benchmark performance measure. See http://www.top500.org/.

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54 TRENDS RELEVANT TO THE BIOLOGICAL WEAPONS CONVENTION An alternative strategy to the use of ever more powerful individ- ual supercomputers is the use of distributed computing.26 This strat- egy allows a network of smaller computers to create the equivalent of a supercomputer, thus enabling wider research access to significant com- putational resources and the analysis of far more complex problems. In his presentation to the workshop, Dr. Etienne de Villiers of the Interna - tional Livestock Research Institute (ILRI) in Kenya cited the successful distributed computing example of Folding@Home, a project based at Stanford University that is devoted to understanding protein folding and the relationship of misfolding to disease (De Villiers, 2010). By down - loading project software, participants donate a portion of their unused computing resources; the project website notes that “since October 1, 2000, over 5,000,000 CPUs throughout the world have participated in Folding@ Home” (http://folding.stanford.edu/), making it the equivalent of the largest computer in the world. Similar types of volunteer distributed computing networks are available worldwide. The Asia@home project promotes the use of volunteer computing resources in Southeast Asia, and a recent “Asia@home hackfest” was held during the International Sympo- sium on Grids and Clouds 2011 in Taiwan and focused on applications for earthquake science (http://event.twgrid.org/isgc2011/asiaathome.html). Project websites generally describe the motivations, goals, and problems being undertaken and may subsequently publish results. Although par- ticipants in these networks control how much of their computing capacity they are willing to make available to the project, they do not know the specific uses to which it is put. More specialized distributed computing networks, such as the Tera- grid system supported by the U.S. National Science Foundation, also pro- vide the research community with access to high-performance computing and data analysis. Teragrid, coordinated through the Grid Infrastructure Group at the University of Chicago, links computers from 11 U.S. partner sites to provide computing capability, online and archival data storage, and access to more than 100 discipline-specific databases (https://www. teragrid.org/). Similarly, EGI in Europe “maintain[s] a pan-European Grid Infrastructure (EGI) in collaboration with National Grid Initiatives (NGIs) and European International Research Organisations (EIROs), to guarantee the long-term availability of a generic e-infrastructure for all European research communities and their international collaborators” (http://www.egi.eu/). These increasingly available distributed comput - 26 Distributed computing “is any computing that involves multiple computers remote from each other” (de Villiers, 2010); the systems exist in various configurations with slightly different properties (e.g., cloud computing, grid computing). For further examples on the uses of distributed computing in life sciences research, see Burrage et al. (2006), den Besten et al. (2009), Schatz et al. (2010).

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55 THE PACE OF DEVELOPMENTS IN THE LIFE SCIENCES ing networks provide researchers with access to computing power, data - bases, software, and other tools. As a result, they can be thought of as evolving toward “knowledge grids,” a term that has come into use in the past decade to represent virtual social environments that enable access to resources and information as well as the sharing and creation of knowl - edge (Konagaya, 2006; Zhuge, 2004). 2.2.3 Communication Technologies Changes in communication technologies, including access to the Internet, email, blogs, social media, mobile communication platforms, and open access publishing, are also enabling widespread dissemination of data and viewpoints and have the potential to change the ways in which scientists work (Meadway, 2010; Royal Society, 2011b). Internet usage has grown very rapidly. For example, China and Tuni- sia have experienced 1,800 and 3,000 percent user growth, respectively, since 2000 (Meadway, 2010). A recent report from the Royal Society on international scientific collaborations notes that “the countries showing the fastest rate of growth in publication output and those rising up the global league tables as collaborative hubs show strong trends of growth in mobile phone usage and in internet penetration” (Royal Society, 2011b). Internet penetration is not yet universal and continues to vary widely even among countries in the same region.27 Despite some remaining access challenges, however, the growth in connectivity enables scientists from multiple countries to search and access information, communicate more easily and informally with each other through means like email and video conferences, and share documents for collaborative editing. Communication tools have enhanced researchers’ access to informa- tion in several ways. The ability to search widely used online journal databases such as PubMed, operated by the U.S. National Library of Medicine, coupled with the ability to link to and download journal arti - cles, has become more global as Internet usage has expanded, although 27 The International Telecommunication Union (ITU) monitors global trends and has created an ICT Development Index (IDI) that reflects multiple factors such as fixed and mo - bile telephone and Internet infrastructure, access, usage, and skills combined into a single score. Among 159 countries in 2008, Sweden had the highest IDI score (7.85), but significant country-to-country variation is present. Argentina, for example, had an IDI score of 4.38 (number 49 on the list), while Bolivia had a score of 2.62 (number 101); in Africa, Morocco had an IDI score of 2.68 (number 97), while Uganda had a score of 1.30 (number 145) (ITU, 2010). Other groups also monitor trends in world Internet usage. For example, although 66 percent of the general population in Argentina reportedly had access to the Internet as of March 2011, only 10.9 percent did in Bolivia. The rate was 41.3 percent in Morocco, versus 9.2 percent in Uganda and only 0.5 percent in Ethiopia (http://www.internetworldstats. com/stats.htm, accessed July 10, 2011).

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56 TRENDS RELEVANT TO THE BIOLOGICAL WEAPONS CONVENTION institutional subscriptions may be required to access an article’s full text. Several online-only life sciences journals also exist (e.g., PLoS One, Nature Communications). These journals frequently employ some system of peer review, but their online-only format can speed up traditional publishing times. In addition, articles that will appear in future issues of a print jour- nal are frequently available electronically in advance of print publication. The Internet also helps scientists identify specialists with whom to col - laborate, although it has been reported that 90 percent of all collaborations are initiated in person (Royal Society, 2011b). However, the Internet and other communication tools certainly help collaborations to develop and move forward once established. In these ways, advances in communica - tions technology continue to improve the ease, speed, and global reach of the traditional ways in which science has been done (in particular, the establishment of individual investigator-to-investigator collaborations that might be initiated at a scientific conference and then carried over to the Internet, ideally leading to the joint publication of a peer-reviewed journal article). As discussed during the workshop, an additional level of interac- tion involving greater social participation and networking can also be increasingly facilitated with “Web 2.0” technologies. Sites such as Wikipe - dia, for example, rely on user-generated content and collective wisdom, and other possibilities include science blogging, direct commenting on scientific articles, tagging of articles of interest to share with fellow users of a particular social networking site, posting updates on Twitter, or oth - ers. It is not yet clear the extent to which use of these types of tools has become widespread among practicing life scientists. Reportedly, fewer than 10 percent of a sample of 19,800 blogs tagged “science” were written by scientists, and only low percentages of U.K. researchers in 2009 used Twitter (10 percent) or regularly wrote a blog (4 percent) (Meadway, 2010). The challenges involved in creating new Web 2.0 resources that will be useful to life scientists and that can effectively integrate with the exist - ing ways in which science is done have been noted by several authors (Crotty, 2008; Stafford, 2009). David Crotty, formerly an executive editor at the Cold Spring Harbor Laboratory Press, suggested in 2008 that some of these tools, such as blogging or tagging, take investments of time and currently yield insufficient benefits for a scientist, given the continuing emphasis on peer-reviewed journal publications as the gold-standard by which academic productivity is judged (Crotty, 2008). There are also varia- tions in the uses of technology by discipline, with fields such as computer science and mathematics reportedly making more widespread use of newer communications technologies than fields such as medical science (Meadway, 2010). Within the biosciences, it appears that the synthetic biol- ogy community may have adopted some of these newer communications tools—the teams participating in the International Genetically Engineered

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57 THE PACE OF DEVELOPMENTS IN THE LIFE SCIENCES Machine (iGEM) competition, for example, all develop wiki pages as one of the competition requirements. 2.2.4 Discussion and Implications of Enabling Technologies There has been particularly rapid progress in both access to and power of enabling technologies that underpin life sciences research, including computational and communication resources and high throughput labo - ratory technologies. The computational power available to researchers continues to increase, through both specialized stand-alone computers and distributed computing networks. The use of high throughput sample handling and analysis methods has become widespread, and these tools increase the speed with which researchers can conduct studies as well as the volume of data they obtain. As discussed above, the uses of high throughput analysis tools and computational resources are enabling faster and cheaper developments in the life sciences while the rapid global spread of the Internet and other forms of electronic and mobile communication significantly enable global scientific collaboration and the dissemination of scientific information. Some of the newer “Web 2.0” tools also have the potential to provide a greater social context to the process of scientific knowledge creation, and dissemination and the use of these types of tools in the life sciences may become more widespread as ways to integrate them into the existing sys - tem of science become more clearly defined. These developments have several general implications for the BWC. First, the technologies underpin other developments in the life sciences and contribute to the pace and nature of advances being made in fields that might have specific relevance to the treaty. For example, high through- put techniques yield large amounts of data to advance systems biology understanding in areas like immunology and neuroscience, while compu- tational capacity is used to address problems such as protein structure as part of screening drug candidates for therapeutics development. Second, the global and widespread use of communication technologies, along with models such as online and open access publishing of experimental results, make efforts to control or restrict access to scientific knowledge ever harder. Finally, the same types of mobile and electronic tools that scientists can use to collaborate and share information could also be used by other types of distributed groups, whether state- or non-state actors, to trade information and knowledge. Technological resources that enable the life sciences are now available worldwide, although access to them is not yet evenly distributed. However, the life sciences community is only one of many communities that use computational and communication technologies. As a result, rapid progress in these fields is driven by many factors beyond the life sciences.

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58 TRENDS RELEVANT TO THE BIOLOGICAL WEAPONS CONVENTION 2.3 SUMMARY REMARKS ON CHALLENGES AND OPPORTUNTIES RELATED TO THE PACE OF S&T DEVELOPMENTS Developments in advancing and enabling areas of S&T provide both opportunities and potential challenges relevant to the BWC. One potential challenge posed by advancing S&T is the possibility that a novel devel - opment will fall outside the scope of the treaty. As discussed in Section 2.1, the committee did not identify any developments among those it surveyed that did so, a finding also reached by the scientific community at a workshop held prior to the Sixth BWC Review Conference in 2006 (Royal Society, 2006a,b). However, rapid advances in the life sciences on many fronts will likely continue to pose challenges for tracking and assessing future research progress—in establishing priorities for which areas to monitor, anticipating new combinations of advances drawn from progress in multiple fields, and expanding the types of expertise required to assess new developments. Advances in S&T also provide opportunities to address specific BWC concerns. For example, knowledge derived from omics, systems biology, and immunology, and the high throughput tools, computational resources, and bioinformatics that enable these fields can support ratio- nal vaccine and drug design, along with efforts to better understand the immune system, pathogen virulence, and how to modulate these factors. This understanding is critical for effective vaccine and countermeasures development. As has already been widely recognized, there is a potential dual nature to advances in many fields of the life sciences, because the informa- tion that could enable scientists to better understand and manipulate fun- damental life processes could potentially also be misused to create harm, and a clear dividing line cannot be drawn between the knowledge, skills, and equipment that would be needed for beneficial or for harmful pur- poses (Atlas and Dando, 2006; Azzi, 2009; NRC, 2004; van der Bruggen, 2011). It has also been widely recognized that engaging the scientific com- munity in discussions on the safety, security, and ethical implications of research are inherently international, given the global nature of the life sciences research enterprise. This global research capacity and growing numbers of international collaborations in the life sciences are discussed further in the following chapter.