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Advances in Technologies with Relevance to Biology: The Future Landscape

This chapter provides an overview and a perspective on the breadth and types of technologies that may have an impact on the life sciences enterprise of the future, with the understanding that there are inherent difficulties in anticipating or predicting how any of these technologies alone or in combination will alter the nature of the future threat “landscape.”

Rather than attempt to cover the technology landscape in a comprehensive manner, this chapter (1) highlights technologies likely to have obvious or high-impact near-term consequences; (2) illustrates the general principles by which technological growth alters the nature of future biological threats; and, (3) highlights how and why some technologies are complementary or synergistic in bolstering defense against future threats while also enhancing or altering the nature of future threats.

There is immense diversity and rapid evolution of technologies with relevance to (or impact on) the life sciences enterprise. Their impact(s) may be beneficial or detrimental depending on how these tools and technologies are applied. Some may be seen as “coming out of left field”; that is, these technologies may have very different applications from those originally intended, or may be combined in unexpected, nontraditional configurations. The combination of nanotechnology and biotechnology is one such example of a synergistic combination.

Many of the technologies discussed in this chapter create novel opportunities for scientists (and others) to explore aspects of biological and chemical diversity that cannot be accessed through natural mechanisms



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Globalization, Biosecurity, and The Future of the Life Sciences 3 Advances in Technologies with Relevance to Biology: The Future Landscape This chapter provides an overview and a perspective on the breadth and types of technologies that may have an impact on the life sciences enterprise of the future, with the understanding that there are inherent difficulties in anticipating or predicting how any of these technologies alone or in combination will alter the nature of the future threat “landscape.” Rather than attempt to cover the technology landscape in a comprehensive manner, this chapter (1) highlights technologies likely to have obvious or high-impact near-term consequences; (2) illustrates the general principles by which technological growth alters the nature of future biological threats; and, (3) highlights how and why some technologies are complementary or synergistic in bolstering defense against future threats while also enhancing or altering the nature of future threats. There is immense diversity and rapid evolution of technologies with relevance to (or impact on) the life sciences enterprise. Their impact(s) may be beneficial or detrimental depending on how these tools and technologies are applied. Some may be seen as “coming out of left field”; that is, these technologies may have very different applications from those originally intended, or may be combined in unexpected, nontraditional configurations. The combination of nanotechnology and biotechnology is one such example of a synergistic combination. Many of the technologies discussed in this chapter create novel opportunities for scientists (and others) to explore aspects of biological and chemical diversity that cannot be accessed through natural mechanisms

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Globalization, Biosecurity, and The Future of the Life Sciences or processes. Given the unpredictable nature of technological change, it is difficult if not impossible to describe in definite terms what the global technology landscape will look like in 5 to 10 years, both with regard to the emergence of technologies with dual-use applications and the global geography of future breakthroughs. New, unexpected discoveries and technological applications in RNAi and synthetic biology arose even during the course of deliberations by this committee. If this report, with the same charge, were prepared even a year or two in the future, many of the details presented in this chapter would likely be different. A CLASSIFICATION SCHEME FOR BIOLOGICAL TECHNOLOGIES Despite the seemingly disparate and scattered goals of recent advances in life sciences technologies, the committee concluded that there are classes or categories of advances that share important features. These shared characteristics are based on common purposes, common conceptual underpinnings, and common technical enabling platforms. Thus, the technologies outlined in this chapter are categorized according to a classification scheme devised by the committee and organized around four groupings: Acquisition of novel biological or molecular diversity. These are technologies driven by efforts to acquire or synthesize novel biological or molecular diversity, or a greater range of specificity, so that the user can then select what is useful from the large, newly-acquired diversity pool. The goal is to create collections of molecules with greater breadth of diversity than found so far in nature, as well as with types of diversity that may not exist in nature. The kinds of molecules that might be generated include, for example, enzymes with enhanced or altered activities, as well as molecules composed of “unnatural” amino acids. Technologies in this category include those dedicated toward DNA synthesis; the generation of new chemical diversity (i.e., through combinatorial chemistry); those that create novel DNA molecules (from genes to genomes) using directed in vitro molecular evolution (e.g., “DNA shuffling”1); and those that amplify or simply collect previously uncharacterized sequences (genomes) directly from nature (i.e., bioprospecting). All of these technologies require a subsequent selection step, such that molecules, macromolecular complexes, or even microbes with the desired properties can be identified and isolated from a large and very diverse pool of possibilities. Toward this end, new high-throughput screening (including the use of robotics and advanced information management systems) have become critical enabling technologies.

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Globalization, Biosecurity, and The Future of the Life Sciences Directed design. These are technologies that involve deliberate efforts to generate novel but predetermined and specific biological or molecular diversity. The use of these technologies begins with a more defined, preexisting understanding of the desired endproduct and its molecular features. One then synthesizes or re-engineers the desired product or its components. Examples include but are not limited to rational, structure-aided design of small-molecule ligands; the genetic engineering of viruses or microbes; and, the emerging field of “synthetic biology.” Understanding and manipulation of biological systems. These are technologies driven by efforts to gain a more complete understanding of complex biological systems and an ability to manipulate such systems. Examples include “systems biology”; gene silencing (e.g., RNA interference); the generation of novel binding (affinity) reagents; technologies focused on developmental programs (e.g., embryonic stem cells); genomics and genomic medicine; the study of modulators of homeostatic systems; bioinformatics; and, advanced network theory. Production, delivery, and “packaging.” These are technologies driven by efforts in the pharmaceutical, agriculture, and healthcare sectors to improve capabilities for producing, reengineering, or delivering biological or biology-derived products and miniaturizing these processes. Examples include the use of transgenic plants as production platforms, aerosol technology, microencapsulation, microfluidics/microfabrication; nanotechnology; and, gene therapy technology. [Some of these technologies are related to the manipulation of biological systems—e.g., nanotechnology—and may also be applied to the generation (category 1) or design (category 2) of novel biological diversity or to the analysis of complex biological systems (category 3).] The classification scheme serves several important purposes. It: highlights commonalities among technologies and, by so doing, draws attention to critical enabling features; provides insight into some of the technical drivers behind biology-related technology; facilitates predictions about future emerging technologies; and, lends insight into the basis for complementarities or synergies among technologies and, as such, facilitates the analysis of interactions that lead to either beneficial or potentially malevolent ends. Limitations of the classification scheme include the fact that it is based on a relatively small number of relevant technologies (i.e., the committee’s

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Globalization, Biosecurity, and The Future of the Life Sciences list of technologies may be biased and is inevitably incomplete) and the acknowledgment that there are many ways to categorize these technologies. As a reflection of the latter dilemma, the committee found that some of the technologies discussed in this chapter could have been classified in more than one category. The category assignment in these cases was guided by the nature of the particular applications that the committee had in mind when considering each of the relevant technologies. The examples below serve as a finite set of future technologies that represent and illustrate each of the four categories. For each example the following issues are addressed: the purpose of the technology, its current state of the art, and future applications. The coverage of these issues for each of the technologies is not intended to be exhaustive. The technologies covered in this chapter include not only those that open up new possibilities for the creation of novel or enhanced biological agents but also those that expose new vulnerabilities (i.e., targets for biological attack). Details are limited to those necessary for a clear explanation of the plausibility of use. 1. ACQUISITION OF NOVEL BIOLOGICAL OR MOLECULAR DIVERSITY 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 create a more successful biological agent? Possibly not, but it is important to understand that “successful” in this context means the most able to survive within, on, or near human populations over time. “Success” does not necessarily equate with virulence or pathogenicity, the ability to cause disease or injury. The kinds of basic biological diversity found in nature today, or those that have potentially evolved in the natural world and been tested for fitness over time, may have been (and are still) limited by certain natural constraints, including available building blocks—nucleotides and amino acids; natural mechanisms for generating genetic diversity; and, the strength and nature of selective pressures over time. Nor has there been enough time over the history of the earth for nature to have explored more than a tiny fraction of the diversity that is possible.2 The technologies described in this section are those that seek to create a much wider and deeper set of diverse biological molecules, many of which may never have been generated or given a fair chance for succeeding in nature (although success may be defined in different ways).3

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Globalization, Biosecurity, and The Future of the Life Sciences Techniques have been developed to expand both the diversity of nucleotide or amino acid sequences of nucleic acids or proteins, respectively (which in both cases ultimately hold the information specifying the folding and thus the conformation of biologically active molecules), or for creating a diversity of small molecules with different shapes, sizes, and charge characteristics. In addition, some investigators are creating unnatural nucleic acids and amino acids in order to test and explore possible structural constraints on molecules with biological function. All of these approaches result in novel types of genetic or molecular diversity that then require assessment of functional potential. This assessment typically takes the form of a screening process (i.e., deliberate examination of all molecules for a desired feature or function) or a selective process (i.e., one that imposes a selective advantage on those molecules that have a property of interest). While the technological processes of assessing and selecting molecules of interest—high-throughput screening and selection—have some features in common with the next category of technologies (i.e., directed design), they are included in this first category because of their critical enabling role in the exploration of molecular and biological diversity. DNA Synthesis Description DNA synthesis is a technology that enables the de novo generation of genetic sequences that specifically program cells for the expression of a given protein. It is not new, but technical enhancements continue to increase the speed, ease, and accuracy with which larger and larger sequences can be generated chemically. By the early 1970s, scientists had demonstrated that they could engineer synthetic genes.4 However, it was the automation of de novo DNA synthesis and the development of the polymerase chain reaction (PCR) in the early 1980s that spawned the development of a series of cascading methodologies for the analysis of gene expression, structure, and function. Our ability to synthesize short oligonucleotides (typically 10 to 80 base pairs in length) rapidly and accurately has been an essential enabling technology for a myriad of advances, not the least of which has been the sequencing of the human genome. The past few years have seen remarkable technological advances in this field, particularly with respect to the de novo synthesis of increasingly longer DNA constructs. The chemical synthesis and ligation of large segments of a DNA template, followed by enzymatic transcription of RNA led to the de novo creation of the poliovirus genome in 2002 (about 7,500 nucleotides in length), from which the infectious, virulent virus was res-

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Globalization, Biosecurity, and The Future of the Life Sciences cued following its transfection into permissive cells.5 The following year scientists announced the successful assembly of a bacterial virus genome.6 Parallel efforts in industry and academia led to the synthesis and assembly of large segments of the hepatitis C virus genome, from which replication competent RNA molecules were rescued. These studies raised concerns in the media that larger, more complex organisms, such as the smallpox virus (which is approximately 186,000 base pairs long), might be within reach.7 DNA synthesis technology is currently limited by the cost and time involved to create long DNA constructs of high fidelity as well as by its high error rate. Current estimates for generating even simple oligonucleotides are at least $0.10 per base (including synthesis of the oligonucleotides plus error correction).8 See Figure 3-1. FIGURE 3-1 Cost per base of sequencing and synthesis. SOURCE: Rob Carlson presentation to the committee, February 2004.

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Globalization, Biosecurity, and The Future of the Life Sciences Current State of the Art Several recent studies have demonstrated important steps toward making gene synthesis readily affordable and accessible to researchers with small budgets, by decreasing its cost and improving its error rate.9 For example, in December 2004, as this committee deliberated its charge, scientists described a new microchip-based technology for the semiautomated multiplex synthesis of long oligonucleotides.10 The researchers used the new technology to synthesize all 21 genes that encode proteins of the E. coli 30S ribosomal subunit. Almost simultaneously, another research group described a novel approach for reducing errors by more than 15-fold compared to conventional gene synthesis techniques, yielding DNA with one error per 10,000 base pairs.11 Future Applications Developments in DNA synthetic capacity have generated strong interest in the fabrication of increasingly larger constructs, including genetic circuitry,12 the engineering of entire biochemical pathways,13 and, as mentioned above, the construction of small genomes.14 As a specific example of a potential future beneficial application of DNA synthesis, one research group has described a method for synthesizing terpenoid, a natural product used in commercial flavors, fragrances, and antimalarial and anticancer therapeutics, using recombinant DNA constructs.15 Terpenoids are normally isolated from plant tissue and can only be recovered in small amounts. DNA synthesis technology could be used as an alternative method for producing high-value compounds. DNA synthesis technology could allow for the efficient, rapid synthesis of viral and other pathogen genomes—either for vaccine or therapeutic research and development, or for malevolent purposes or with unintentional consequences. Given the latter risks, in 2004, George Church (Harvard Medical School, Cambridge, MA) drafted a proposal for decreasing biohazard risks (i.e., creating nearly extinct human viruses, such as polio, or novel pathogens, like IL-4 poxvirus) while minimizing the impact on legitimate research. The proposal focuses on instrument and reagent licensing (e.g., restricting the sale and maintenance of oligonucleotide synthesis machines to licensed entities); regulation for the screening of select agents; establishing a method for testing these newly implemented licensing and, screening systems; criteria for exemption from the whole process; and, strategies for keeping the cost down.16 The proposal is mentioned here not to endorse it, but rather to highlight the need for a careful analysis and thoughtful discussion of the issues.

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Globalization, Biosecurity, and The Future of the Life Sciences DNA Shuffling Description Classical genetic breeding has proven itself over and over again throughout human history as a powerful means to improve plant and animal stocks to meet changing societal needs. The late 20th century discovery of restriction endonucleases, enzymes that cut DNA molecules at sites comprising specific short nucleotide sequences, and the subsequent emergence of recombinant DNA technology provided scientists with high-precision tools to insert (or remove) single genes into the genomes of a variety of viruses and organisms, leading, for example, to the introduction of production-enhancing traits into crop plants.17 Most recently, a powerful mode of directed evolution known as “DNA shuffling”—also known as multigene shuffling, gene shuffling, and directed in vitro molecular evolution—has allowed scientists to greatly improve the efficiency with which a wide diversity of genetic sequences can be derived. A quantum leap in the ability to generate new DNA sequences, DNA shuffling can be used to produce large libraries of DNA that can then be subjected to screening or selection for a range of desired traits, such as improved protein function and/or greater protein production. “Classical” single-gene breeding starts with a “parental” pool of related sequences (genes, etc.) and then breeds “offspring” molecules, which are subjected to screening and selection for the “best” offspring. The process is repeated for several generations. With DNA shuffling, sequence diversity is generated by fragmenting and then recombining related versions of the same sequence or gene from multiple sources (e.g., related species), resulting in “shuffling” of the DNA molecules. Basically, it allows for the simultaneous mating of many different species. The result is a collection of DNA mosaics. The reassortment that occurs during the shuffling process yields a higher diversity of functional progeny sequences than can be produced by a sequential single-gene approach. In one of the earliest demonstrations of the technology, which involved shuffling four separately evolved genes (from four different microbial species), the shuffled “hybrids” encoded proteins with 270 to 540 times greater enzymatic activity than the best parental sequence.18 Even if that same recombined enzyme could have been evolved through single-gene screening, the process would have been dramatically slower. But chances are it never would have evolved. Evidence from at least one study shows that the best parent is not necessarily the one closest in sequence to the best chimeric offspring and thus would probably not represent the best starting point for single-gene evolution (i.e., some other better-look-

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Globalization, Biosecurity, and The Future of the Life Sciences ing parental sequence would have been chosen for single-gene directed evolution).19 Current State of the Art The technology has developed quickly, such that scientists are not just shuffling single genes, they are shuffling entire genomes. In 2002, biologists used whole-genome shuffling for the rapid improvement of tylosin production from the bacterium Streptomyces fradiae; after only two rounds of shuffling, a bacterial strain was generated that could produce tylosin (an antibiotic) at a rate comparable to strains that had gone through 20 generations of sequential selection.20 Also in 2002, a portion of the HIV genome was shuffled to create a new strain of HIV that was able to replicate in a monkey cell line that previously had been resistant to viral infection.21 By 2003 the technique had advanced to the point where many mammalian DNA sequences could be shuffled together in a single bacterial cell line. In one study, scientists shuffled one gene of a cytokine from seven genetically similar mammalian species (including human) to generate an “evolved” cytokine that demonstrated a 10-fold increase in activity compared to the human cytokine alone.22 It should be emphasized that the power of this technology (and any diversity generating procedure) is only fully realized if the molecules generated with the most enhanced, desired properties can be identified and isolated. Despite continual improvements in the throughput of current screening procedures, the use of conditions that impose strong selective pressures for emergence of molecules with the desired properties is far more efficient in finding the most potent molecule in the pool. Future Applications Ultimately, this rapid molecular method of directed evolution will allow biologists to generate novel proteins, viruses, bacteria, and other organisms with desired properties in a fraction of the time required with classical breeding and in a more cost-effective manner. For example, virologists are using DNA shuffling to optimize viruses for gene therapy and vaccine applications.23 Synthetic biologists are using the technology to speed up their discovery process (see “Synthetic Biology” later in this chapter).

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Globalization, Biosecurity, and The Future of the Life Sciences Bioprospecting Description24 Bioprospecting is the search for previously unrecognized, naturally occurring, biological diversity that may serve as a source of material for use in medicine, agriculture, and industry. These materials include genetic blueprints (DNA and RNA sequences), proteins and complex biological compounds, and intact organisms themselves. Humans have been exploiting naturally-derived products for thousands of years. Even as high-throughput technologies like combinatorial chemistry, described above, have practically revolutionized drug discovery, modern therapeutics is still largely dependent on compounds derived from natural products. Excluding biologics (products made from living organisms), 60 percent of drugs approved by the Food and Drug Administration and pre-new drug application candidates between 1989 and 1995 were of natural origin.25 Between 1983 and 1994, over 60 percent of all approved cancer drugs and cancer drugs at the pre-new drug application stage and 78 percent of all newly approved antibacterial agents were of natural origin.26 Taxol, the world’s first billion-dollar anticancer drug, is derived from the yew tree.27 Artemisinin, one of the most promising new drugs for the treatment of malaria, was discovered as a natural product of a fernlike weed in China called sweet wormwood. And aspirin—arguably one of the best known and most universally used medicines—is derived from salicin, a glycoside found in many species in the plant genera Salix and Populus. Bioprospecting is not limited to plants, nor is drug discovery its only application. Most recently, with the use of molecular detection methods, scientists have uncovered a staggering number of previously unrecognized and uncharacterized microbial life forms.28 Indeed, microbial genomes represent the largest source of genetic diversity on the planet—diversity that could be exploited for medical, agricultural, and industrial uses. Natural products discovered through bioprospecting microbial endophytes—microorganisms that reside in the tissues of living plants—include antibiotics, antiviral compounds, anticancer agents, antioxidants, antidiabetic agents, immunosuppressive compounds, and insectides. With respect to the last, bioinsecticides are a small but growing component of the insecticide market. Bioprospected compounds exhibiting potent insecticidal properties include nodulisporic compounds for use against blowfly larvae (isolated from a Nodulisporium spp. that inhabits the plant Bontia daphnoides)29 and benzofuran compounds for use against spruce budworm (isolated from an unidentified endophytic fungus from winter-green, Gaultheria procumbens).30 Of note, naphthalene, the ingredient in

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Globalization, Biosecurity, and The Future of the Life Sciences mothballs, is a major product of an endophytic fungus, Muscodor vitigenus, which inhabits a liana, Paullina paullinioides.31 Prospecting directly for DNA and RNA sequences that encode novel proteins with useful activities has become a potentially important scientific and business enterprise. This approach entails searches based on random expression of thousands or millions of sequences, followed by screening or selection for products with desired activities.32 Sometimes the search focuses on families of related sequences that are predicted to encode products of interest, which are recovered directly from environments using sequence amplification technology. This kind of approach can synergize with the DNA shuffling technology described above. Recent, early forays into “community genomics,” or large-scale random sequencing of the DNA from complex environmental microbial communities, reflect the immense future potential of this approach for the discovery and harnessing of previously unimagined biological activities.33 For example, Diversa Corporation (San Diego, CA) utilizes bioprospecting of microbial genomes to develop small molecules and enzymes for the pharmaceutical, agricultural, chemical, and industrial markets.34 After collecting environmental samples of uncultured microorganisms and extracting the genetic material, researchers search for novel genes and gene pathways for potentially useful products, like enzymes with increased efficiencies and stabilities (e.g., high and low temperature stability, high or low pH tolerance, high or low salt tolerance). The samples are collected from environments ranging from thermal vents to contaminated industrial sites to supercooled sea ice. Bioprospecting has also been applied to the discovery of microbial agents in efforts to better understand the diversity of microbes in the environment that might serve as human pathogens if provided the opportunity. It has been argued that by deliberately scrutinizing the kinds of vectors and reservoirs that exist in a local environment for previously unrecognized microbes, novel agents might be identified long before they are discovered to be human, animal or plant pathogens, thus providing early warning of potential disease-causing agents.35 At the least, these surveys could expand our appreciation of microbial diversity and inferred microbial function.36 For example, in 2002, using a broad-range PCR approach (i.e., using conserved priming sites for a group of related sequence targets, as opposed to specific primers for single unique targets), scientists discovered four novel Bartonella DNA sequences in 98 arthropod specimens (fleas, lice, and ticks) from Peru; three of the sequences were significantly different from previously characterized Bartonella species.37 Bartonella s are vectorborne bacteria associated with numerous human and animal infections.38 Rather than having any immediate known clinical

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Globalization, Biosecurity, and The Future of the Life Sciences     tides, solid phase synthesis was gradually extended to produce libraries of druglike small molecules, which were of greater interest to the drug discovery industry. In the early 1990s, Jonathan A. Ellman, University of California, Berkeley, used Geyson’s multi-pin approach to create a library of 192 structurally diverse benzodiazepines. Concurrently, Sheila H. DeWitt, then at Parke-Davis Pharmaceutical Research, Michigan, reported a technique and apparatus for the multiple, simultaneous synthesis of so-called “diversomers” (collections of organic compounds, including dipeptides, hydantoins, and benzodiazepines). These studies represented some of the earliest techniques for generating small molecule libraries. 45   Sanchez-Martin, R.M. et al. 2004. The impact of combinatorial methodologies on medicinal chemistry. Current Topics in Medicinal Chemistry 4(7): 653-669. 46   Needles, M.C. et al. 1993. Generation and screening of an oligonucleotide-encoded synthetic peptide library. Proceedings of the National Academy of Sciences 90(22):10700-10704. 47   Ohlmeyer, M.H.J. et al. 1993. Complex synthetic chemical libraries indexed with molecular tags. Proceedings of the National Academy of Sciences 90(23):10922-10926; Moran, E. J., et al. 1995. Radio frequency tag-encoded combinatorial library method for the discovery of tripeptide-substituted cinnamic acid inhibitors of the protein tyrosinase phosphatase PTP1B. Journal of the American Chemical Society 117(43):10787-10788; Nicolau, K.C. et al. 1995. Radiofrequency encoded combinatorial chemistry. Angewandte Chemie International Edition 34(20): 2289-2291. 48   Reader, J. C. 2004. Automation in medicinal chemistry.Current Topics in Medicinal Chemistry 4(7):671-686. 49   Matzger, A.V. et al. 2000. Combinatorial approaches to the synthesis of vapor detector arrays for use in an electronic nose. Journal of Combinatorial Chemistry 2(4):301-304. 50   Wheelis, M. 2002. Biotechnology and biochemical weapons. The Nonproliferation Review Spring:48-53. 51   Austin, C.P., L.S. Brady, T.R. Insel, and F.S. Collins. 2004. NIH Molecular Libraries Initiative. Science 306(5699):1138-1139. 52   See also, discussion of this issue in Chapter 1 “The NIH Roadmap.” 53   Major Histocompatibility Complex (protein complexes that present antigens to lymphocytes). 54   Berman, H.M., J. Westbrook, Z. Feng, G. Gilliland, T.N. Bhat, H. Weissig, I.N. Shindyalov, and P.E. Bourne. 2004. The Protein Data Bank. Nucleic Acids Research 28(1):235-242. See pdbbeta.rcsb.org/pdb/static.do?p=general_information/pdb_statistics/content_growth_graph.html [accessed January 5, 2006]. 55   The Smallpox Research Grid project distributed a screensaver to thousands of home computer owners to perform these calculations to identify drugs that might interfere with the enzyme that unwinds variola DNA to permit replication. The project is described at www.chem.ox.ac.uk/smallpox/news.html. (Altogether over 39,000 years of computer time were devoted to the project in less than six months, screening 35 million molecules against eight models of the target protein.) 56   Yokobayashi, Y. et al. 2002. Directed evolution of a genetic circuit. Proceedings of the National Academy of Sciences 99(26):16587-16591.

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Globalization, Biosecurity, and The Future of the Life Sciences 57   Registry of Standard Biological Parts. The Endy Lab, Massachusetts Institute of Technology. See parts.mit.edu/ [accessed January 5, 2006]. 58   Elowitz, M.B. and S. Liebler. 2000. A synthetic oscillatory network of transcriptional regulators. Nature 403(6767):335-338. 59   Atkinson, M.R. et al. 2003. Development of genetic circuitry exhibiting toggle switch or oscillatory behavior in Escherichia coli. Cell 113(5):597-607. 60   Looger, L.L. et al. 2003. Computational design of receptor and sensor proteins with novel functions. Nature 423 (6936):185-90; DeGrado, W.F. 2003. Biosensor Design. Nature 423(6936):132-133. 61   Benenson, Y. et al. 2004. An autonomous molecular computer for logical control of gene expression. Nature 429(6990):423-429. 62   Ferber, D. 2004. Microbes made to order. Science 303(5655):158-161. 63   The Center for Strategic & International Studies (CSIS), the J. Craig Venter Institute (Venter Institute), and the Massachusetts Institute of Technology (MIT) have initiated a project, funded by the Alfred P. Sloan Foundation, to examine the societal implications of synthetic genomics, exploring risks and benefits as well as possible safeguards to prevent abuse, including bioterrorism. See further description online at www.csis.org/press/pr05_23.pdf. 64   Racaniello, V.R. and Baltimore, D. 1981. Cloned poliovirus complementary DNA is infectious in mammalian cells. Science 214(4523):916-919. 65   Ahlquist, P. et al. 1984. Multicomponent RNA plant virus infection derived from cloned viral cDNA. Proceedings of the National Academy of Sciences 81(22):7066–7070. 66   Rice, C.M., et al. 1989. Transcription of infectious yellow fever RNA from full-length cDNA templates produced by in vitro ligation. New Biologist1(3):285-296. 67   Rice, C.M. et al. 1987. Production of infectious RNA transcripts from Sindbis virus cDNA clones: mapping of lethal mutations, rescue of a temperature-sensitive marker, and in vitro mutagenesis to generate defined mutants.Journal of Virology 61(12): 3809–3819. 68   Satyanarayana, T. et al. 1999. An engineered closterovirus RNA replicon and analysis of heterologous terminal sequences for replication. Proceedings of the National Academy of Sciences 96(13):7433-7438. 69   Van Dinten, L.C. et al. 1997. An infectious arterivirus cDNA clone: Identification of a replicase point mutation that abolishes discontinuous mRNA transcription. Proceedings of the National Academy of Sciences 94(3):991–999. 70   Masters, P.S. 1999. Reverse genetics of the largest RNA viruses. Advances in Virus Research 53:245-64. 71   Almazán, F., et al. 2000. Engineering the largest RNA virus genome as an infectious bacterial artificial chromosome. Proceedings of the National Academy of Sciences 97(10):5516–5521. 72   Yount, B., et al. 2003. Reverse genetics with a full-length infectious cDNA of severe acute respiratory syndrome coronavirus. Proceedings of the National Academy of Sciences 100(22):12995–13000. 73   Negative-stranded RNA viruses have a genome consisting of one or more molecules of single-stranded RNA that is of opposite polarity (i.e., complementary) to the positive-sense mRNA that encodes their proteins.

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Globalization, Biosecurity, and The Future of the Life Sciences 104   See phx.corporate-ir.net/phoenix.zhtml?c=141787&p=irol-newsArticle&ID=610478&highlight= 105   Soutschek, J. et al. 2004. Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs. Nature 432(7014):173-178. 106   Check, E. 2004. Hopes rise for RNA therapy as mouse study hits target. Nature 432(7014):136. 107   Voorhoeve, P.M. and R. Agami. 2003. Knockdown stands up. Trends in Biotechnology 21(1):2-4. 108   Ellington, A.D. and J. W. Szostak. 1990. In vitro selection of RNA molecules that bind specific ligands. Nature 346(6287):818-822; Tuerk, C. and L. Gold. 1990. Systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymerase. Science 249(4968):505-510. 109   Block, C. et al. 2004. Photoaptamer arrays applied to multiplexed proteomic analysis. Proteomics 4(3):609-618; Jayasena, S.D. 1999. Aptamers: an emerging class of molecules that rival antibodies in diagnostics. Clinical Chemistry 45(9):1628-1650; Mayer, G. and A. Jenne. 2004. Aptamers in research and drug development. Biodrugs 18(6): 351-359. 110   Mayer, G. and A. Jenne. 2004. Aptamers in research and drug development. Biodrugs 18(6):351-359. 111   Wang, K.Y. et al. 1993. A DNA aptamer which binds to and inhibits thrombin exhibits a new structural motif for DNA. Biochemistry 32(8):1899-1904; Li, W.X., et al. 1994. A novel nucleotide-based thrombin inhibitor inhibits clot-bound thrombin and reduces arterial platelet thrombus formation. Blood 83(3):677-82. 112   See www.archemix.com/press/pr_jun04.html [accessed March 27, 2005]. 113   See www.eyetk.com/clinical/clinical_index.asp [accessed March 27. 2005]. 114   Burbulis, I. et al. 2005. Using protein-DNA chimeras to detect and count small numbers of molecules. Nature Methods 2(1):31-37. 115   Mayer, G. and A. Jenne. 2004. Aptamers in research and drug development. Biodrugs 18(6):351-359. 116   The following section is taken from the Executive Summary of an NRC report entitled: Catalyzing Inquiry at the Interface of Computing and Biology (December 2005). 117   National Research Council. 2005. Catalyzing Inquiry at the Interface of Computing and Biology. Washington, DC: The National Academies Press. 118   Pacific Northwest National Laboratory. 2005. Genomic sequences processed in minutes, rather than weeks. The Daily Nonproliferator, June 21. Available online at www.pnl.gov/news/2005/05-45.stm. 119   Wolkenhauer, O. et al. 2005. The dynamic systems approach to control and regulation of intracellular networks. FEBS Letters 579(8):1846-1853. 120   Goldbeter, A. 2004. Computational biology: a propagating wave of interest. Current Biology 14(15):601-602; Uetz, P. and R.L. Finley, Jr. 2005. From protein networks to biological systems. FEBS Letters 579(8):1821-1827; Aloy, P. and R.B. Russell. 2005. Structure-based systems biology: a zoom lens for the cell. FEBS Letters 579(8):1854-58; Rousseau, F. and J. Schymkowitz. 2005. A systems biology perspective on protein structural dynamics and signal transduction. Current Opinion in Structural Biology 15(1):23-30. 121   Apic, G. et al. 2005. Illuminating drug discovery with biological pathways.

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Globalization, Biosecurity, and The Future of the Life Sciences     FEBS Letters 579(8):1872-1877; Young, J.A. and E.A. Winzeler. 2005. Using expression information to discover new drug and vaccine targets in the malaria parasite Plasmodium falciparum. Pharmacogenomics 6(1):17-26. 122   Hood, L. et al. 2004. Systems biology and new technologies enable predictive and preventative medicine. Science 306(5696):640-643. 123   AfCS Nature; The Signalling Gateway; See www.signaling-gateway.org/update/updates/200201/nrn714.html. 124   Balakrishnan, V.S. et al. 2005. Genomic medicine, gene polymorphisms, and human biological diversity. Seminars in Dialysis 18(1):37-40; Carr, K.M. et al. 2004. Genomic and proteomic approaches for studying human cancer: prospects for true patient-tailored therapy. Human Genomics 1(2):134-140. 125   Guillermo Paez, J. et al. 2004. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304(5676):1497-1500. 126   Marietti, C. 1999. Body Language; Health Care Informatics. Healthcare Informatics [Online]. Available online at www.healthcare-informatics.com/issues/1999/01_99/body.htm [accessed January 5, 2006]. 127   Workman, P. 2001. New drug targets for genomic cancer therapy: Successes, limitations, opportunities and future challenges. Current Cancer Drug Targets 1(1):33-47. 128   Ibid. 129   Schinder, T., W. Bornmann, P. Pellicena, W.T. Miller, B. Clarkson, J. Kuriyan. 2000. Structural mechanism for STI-571 inhibition of Abelson tyrosine kinase. Science 289(5486):1938-1941. 130   Workman, P. 2001. New drug targets for genomic cancer therapy: Successes, limitations, opportunities and future challenges. Current Cancer Drug Targets 1(1):33-47. 131   Daar, A.S. and P.A. Singer. 2005. Pharmacogenetics and geographical ancestry: implications for drug development and global health. Nature Reviews. Genetics 6(3):241-246. 132   National Research Council/Institute of Medicine. 2005. An International Perspective on Advancing Technologies and Strategies for Managing Dual-Use Risks. Washington, DC: The National Academies Press. 133   Ibid. 134   While the vaccine was not one that would specifically target black as opposed to white people, it was clearly intended to be used to limit fertility in black women. 135   Glasgow, J.N. et al. 2004. An adenovirus vector with a chimeric fiber derived from canine adenovirus type 2 displays novel tropism. Virology 324(1): 103-16. 136   Nettelbeck, D.M. et al. 2004. Retargeting of adenoviral infection to melanoma: combining genetic ablation of native tropism with a recombinant bispecific single-chain diabody (scDb) adapter that binds to fiber knob and HMWMAA. International Journal of Cancer 108(1):136-45. 137   Suzuki, T. et al. 2000. Adenovirus-mediated ribozyme targeting of HER-2/neu inhibits in vivo growth of breast cancer cells. Gene Therapy 7(3):241-248. 138   Rein, D.T. et al. 2004. Gene transfer to cervical cancer with fiber-modified adenoviruses. International Journal of Cancer 111(5):698-704.

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Globalization, Biosecurity, and The Future of the Life Sciences 139   A company called DNAprint Genomics has identified a number of genetic markers that correlate highly with racial or ethnic designations, many of them having to do with metabolizing toxins found in foods that are indigenous to certain areas. The markers identified by this firm are used to provide quantitative measures of an individual’s ancestry, according to four different “anthropological groups”—Native American; East Asian; Sub-Saharan Africa; and European. “European” can be broken down into Northern European; Southeastern European, Middle Eastern, and South Asian. For additional information on this company’s “products” see www.dnaprint.com/welcome/, and in particular a related site, www.ancestrybydna.com/welcome/home/. 140   The Sunshine Project. 2003. Emerging Technologies: Genetic Engineering and Biological Weapons. Background Paper #12. Available online at www.sunshine-project.org/publications/bk/bk12.html#sec6 [accessed January 5, 2006]. 141   Kagan, E. 2001 Bioregulators as instruments of terror. Clinics in Laboratory Medicine 21(3): 607-618. See also, Wheelis, M. 2004. Will the new biology lead to new weapons? Arms Control Today 34(July/August):6-13; and, Dando, M. 1999. Biotechnology, Weapons, and Humanity. British Medical Association. Amsterdam: Harwood Academic Publishers, especially Chapter 4 on “Genetic weapons.” See also Dando, M. 1996. A New Form of Warfare: The Rise of Non-Lethal Weapons. Dulles, VA: Potomac Books, Inc., especially Chapters 5 and 8. 142   Wang, D. et al. 1999. Encapsulation of plasmid DNA in biodegradable poly(D, L-lactic-co-glycolic acid) microspheres as a novel approach for immunogene therapy. Journal of Controlled Release 57(1): 9-18; National Research Council/Institute of Medicine. 2005. An International Perspective on Advancing Technologies and Strategies for Managing Dual-Use Risks. Washington, DC: The National Academies Press. 143   Neuropeptides, a type of bioregulator found in nervous system tissue, have a powerful modulatory effect on the nervous and immune systems. 144   Wheelis, M. 2002. Biotechnology and biochemical weapons. The Nonproliferation Review 9(Spring):48-53. Available online at cns.miis.edu/pubs/npr/vol09/91/91whee.pdf [accessed January 5, 2006]. 145   Healy, M. 2004. Sharper minds. Los Angeles Times (December 20): F1; Tully, T. et al. 2003. Targeting the CREB pathway for memory enhancers. Nature Reviews. Drug Discovery 2(4):267-77. 146   National Research Council/Institute of Medicine. 2005. An International Perspective on Advancing Technologies and Strategies for Managing Dual-Use Risks. Washington, DC: The National Academies Press. 147   Ibid. 148   Arntzen, C. et al. 2005. Plant-derived vaccines and antibodies: potential and limitations. Vaccine. 23(15):1753-1756; Huang, Z. et al. 2005. Virus-like particle expression and assembly in plants: hepatitis B and Norwalk viruses. Vaccine 23(15): 1851-1858; Thanavala, Y. et al. 2005. Immunogenicity in humans of an edible vaccine for hepatitis B. Proceedings of the National Academy of Sciences 102(9):3378-3382. 149   National Research Council/Institute of Medicine. 2005. An International Perspective on Advancing Technologies and Strategies for Managing Dual-Use Risks. Washington, DC: The National Academies Press. 150   Petro, J.B. et al. 2003. Biotechnology: Impact on biological warfare and

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Globalization, Biosecurity, and The Future of the Life Sciences     biodefense. Biosecurity and Bioterrorism: Biodefense Strategy, Practice, and Science. 1(3):161-168. 151   Walt, D.R. 2005. Miniature analytical methods for medical diagnostics. Science 308(5719):217-219. 152   Ibid. 153   This section is based on the workshop presentation of N. Seeman, in National Research Council/Institute of Medicine. 2005. An International Perspective on Advancing Technologies and Strategies for Managing Dual-Use Risks. Washington, DC: The National Academies Press. 154   Seeman, N.C. and A.M. Belcher. 2002. Emulating biology: building nanostructures from the bottom up. Proceedings of the National Academy of Sciences 99(Suppl 2):6451-6455. 155   Seeman, N.C. 1982. Nucleic acid junctions and lattices. Journal of Theoretical Biology 99(2): 237-247; Seeman, N.C. 1999. DNA engineering and its application to nanotech-nology. Trends in Biotechnology 17(11):437-443. 156   Winfree, E. 1995. On the computational power of DNA annealing and ligation. In Lipton, R. and E. Baum, eds. 1995. DNA Based Computers Volume 27, Proceedings of a DIMACS Workshop. Am. Math. Society:199-215; and Adleman, L. 1994. Molecular computation of solutions to combinatorial problems. Science 266(5187): 1021-1024. 157   Chen, Y. and C. Mao. 2004. Putting a brake on autonomous DNA nanomotor. Journal of the American Chemical Society 126(28):8626-8627; Emerich, D.F. 2005. Nanomedicine—prospective therapeutic and diagnostic applications. Expert Opinion in Biological Therapy 5(1):1-5. 158   Kohli, P. and Martin, C.R. 2005. Smart nanotubes for biotechnology. Current Pharmaceutical Biotechnology 6(1):35-47; Kubik, T. et al. 2005. Nanotechnology on duty in medical applications. Current Pharmaceutical Biotechnology 6(1):17-33. 159   www.ibn.a-star.edu.sg/news_interface_article.php?articleid=54. 160   Fortina, P. et al. 2005. Nanobiotechnology: the promise and reality of new approaches to molecular recognition. Trends in Biotechnology 23(4):168-173; Patolsky, F. et al. 2004. Electrical detection of single viruses. Proceedings of the National Academy of Sciences 101(39):14017-14022. 161   Warheit, D. et al. 2004. Comparative pulmonary toxicity assessment of single-wall carbon nanotubes in rats. Toxicological Sciences 77:117-125; Oberdorster, E. 2004. Manufactured nanomaterials (fullerenes, C60) induce oxidative stress in the brain of juvenile largemouth bass. Environmental Health Perspectives 112(10):1058-62. 162   Main, C.E. 2003. Aerobiological, ecological, and health linkages. Environment International 29(2-3):347-349. 163   Bauce, E. et al. 2004. Bacillus thuringiensis subsp. kurstaki aerial spray prescriptions for balsam fir stand protection against spruce budworm (Lepidoptera: Tortricidae). Journal of Economic Entomology 97(5):1624-1634. 164   Martonen, T.B. and J.D. Schroeter. 2003. Risk assessment dosimetry model for inhaled particulate matter: I. human subjects. Toxicology Letters 138(1-2): 119-132. 165   Paez-Rubio, T. et al. 2005. Source bioaerosol concentration and rRNA gene-

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Globalization, Biosecurity, and The Future of the Life Sciences     based identification of microorganisms aerosolized at a flood irrigation wastewater reuse site. Applied and Environmental Microbiology 71(2):804-810. 166   Tanner, B.D. et al. 2005. Bioaerosol emission rate and plume characteristics during land application of liquid class B biosolids. Environmental Science and Technology 39(6):1584-90; Brooks, J.B. et al. 2005. Estimation of bioaerosol risk of infection to residents adjacent to a land applied biosolids site using an empirically derived transport model. Journal of Applied Microbiology 98(2):397-405. 167   Brown, J.R. et al. 2005. Aerial optimization and canopy penetration study of Dibrom 14 Concentrate. Journal of the American Mosquito Control Association 21(1): 106-113. 168   Chan, H.K. 2003. Inhalation drug delivery devices and emerging technologies. Expert Opinion on Therapeutic Patents 13(9):1333-1343. 169   Edwards, D. 2002. Delivery of biological agents by aerosols. American Institute of Chemical Engineers Journal 48(1):2-6. 170   LiCalsi, C., M.l Maniaci, T. Christensen, E. Phillips, G.H. Ward, and C. Witham. 2001. A powder formulation of measles vaccine for aerosol delivery. Vaccine 19(17-19):2629-2636. The authors describe a method to deliver live, attenuated, measles vaccine via the lungs. “In this study, live attenuated measles vaccine is micronized by jet milling to generate particle sizes appropriate for pulmonary delivery (1-5 µm). Milling does not induce detectable physical change and significant viral potency is maintained…. The measles vaccine formulation is dispersible …” 171   Clark, A.R. 1995. Medical aerosol inhalers: past, present, and future. Journal of Aerosol Science and Technology 22:374-381. 172   Chan, H.K. 2003. Inhalation drug delivery devices and emerging technologies. Expert Opinion on Therapeutic Patents 13(9):1333-1343. 173   Crowder, T.M. 2002. Fundamental effects of particle morphology on lung delivery: predictions of Stokes’ Law and the particular relevance to dry powder inhaler formulation and development. Pharmaceutical Research 19(3):239-245. 174   Garcia-Contreras, L. and H.D.C. Smyth. 2005. Liquid-spray or dry-powder systems for inhaled delivery of peptide and proteins? American Journal of Drug Delivery 3(1):29-45. 175   Chan, H.K. 2003. Inhalation drug delivery devices and emerging technologies. Expert Opinion on Therapeutic Patents 13(9):1333-1343. 176   Tan, H.S. and S. Borsadia. 2001. Particle formation using supercritical fluids: pharmaceutical applications. Expert Opinion on Therapeutic Patents 11(5):861-872. 177   Based on Elliott Kagan’s presentation at the Cuernavaca workshop. See National Research Council/Institute of Medicine. 2005. An International Perspective on Advancing Technologies and Strategies for Managing Dual-Use Risks. Washington, DC: The National Academies Press. 178   Wang, D. et al. 1999. Encapsulation of plasmid DNA in biodegradable poly(D,L-lactic-co-glycolic acid) microspheres as a novel approach for immunogene delivery. Journal of Controlled Release 57(1):19-18. 179   Dai, C. et al. 2005. Microencapsulation peptide and protein drugs delivery system. Colloids and Surfaces B: Biointerfaces 41(2-3):117-20. 180   See www.controlledrelease.org/about/index.cgi [accessed May 12, 2005].

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Globalization, Biosecurity, and The Future of the Life Sciences 181   See www.swri.org/4org/d01/microenc/microen/default.htm [accessed May 12, 2005]. 182   Randall, P. and S. Chattopadhyay. 2004. Advances in encapsulation technologies for the management of mercury-contaminated hazardous wastes. Journal of Hazardous Materials 114(1-3):211-223. 183   Hao, S. et al. 2005. A novel approach to tumor suppression using microencapsulated engineered J558/TNF-alpha cells. Experimental Oncology 27(1):56-60. 184   Weinbreck, F. et al. 2004. Microencapsulation of oils using whey protein/gum Arabic coacervates. Journal of Microencapsulation 21(6):667-679. 185   Yamaguchi, Y. et al. 2005. Successful treatment of photo-damaged skin of nano-scale atRA particles using a novel transdermal delivery. Journal of Controlled Release 104(1):29-40. 186   See www.advancedbionutrition.com/html/news_press.html#2005_5 [accessed May 12, 2005]. 187   Chang, T.M. 2005. Therapeutic applications of polymeric artificial cells. Nature Reviews. Drug Discovery 4(3):221-235; and Orive, G. et al. 2004. History, challenges and perspectives of cell microencapsulation. Trends in Biotechnology 22(2):87-92. 188   A new technology, which will allow weapons and vehicles to be released from submarines even if they were not originally designed for undersea use. 189   Izumikawa, M. et al. 2005. Auditory hair cell replacement and hearing improvement by Atoh1 gene therapy in deaf mammals. Nature Medicine 11(3):271-276. 190   Parsons, D. 2005. Airway gene therapy and cystic fibrosis. Journal of Paediatrics and Child Health 41(3):94-96. 191   Although “convergent technology” is a common term often used to refer to the convergence of specific types of technologies, we use it here loosely to refer to the convergence of any technologies. 192   Benenson, Y. et al. 2004. An autonomous molecular computer for logical control of gene expression. Nature 429(6990):423-429. 193   Kagan, E. 2001 Bioregulators as instruments of terror. Clinics in Laboratory Medicine 21(3): 07-618. See also, Wheelis, M. 2004. Will the new biology lead to new weapons? Arms Control Today 34(July/August):6-13; and Dando, M. 1999. Biotechnology, Weapons, and Humanity British Medical Association. Amsterdam: Harwood Academic Publishers, especially Chapter 4 on “Genetic weapons.” See also Dando, M. 1996. A New Form of Warfare: The Rise of Non-Lethal Weapons. Dullas, VA: Potomac Books, Inc., especially Chapter 8: “An assault on the brain?” and Chapter 5: “Lethal and non-lethal chemical agents.” 194   Ibid. 195   Nixdorff, K. and W. Bender. 2002. Ethics of university research, biotechnology and potential military spin-off. Minerva 40:15-35. See also Nixdorff, K., N. Davison, P. Millett, and S. Whitby. 2004. Technology and biological weapons: Future threats. Science and Technology Report, Number 2, University of Bradford, Department of Peace Studies. Available online at www.brad.ac.uk/acad/sbtwc/ST_Reports/ST_Report_No_2.pdf [accessed January 5, 2006].

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