3
Drivers of International Biotechnology Development

The rapid growth, global proliferation, and application of advancing technologies are driven by a range of economic, social, and political factors. This chapter summarizes the several workshop presentations and discussions that revolved around the multitude and complex nature of these drivers, how future marketplace trends will likely drive technological advances, and obstacles that slow growth. As will be evident from the information presented, the driving forces behind the global proliferation of technology are complex and interacting.

Although market-driven profits, particularly within the pharmaceutical industry, have and will likely continue to serve as major drivers of advancing technologies, goals to improve global public health and efforts to strengthen human security and national security play vitally important roles as well. Indeed, many would agree that reducing the enormous inequities in global health is among the most important ethical challenges facing humankind today—a challenge that could be addressed through innovative technological applications.

An important theme that emerged from the presentations and discussions summarized here is that dual-use applications created by the global dissemination of advancing technologies and the know-how to use such technology do not necessarily derive from the growth of the industry per se. Rather, the alarm sounds from the characteristics of this growth. For example, the number of small biotech companies is growing much more rapidly than are the numbers of chemical or nuclear companies. Plus, the number of agents created by the life sciences revolution (e.g., via recombi-



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An International Perspective on Advancing Technologies and Strategies for Managing Dual-Use Risks: Report of a Workshop 3 Drivers of International Biotechnology Development The rapid growth, global proliferation, and application of advancing technologies are driven by a range of economic, social, and political factors. This chapter summarizes the several workshop presentations and discussions that revolved around the multitude and complex nature of these drivers, how future marketplace trends will likely drive technological advances, and obstacles that slow growth. As will be evident from the information presented, the driving forces behind the global proliferation of technology are complex and interacting. Although market-driven profits, particularly within the pharmaceutical industry, have and will likely continue to serve as major drivers of advancing technologies, goals to improve global public health and efforts to strengthen human security and national security play vitally important roles as well. Indeed, many would agree that reducing the enormous inequities in global health is among the most important ethical challenges facing humankind today—a challenge that could be addressed through innovative technological applications. An important theme that emerged from the presentations and discussions summarized here is that dual-use applications created by the global dissemination of advancing technologies and the know-how to use such technology do not necessarily derive from the growth of the industry per se. Rather, the alarm sounds from the characteristics of this growth. For example, the number of small biotech companies is growing much more rapidly than are the numbers of chemical or nuclear companies. Plus, the number of agents created by the life sciences revolution (e.g., via recombi-

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An International Perspective on Advancing Technologies and Strategies for Managing Dual-Use Risks: Report of a Workshop nant and transgenic technology and even synthetic biology) is increasing practically exponentially. So while there are only half a dozen fissile nuclear materials and dozens of “dual-use” chemicals that could be diverted for malevolent purposes, the number of potentially harmful biological agents is virtually limitless. In 15 to 20 years, dual-use technologies that have direct or indirect applications to the life sciences enterprise will continue their global expansion and local adaptations. China, for example, is expected to overtake the United States as the biggest producer of transgenic crops over the next 10 to 15 years. ECONOMIC DRIVERS1 This section summarizes information presented during the workshop on how future market trends are expected to drive the growth and global dissemination of extant and emerging technologies. The focus of this discussion was the life sciences industry; and for the purposes of this discussion, the industry was divided into six sectors: pharma, medicine, agriculture, biomaterials, computing, and military. All of the market trends described below and the advancing technologies that enable them, and are thus driven by them, are summarized in Table 3-1. Although certain technology trends are more relevant to particular commercial goals (e.g., aerosol technology obviously plays a much greater role in efforts to develop new means of drug delivery than it does for most of the other industrial pursuits), some are common to many or all. Of note, advances in bioinformatic technology will play an important role in all areas of application. The Pharmaceutical Industry Worth approximately U.S. $400 billion, the global pharmaceutical market dominates the life sciences industry and, as such, arguably determines the trajectory of life sciences-related technological development and global spread. North America and the European Union together account for three-quarters of the financial activity within the pharmaceutical industry (see Table 3-2). North America comprises 51 percent of the global market (U.S. $204 billion) and enjoys an annual growth rate of 12 percent. At U.S. $102 billion, the European Union comprises 25 percent of the global market and has an annual growth rate of 8 percent. 1   This section is based on the workshop presentation of Terence Taylor, September 21, 2004.

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An International Perspective on Advancing Technologies and Strategies for Managing Dual-Use Risks: Report of a Workshop TABLE 3-1 Future Technological Trends Sectors Trend Goal Enabling Technologies Pharmaceuticals Designer drugs Patient- and genome-specific drugs Gene chips, biomedical databases, computing Gene profiling Optimum therapy Gene chips, databases Drug delivery Alternative routes for drug administration Nanotechnology, aerosol technology Medicine Diagnosis Automatic analysis of genomic tests Databases, gene chips Infectious disease Better treatments Biomedical and genome databases, nanotechnology Gene therapy Identify and treat defective genes Databases, gene chips, high performance computing Life extension Identify and control the molecular basis for ageing Gene chips, sequence databases, embryonic stem cells Xenotrans-plantation Develop rejection-free tissues and organs for transplantation Databases, animal models, recombinant methods Agriculture Transgenic foods Develop higher nutrition foods, vehicles for drug delivery Genome sequencing methods, databases Biomaterials Artificial organs Develop tissue and associated engineering methods Databases, transgenic crops/animals, nanotechnology Biopolymers New materials for biological and industrial applications Databases, computing, transgenic crops/animals, nanotechnology Biotech Computing Performance Faster computing for intensive analysis and filtering Grid computing and super computers Applications Develop biotech-specific software tools Advanced software and search algorithms Military Defense capabilities Vaccines and prophylactics, detectors and forensics Gene chips, databases, nanotechnology, detector hardware Weapons Development of effective biological weapons Databases, gene chips, molecular synthesis methods, high performance computing NOTE: Adapted from Terence Taylor’s PowerPoint presentation, September 21, 2004.

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An International Perspective on Advancing Technologies and Strategies for Managing Dual-Use Risks: Report of a Workshop TABLE 3-2 The Global Pharmaceutical Market Region Annual Worth Market Share Annual Growth North America $204Bn 51% 12% Europe $102Bn 25% 8% Japan $47Bn 12% 1% Asia, Africa, Australia $32Bn 8% 11% Latin America $17Bn 4% −10% NOTE: Adapted from Terence Taylor’s PowerPoint presentation, September 21, 2004. For comparison, it was noted that the North American and European Union (EU) biotech sector—that is, nonpharmaceutical companies involved with living organisms (as opposed to chemical synthesis)—are together worth about U.S. $33 billion. As of 2002 (i.e., prior to the entrance of new countries into the EU this past year), the EU biotech sector involved some 1700 companies and was worth approximately U.S. $8 billion. Also as of 2002, the United States had about 1400 biotech companies, together worth about U.S. $25 billion. Worth about U.S. $47 billion, the Japan pharmaceutical sector represents about 12 percent of the global market but with a very small annual growth rate (i.e., only 1 percent). Its limited growth is due to domestic drug price caps, although Japanese companies have become more aggressive and are seeking growth opportunities in international markets. Again for comparison, based on information from the Japanese Biotechnology Association, the Japanese biotech sector is rapidly and remarkably growing. The number of Japanese biotech companies doubled between 2001 and 2003. In terms of number of companies, if this growth rate continues, Japan, by 2010, will have a biotech sector comparable to that of the United States and the United Kingdom combined. Asia, Africa, and Australia together comprise the next largest sector of the pharmaceutical industry. Key areas include Singapore (see discussion in Chapter 2), South Korea, China, Taiwan, and Australia. Worth about U.S. $32 billion, this regional market constitutes 8 percent of the global market and enjoys an annual growth rate of 11 percent. With an annual growth rate of −10 percent, the pharmaceutical industry in Latin America has recently contracted as a result of economic recession. Worth about U.S. $17 billion, it makes up only 4 percent of the global market. The majority of the global market is targeted toward chronic diseases among the older sector of the population (i.e., persons over the age of 65).

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An International Perspective on Advancing Technologies and Strategies for Managing Dual-Use Risks: Report of a Workshop The best-selling pharmaceuticals (and their annual market value in parentheses) are: anti-ulcerants ($22 billion), cholesterol reducers ($22 billion), anti-depressants ($27 billion), anti-rheumatics ($12 billion), calcium antagonists ($10 billion), anti-psychotics ($10 billion), and oral anti-diabetics ($8 billion). The figures above represent worldwide trends and include purchases in developing countries where the older population is rapidly growing. Based on a report by the U.S. Census Bureau, the population in Northwest Europe 60 years of age and older, for example, is expected to increase between 50 and 60 percent over the next 20 years or so.2 But in the developing world, the aging population3 is expected to increase 200 percent over the same time period. From the point of view of a pharmaceutical company, the developing world is and will be producing a larger market for these same drugs in the years to come, despite the critically serious global public health threat of emerging infectious diseases. Three likely major future trends in the global pharmaceutical industry were identified. First will be the development of patient- and genome-specific “designer drugs.” (See Chapter 2 for a discussion on genomic medicine initiatives in Mexico and Singapore.) Technical developments that will enable (and already enable) this trend include advances in gene chip technology, improvements in biomedical database technology, and increased computing power. One participant questioned whether the individualization of pharmaceuticals (i.e., genome-specific drugs) might not limit, rather than expand, the market for such drugs. It is unclear how the economics of this specificity will play out in the future, in terms of profitability. It was suggested that perhaps community-level pharmacogenomics might be more profitable than individual-level genomic medicine (i.e., by targeting larger markets). On the other hand, the chief industry advantage of genomic medicine will be the tremendous cost savings and reduced risk achieved by pre-selecting individuals for phase three clinical trials. Genomic-based pre-selection will save money by reducing the size of the phase three clinical trial and shortening time to market. Presumably, the savings from 2   Kinsella, K. and Victoria Velkoff. 2001. “An Aging World: 2001.” U.S. Departments of Health and Human Services, and Commerce; November (P95/01-1). 3   This refers to the sector of the population over 60 years of age.

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An International Perspective on Advancing Technologies and Strategies for Managing Dual-Use Risks: Report of a Workshop smaller, directed studies would lead to the development (including phase three clinical trials) of multiple additional drugs at a net savings. The pharmaceutical industry may also be interested in the use of gene profiling to develop optimum therapies based on an individual’s genetic make-up. As with individualized medicine, these efforts will be enabled by advances in gene chip and database technologies. A second major trend, and perhaps the most important with respect to dual-use risk of advancing technologies, will be the development of new means of drug delivery, the success of which will be enabled by developments in nanotechnology, aerosol technology, and perhaps other areas. The fact that finding new and alternative ways to deliver drugs is expected to be a major future trend points to the importance of considering technology related to delivery, in addition to the pathogens themselves, when evaluating emerging bioweapon and bioterrorist threats. A comment was made with respect to how nanotechnology might impact the drug market far in the future. (See Chapter 4 for a more detailed discussion of nanotechnology.) If intelligent nanotech drug delivery systems become a reality (i.e., systems with the capacity to read genomic or other diagnostic markers and then deliver drugs accordingly), presumably the same delivery system would be administered to everybody. It is unclear how the market would adapt to this kind of technology. There was a question about the role of intellectual property in the global dissemination of these various pharmaceutical-enabling technologies. Over the next five years, a number of blockbuster drugs will be coming off patent, thus providing even greater opportunities for developing countries to participate more actively in the global expansion of the life sciences industry by utilizing their manufacturing capabilities to build a new, cost-competitive market. Yet, at the same time, as developing countries join the World Trade Organization and, by doing so, sign on to a 20-year patent protection obligation, certain drugs may become more expensive and pose yet another dilemma in addressing the health needs of developing countries. Medicine The medical sector of the life sciences industry is expected to experience several major changes in the near future: Improved diagnosis, with the goal of automating genomic analyses; enabling technologies will include database and gene chip technology. Better treatments for infectious diseases; enabling technologies will include medical and genomic databases, high-throughput screening of compound libraries, and nanotechnology.

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An International Perspective on Advancing Technologies and Strategies for Managing Dual-Use Risks: Report of a Workshop Gene therapy for overcoming host defense defects; enabling technologies will include bioinformatics. Xenotransplantation and the drive to find rejection-free tissue and organs for transplantation; enabling technologies will include database and recombinant technologies (i.e. the latter will lead to advances in animal modeling). Again, these predicted changes derive from expected future trends. Efforts to extend life through modification of aging processes may not be viewed as a major trend today, but there is reason to expect that it will become a market driver in the future. Biomaterials Major expected future trends in the biomaterials industry include expansions of the artificial organ and biopolymer markets, the latter with the aim of finding new materials for biological and other industrial applications. Both developments will be enabled by improvements in database and computing technologies, transgenic crop and animal technologies, and nanotechnology. Agriculture: Transgenic Crops With regards to agriculture, one of the major future trends will be the expansion of transgenic crops, as described in Chapter 2. Potential benefits of transgenic agriculture range from the development of more disease-resistant crops to the production of better-tasting foods. Societal benefits notwithstanding, ultimately, as with the pharmaceutical industry, economics is the bottom line. Any technology that results in lower production costs, and higher profit margins, will likely progress more rapidly than other, lower-yield ventures. Computing In the computing industry, future major trends will likely include performance improvement and application expansion. The former will result in faster overall computing and the convergence of technologies that feed into each other, efforts that will be enabled by advances in grid and super computing. The development of new or improved computing applications, a trend driven in large part by the need to strengthen biotech-specific software, will be enabled by software advances and more advanced search algorithms.

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An International Perspective on Advancing Technologies and Strategies for Managing Dual-Use Risks: Report of a Workshop Military In terms of market value, military needs are not considered a significant driver of technological development and dissemination. However, with respect to the life sciences, an important future military trend will involve strengthening biodefense capabilities. Specific goals will include the improvement and production of a select list of vaccines and prophylactics, rapid diagnostics, pathogen detectors, and forensic tools. Enabling technologies will include database and gene chip advancements, nanotechnology, and improvements in detector hardware. Another expected and controversial future military trend will be the development of bioweapons by certain governments and non-government (terrorist) groups, despite the illegality of developing such weapons. The development of effective bioweapons will be enabled by advances in database and gene chip engineering, molecular synthesis methods, and high performance computing. Changing Geographical Trends Although the United States and the European Union dominate the global life sciences industrial marketplace, they are not by any means the only players. The diffusion of the technologies that enable, or will enable, all of the above listed market trends is and will continue to be truly global. In other words, technological breakthroughs could come from anywhere in the world. As discussed in the previous chapter, biotechnological growth in Singapore embodies the diverse geo-political efforts directed toward becoming regional or global advancing technology leaders. In January 2003, Novartis opened the Novartis Institute for Tropical Diseases (NITD) in Singapore.4 In the late 1990s, Eli Lilly and Company opened its only Lilly Clinical Pharmacological unit outside of the United States in Singapore and is recruiting talent from around the globe.5 More recently, in 2001, Eli Lilly entered into an agreement with the Singapore Economic Development Board to establish an R&D center in Singapore to focus on systems biology.6 As another example, China leads the world in agricultural technology development, having created some 150 transgenic crops, of which about 50 are patented or marketed for U.S. purchase. The Chinese military is very active in the country’s biotechnology efforts. For example, in 1998, a 4   http://www.nitd.novartis.com. Accessed on October 21, 2004. 5   http://www.med.nus.edu.sg/lilly/. Accessed on October 21, 2004. 6   http://www.lsb.lilly.com.sg/. Accessed on October 21, 2004.

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An International Perspective on Advancing Technologies and Strategies for Managing Dual-Use Risks: Report of a Workshop tissue engineering research center was set up at the Academy for Military Medicine and Sciences. China also leads the world in the production of protein-enhanced material, mostly for domestic and regional use. Additionally, China produces about 11,000 tons of antibiotics per year, which is about half of the world’s total. Cuba provides another good example of the global diffusion of advancing technologies. It was the first country in the world to have successfully developed a vaccine against meningitis B, which even the United States is now willing to import despite its trade embargo against Cuba.7 South Korea has utilized its biotechnological potential as part of its effort to transform itself rapidly from a developing into a developed country, attracting worldwide attention when scientists performed the first successful therapeutic cloning experiment. In addition, Brazil, Egypt, India, South Africa, and other countries, are also exploiting various technologies both to address health issues and as mechanisms for economic development. There were questions about whether and how government involvement impacts sustainable, long-term market growth. In other words, does a proactive government increase the likelihood of advancing technological expansion? It seems that the government plays different roles in different places. In the United States and the European Union, for example, where the life sciences industry is almost exclusively privately financed, the government sector plays a largely consumer role (i.e., it purchases products). But in Singapore, for example, the government plays much more than a consumer role. It also provides a highly regulated environment for conducting life sciences, including stem cell, research; and it offers incentives to encourage companies to do business there. Likewise in Cuba and Brazil, for example, where industrial and commercial expansion appears to be occurring in areas where the government is similarly proactive. SOCIAL DRIVERS8 … there can be no peace, no security, nothing but ultimate disaster, when a few rich countries with a small minority of the world’s people alone have access to the brave, and frightening, new world of technol- 7   The meningitis B vaccine was developed in the 1980s at the Finlay Institute in Cuba, and is considered the world’s first effective vaccine against this child-killer disease. The Clinton Administration agreed to authorize the British firm, SmithKline Beecham Pharmaceuticals, to market the Cuban anti-meningitis vaccine in the United States. 8   This section is based largely on the workshop presentations of Abdallah Daar, David Banta, Rosiceli Barreto Goncalves Baetas, and Decio Ripandelli.  

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An International Perspective on Advancing Technologies and Strategies for Managing Dual-Use Risks: Report of a Workshop ogy, science, and of high material living standards, while the large majority live in deprivation and want, shut off from opportunities of full economic development; but with expectations and aspirations aroused far beyond the hope of realizing them. —Lester B. Pearson9 This section summarizes the workshop presentations and discussions that revolved around the societal benefits of advancing technologies’ growth and globalization. In particular, how can technological advances be used to address the unique public health needs of the developing world and close the growing development gap between the North and South? The promise of genomics figured prominently in this dialogue, as did the notion of a new vaccine market and efforts by the Italy-based International Center for Genetic Engineering and Biotechnology to engage the developing world in the development and application of advancing technologies. However, even as technology growth may provide at least a partial solution to some of these problems, the steadfast challenges associated with the prevention and control of emerging infectious diseases were highlighted as a reminder of the many obstacles still ahead. The Promise of Biotechnology10 In light of growing recognition that technology can and has benefited human development, there have been several recent pleas by individuals and organizations for the use of technology advances to bridge the growing public health gap between developed and developing nations.11,12,13 Importantly, although genomic medicine was highlighted during this workshop, it is not by any means the only technology application with potential to improve health in developing countries. A technology foresight study conducted by the University of Toronto Joint Centre for Bioethics (JCB), in partnership with 29 scientists with expertise in health and 9   Lester B. Pearson’s Public Address at St. Martin-in-the-Fields, London, June 13, 1972, on the Occasion of the Presentation to Him of the Victor Gollancz Humanity Award. The full address can be found at http://www.unac.org/en/link_learn/canada/pearson/speechgollancz.asp. 10   This subsection based on the presentation by Abdullah Daar. 11   WHO. 2002. Genomics and World Health. http://www3.who.int/whosis/genomics/genomics_report.cfm. Accessed on October 28, 2004. 12   Singer, P. A. and A. S. Daar. 2001. “Harnessing genomics and biotechnology to improve global health equity.” Science 294:87-89. 13   UNDP. 2004. Making New Technologies Work for Human Development. Oxford University Press, New York, 2001. http://hdr.undp.org/reports/global/2001/en/. Accessed on October 28.

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An International Perspective on Advancing Technologies and Strategies for Managing Dual-Use Risks: Report of a Workshop biotechnology and in-depth knowledge about public health problems in developing countries, identified the top ten biotechnologies that are likely to improve human health in developing countries within the next 5 to 10 years:14 Molecular diagnostics Recombinant vaccines Drug and vaccine delivery systems Bioremediation Sequencing pathogen genomes Female-controlled STI protection Bioinformatics Enriched GM crops Recombinant drugs Combinatorial chemistry In a follow-up report entitled “Genomics and Global Health,”15 JCB identified how these ten biotechnologies could appropriately be used to address some of the UN Millennium Development Goals.16 The above list is partly intended to serve as a political advocacy tool. Basic science and basic science training are not included on the list but are considered vital investments in the internalization of knowledge and development of innovation capacities. The Notion of a New Vaccine Market17 The fact that many developing world diseases are not on R&D lists of most industrialized nations is a reminder of how vitally important it is that the biotechnology capacity of the developing world be strengthened. This is perhaps nowhere more evident than with vaccines. Since vaccines have, along with clean water, arguably had the greatest historical impact on human health, from a public health standpoint, vaccine R&D could drive the global proliferation of vaccine R&D-enabling technologies. However, as mentioned in the previous chapter, the infectious disease vaccine market is a high-risk endeavor in terms of profitability, 14   Daar, A. S. et al. 2002. “Top 10 biotechnologies for improving health in developing countries.” Nature Genetics 32:229-232. 15   Canadian Program on Genomics and Global Health, University of Toronto Joint Centre for Bioethics, 2004, “Genomics and Public Health.” 16   Acharya, T. et al. 2003. “Biotechnology and the UN Millenium Development Goals.” Nature Biotechnology 21:1434-1436. 17   This subsection based on the presentation by Rosiceli Baetas.

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An International Perspective on Advancing Technologies and Strategies for Managing Dual-Use Risks: Report of a Workshop particularly given the high number of competitors and clients with high bargaining power (e.g., governments, UNICEF, etc.). Navigating the R&D pipeline requires significant investment and time, usually about 10 years, and the situation is getting worse. In the 1980s, production costs for new vaccines were between U.S. $10 million and 15 million; in the 1990s, between $50 million and 200 million. Those figures are expected to rise to $200 million to 250 million over the next 10 years. Moreover, regulatory requirements are becoming more complex. For these reasons, most major vaccine manufacturers in the industrialized world are transitioning into the production of therapeutic vaccines, such as for cancer, allergies, fertility, and various other non-infectious diseases. By 2006, the therapeutic vaccine industry is expected to be worth $10 billion. This new vaccine arena has very high entry barriers (i.e., higher than the traditional vaccine market), more intellectual property restrictions, and requires a longer development time. But its higher-priced products bring greater profits. With a 200 year history since the inception of virology, scientists have long sought the “ideal” preventive vaccine: one that is effective with a single dose, immunizes at birth, works against many diseases, is easy to administer, can be stored for long periods of time, is genetically stable, does not cause adverse effects, and is affordable. Still, effective vaccines are lacking for many significant infectious diseases, not the least of which is HIV/AIDS. This is true, despite the fact that the newer (i.e., 21st century) third and even fourth generation genomic and bioinformatics-based vaccines represent a doubling in the number of vaccines available since the 1980s, when there were only about 25 vaccines (i.e., there were 51 different vaccines available in 2000). The need for infectious disease vaccines is as great as ever but without a market to sustain continued R&D. As major vaccine manufacturers in the industrial world direct their attention elsewhere, it has been suggested that developing countries promote their own vaccine industries to fill the gap, produce vaccines of interest to them, and eventually develop the capacity to engineer novel vaccines. Local and/or state-owned manufacturers, as well as international organizations, will play a vital role in this effort; and the public and private sectors will need to integrate their efforts and adjust policies accordingly. With this vision in mind, some regional networks have been initiated. For example, the Pan American Health Organization (PAHO) has begun efforts in ten Latin American countries to explore the potential for the development of new vaccines. In summary, it appears that the shift toward more profitable vaccines may serve as yet another economic driver of the global spread of technology, at least among high-income countries. Meanwhile, in low- and

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An International Perspective on Advancing Technologies and Strategies for Managing Dual-Use Risks: Report of a Workshop middle-income countries, public health crises are prompting consideration of a new vaccine industry. (As described in Chapter 2, plant-based vaccine manufacture was proposed as a plausible cost-effective solution to the inaccessibility of vaccine production.) International Center for Genetic Engineering and Biotechnology (ICGEB): Efforts to Involve the Developing World18 The ICGEB, with headquarters in New Delhi, India, and Trieste, Italy, was founded in 1983 as a mechanism for involving developing countries in the emerging biotechnology field. It is an intergovernmental organization with 69 signature States, 52 member States, and a 35-center network. The Center recently issued a mandate to establish a code of conduct for scientists, as described in Chapter 5. Despite its global reach, most high-income countries, including the United States, are not affiliated for several reasons, including industrial sector concerns that transferring technology to developing countries would increase competition and potentially reduce profits, and a general preference for bilateral collaborations, which allow greater control than multilateral efforts. Even some member States view the ICGEB as a nonpolitical provider of technology, training, and research, and believe that its mandate should not extend to issues of prevention and misuse. In a sense, it is a catch-22 situation, since the highest-income countries will have little reason to join if the Center continues without the added value afforded by such activities. The ICGEB performs several functions, details of which can be viewed on its Web site:19 Research (i.e., there are approximately 400 affiliated scientists working on a range of basic and applied topics) Long-term training for pre- and post-doctoral researchers (i.e., the Center trains about 60-70 people a year) Short-term courses, many of which are of particular interest to scientists in the developing world (e.g., an upcoming course is entitled “The Molecular Biology of Leishmania”) Collaborative research with the affiliated centers, whereby the ICGEB provides funding for affiliate-prioritized research Cooperation with the industrial sector Scientific services, such as the provision of databases and software 18   This subsection based on the presentation by Decio Ripandelli. 19   http://www.icgeb.trieste.it. Accessed on November 1, 2004.

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An International Perspective on Advancing Technologies and Strategies for Managing Dual-Use Risks: Report of a Workshop Institutional services Policy advice regarding intellectual property Risk assessment regarding genetically modified organisms Issues related to implementation of article X of the Biological Weapons Convention (Article X of the BWC is aimed at avoiding the hampering of state economic or technological development, particularly in low- and middle-income countries; fostering the exchange of equipment, materials, and scientific and technological information within a collective framework; and enhancing international cooperation aimed at developing and applying scientific discoveries for peaceful purposes. Article X represents the eminent value of joining the BWC for those countries who may not otherwise be interested in joining because they do not perceive any threats.) Lessons from Emerging Infectious Diseases: Obstacles to Biotechnology Proliferation20 By examining the current status of prevention and treatment programs for emerging infectious diseases worldwide, it is quite evident that there still is an enormous discrepancy in technology development among different parts of the world. This is particularly true for non-clinical technologies, such as information and systems technologies. Even if the perfect drug for a particular condition exists, if there is no way to deliver the drug to the people who need it for lack of money, a weak public health system, lack of planning, or poor information, etc., then the pharmaceutical is not useful. The current situation in the developing world with regards to four emerging infectious diseases—HIV/AIDS, tuberculosis (TB), trypanosomiasis, and leishmaniasis—was used to illustrate how, despite the global growth of technology, many countries still encounter significant obstacles to accessing such technology. HIV/AIDS Of the estimated 40 million people worldwide infected with HIV/ AIDS, fewer than 400,000 in low- and middle-income countries have access to life-sustaining antiretroviral (ARV) therapy. The high AIDS mortality in sub-Saharan Africa, which remains the worst-affected region of the world, contrasts sharply with the decreasing HIV-related death rate in high-income countries where ARVs are widely available and affordable.21 20   This subsection based on the presentation by David Banta. 21   Institute of Medicine. 2004. Scaling up treatment for the global AIDS Pandemic: Challenges and Opportunities. Washington, DC: The National Academies Press.

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An International Perspective on Advancing Technologies and Strategies for Managing Dual-Use Risks: Report of a Workshop Clearly, there is an enormous global discrepancy in the application of effective biotechnology. It was pointed out that since most HIV/AIDS drugs have been researched and developed with NIH funding and then licensed to pharmaceutical companies (i.e., contrary to popular opinion that the R&D was privately funded), it seems that there ought to have been some sort of provision for the development of these same drugs in developing countries. Such is not the case. However, ARV drug prices have fallen sharply in recent years and donor funding has risen, thus encouraging a number of ARV scale-up programs worldwide and fueling WHO’s ambitious “3-by-5” campaign, with the global target of providing ARV therapy to 3 million people with HIV/AIDS in developing countries by the end of 2005.22 Still, drugs alone are neither the only problem nor the sole solution. As identified during this workshop, there are two major obstacles to the effective management of the global HIV/AIDS crisis: complications associated with patent restrictions and a range of systems-level problems. With regard to the former, a patent is by definition a grant of monopoly power. Under the present World Trade Organization (WTO) rules, new drugs are under patent for at least 20 years with a number of ways to extend that time period. The expansion of the WTO (e.g., in 2005, India will join the WTO) will call into question the ability to make and export generic ARVs. The 2001 Doha resolution23 addressed this problem to some extent by allowing compulsory licensing (i.e., countries with the capacity to do so can reproduce patented drugs without permission of the patent holder). However, countries without their own pharmaceutical industry will be in much the same situation that pre-dated the dramatic drop in ARV costs, that is with little recourse. Despite access to ARVs, many HIV/AIDS treatment programs fail due to so-called “systems technology” problems, particularly at the national level (e.g., due to the lack of a national HIV/AIDS coordinating authority.) It is vitally important that a national policy and single monitoring and evaluation system be in place in every country. In fact, the need for this national-level focus inspired the “three ‘ones’ principle” for HIV/ AIDS: one agreed national HIV/AIDS action framework as the basis for 22   Institute of Medicine. 2004. Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities. Washington, DC: The National Academies Press; WHO. 2003. “Treating 3 Million by 2005. Making it Happen. The WHO Strategy.” Geneva, WHO. http://www.who.int/3by5/en/. Accessed on October 21, 2004. 23   World Trade Organization. “Declaration on the TRIPS agreement and public health. Adopted November 14, 2001. (known as the Doha Resolution). Available at http://www.wto.org/english/thewto_e/minist_e/min01_e/mindecl_trips_e.htm.

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An International Perspective on Advancing Technologies and Strategies for Managing Dual-Use Risks: Report of a Workshop coordinating work; one national HIV/AIDS coordinating authority; and one agreed country-level monitoring and evaluation system. Tuberculosis One-third of the world’s population is infected with Mycobacterium tuberculosis (TB), and 2 million people die from TB every year. The main pillar of treatment is still isoniazid, and there is an enormous need for new, better drugs. Drugs requiring only a relatively short treatment course could solve problems associated with poor adherence and the consequent rise of multi-drug resistant TB, which is increasing in incidence not only in the developing world but also throughout the United States and the European Union. In fact, middle-income Russia is believed to have one of the fastest growing rates of multi-drug resistant TB, and TB is increasing in the UK at a rate far greater than any other western EU country. Despite these trends and international efforts to encourage anti-TB drug development, there has been very little R&D, either private or public, directed toward new therapies. In addition to new drugs, there is an urgent need for improved diagnostics and public health monitoring technologies. The ones currently in use were developed more than a century ago by Robert Koch himself. Fortunately, the biotech industry has recently expressed considerable interest in developing new TB diagnostic tools, some of which should be ready for testing and perhaps deployment within the next 5 years or so. As with HIV/AIDS, irrespective of whether effective drugs exist or not, systems-level problems limit the capacity to manage effectively the global TB crisis. Most notably, inconsistent or poor adherence to the 6-9 month course of drug therapy is a major reason for the rapid emergence of multi-drug resistant TB, even among patients who attend clinics participating in the DOTS (Directly Observed Treatment Short Course) program. In many parts of the world, attending a clinic daily for at least two months is simply not a feasible reality. This is not to imply that DOTS has not been a very important step forward, as it has proven to be a very effective strategy. However, it either needs to be improved in ways that will allow it to reach more people, or alternative strategies need to be sought. Neglected diseases Neglected, or so-called tropical diseases, continue to be significant public health problems worldwide. These include drug-resistant malaria, African trypanosomiasis (also known as sleeping sickness), visceral leishmaniasis (also known as kala azar), Chaga’s disease, lymphatic filariasis, and schistosomiasis. Even TB is sometimes considered a neglected dis-

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An International Perspective on Advancing Technologies and Strategies for Managing Dual-Use Risks: Report of a Workshop ease because of the lack of anti-TB drug R&D. Tropical diseases are considered neglected because, although they account for about 90 percent of the global burden of disease, they draw only about 10 percent of the world’s health research expenditure. For example, only 1 percent of the almost 1400 drugs registered between 1979 and 1999 were indicated for use against “neglected” diseases. The current situation with regard to sleeping sickness highlights the neglect. Sleeping sickness is endemic in 36 African countries, where altogether it infects some 300,000 persons every year. The disease has been controlled in the past almost exclusively by the use of insecticides, fly-trapping, and other vector control strategies. Despite successful past control efforts and largely because of armed conflict in endemic areas, trypanosomiasis has reemerged in many localities. The primary treatment, melarprosol, is an old, arsenic-based drug with many side effects, including encephalopathy, which occurs in 5 to 10 percent of all patients and kills half of those affected. Interestingly, a newer drug, eflornithine, was known to have anti-trypanosomal potential but was not commercially developed until its hair-removing effects were discovered. Now, Aventis, in cooperation with WHO, provides the drug free of charge. Still, drug delivery poses a problem since, although effective, eflornithine requires four daily IV infusions for two weeks. As with DOTS, in an African setting, this is not very practical. POLITICAL DRIVERS24 The lack of interest on the part of governments to fund certain types of scientific research and insufficient scientific policy for directing research were cited as major impediments to the global proliferation of certain technologies. For example, the Mexican government is apparently not particularly interested in funding transgenic crop research, although quite the opposite seems to be the case with genomic medicine. Part of the problem is the transitory nature of governmental administrations: one administration may favor one technology, while the next does not. It was suggested that a more informed public and government (i.e., informed about the beneficial applications of scientific knowledge and technology) would create more sustainable governmental commitment. Of note is Canada’s recent commitment to international R&D. In the February 2, 2004 Speech from the Throne (which officially opens every 24   This section is based on individual comments by multiple workshop participants, comments on Canada by Daar, comments on Singapore by Patrick Tan Boon Ooi, and the summary of South Africa’s Project Coast by Jerome Amir Singh.

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An International Perspective on Advancing Technologies and Strategies for Managing Dual-Use Risks: Report of a Workshop new session of Parliament by setting out broad goals and directions of the government), the following declaration was made: “We are a knowledge-rich country. We must apply more of our research and science to help address the most pressing problems of developing countries.” The following day, Prime Minister Martin replied by announcing the country’s “5 percent commitment”: “Our long-term goal as a country should be to devote no less than 5 percent of our R&D investment to a knowledge-based approach to develop assistance for less fortunate countries.” Biodefense25 Most experts consider biodefense a relatively minor economic driver of biotechnology. After all, the annual global pharmaceutical market is worth more than 70 times the $6.5 billion that the U.S. government has promised for the purchase of vaccines and drugs over the next 10 years.26 Nonetheless, several workshop participants questioned whether the United States biodefense efforts might be setting a significant “tone” or “backdrop,” which may nonetheless impact the global transfer of technology. As an example of how terrorism-conscious thinking pervades national dialogue even outside the United States, those who are involved with establishing the new national genomics medicine platform in Mexico are aware that such a platform will serve a dual biodefense role (see Chapter 2 for details). In other words, if genome-specific medicines can be made specifically for use in the ethnically diverse Mexican population, so too can genome-specific bioweapon or bioterrorist agents. Even though biodefense efforts may not greatly impact the absolute growth and spread of technology, they could pose disproportionately greater dual-use risks. For example, a question was raised about whether a greater investment in biodefense might increase the dual-use risk posed by knowledgeable, skilled insiders. A question was asked regarding the dual-use potential of agricultural transgenic technology and whether any U.S. biodefense research efforts were being driven by this particular threat. In response, it was mentioned that the USDA recently called for proposals but that only a trivial amount of money was dedicated to the consideration of plant pathogens as biothreats. A similar concern was expressed about plant-based vaccines: if plants can be used as delivery vehicles for vaccines, might they not also 25   This section summarized comments made by individual workshop participants throughout the course of the workshop. 26   Project BioShield. Available at http://www.whitehouse.gov/bioshield/.

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An International Perspective on Advancing Technologies and Strategies for Managing Dual-Use Risks: Report of a Workshop serve as delivery vehicles for bioweapons? A recent experiment generating considerable attention along these lines involved the engineered expression of insecticidal viruses by plants, in order to kill insect predators that happen upon the plant.27 This type of work has immediate dual-use implications for plant biotechnology. Questions were raised about whether and the extent to which future increased investments in biodefense might dissuade international R&D donors from supporting developing countries with capabilities that could conceivably be used by either state bioweapons or non-state bioterrorist programs. Anecdotal reports suggest that some international R&D companies are reluctant to support countries with capabilities that may be directed towards the production of bioweapons. No specific cases were mentioned. Along the same lines, concern was expressed that the limited entry of foreign nationals into U.S. training programs may have an enormous negative effect on the global dispersion of beneficial knowledge and talent in relevant technologies. There was concern regarding how the current focus on bioterrorism in the United States may be impacting, perhaps worsening, the general public perception of biotechnology. Does the bioterrorist backdrop make it more difficult to convince people that these products are safe to eat or use? Looking to the bright side, some workshop participants wondered if the investment and attention paid to biodefense might not provide “terrific opportunities” for the continued global proliferation of knowledge and biotechnology. For example, technical breakthroughs in the area of rapid diagnostics not only will strengthen biodefense capabilities but may benefit public health generally (i.e., by improving early diagnostic capabilities with regards to naturally occurring infectious diseases). As one workshop participant noted, “There is almost a seamless boundary between the needs and issues in defense against natural disease and the needs and issues in defense against disease of deliberate or malevolent origin.” It was noted that the information technology industry was initially a non-commercial endeavor started by the military but was then quickly and ultimately driven by commercial demands. Singapore and Biodefense28 A question was raised about whether the degree to which concern about bioterrorism drives biotechnology investment in Singapore in 27   Ranjekar, P. K., A. Patankar, V. Gupta, R. Bhatnagar, J. Bentur, and P. A. Kumar. 2003 “Genetic engineering of crop plants for resistance.” Current Science 84(3):321-329. 28   This section based on the presentation by Patrick Tan Boon Ooi.

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An International Perspective on Advancing Technologies and Strategies for Managing Dual-Use Risks: Report of a Workshop biodefense, given its rapidly growing biotechnological capacity and the fact that the country is surrounded by Indonesia, Thailand, and Malaysia, all predominantly Muslim countries with known Al Quaeda terrorist cells. An important theme that emerged from this discussion was the difference in prioritization of specific “select” agents as a function of geographic location around the world. For example, the CDC-identified category B biological agent Burkholderia pseudomallei is not viewed as a high priority agent of concern by Singaporean authorities, given the ubiquity of this bacterium in the local natural environment. In general, naturally occurring emerging infectious diseases are generally considered a greater threat to national security than bioterrorism. Investment in public health infrastructure and detection/diagnostic technologies is viewed as an attractive strategy. For example, because of its strong domestic DNA sequencing and other relevant technology capacities, Singapore was able to contribute to the global SARS response by genetically profiling a number of different viral isolates. The same capabilities could be used in the event of a bioterrorist attack. In addition to the more immediate threat posed by naturally emerging pathogens, there is a general sense that chemical (e.g., something being introduced into the water supply) and physical attacks (e.g., car bomb) are more likely than a biological attack. Singapore has also acknowledged the existence of a black market in the trafficking in these terrorist tools and the difficulty in curtailing the spread of established dual-use agents and advancing technologies. However, the chance that a bioterrorist attack could happen is definitely on the table. In April 2004, for example, an outbreak of melioidosis that killed 15 people prompted a genotyping effort to determine whether the strains originated from a single source or a variety of sources, the latter an indication of natural emergence. Generally, even outside the context of the changing global climate with respect to terrorism, Singapore security is very tight; everyone is screened, public institutes require card-key access, and the military has very strict entry guidelines. Bioweapons: South Africa’s Past29 Although bioweapons programs are illegal in accordance with the 1972 Biological Weapons Convention,30 some experts nonetheless consider them a driver of the global proliferation of dual-use agents, knowledge, and technology. There is concern that as the means to acquire or engineer 29   This section based on the presentation by J. A. Singh. 30   http://www.opbw.org/. Accessed on October 28, 2004.

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An International Perspective on Advancing Technologies and Strategies for Managing Dual-Use Risks: Report of a Workshop more lethal bioweapons become easier and cheaper, state actors that have not been involved with biological weapons in the past (e.g., because such weapons have not been considered accessible or particularly useful) may start developing new bioweapons programs. Some believe that this may already be occurring under the cover of defensive weapons research. The now defunct offensive bioweapons program of South Africa—known as “Project Coast”—illustrates how biotechnology has been used for malevolent purposes in the past, in this case at the state level and unbeknownst to the rest of the world.31 Apartheid South Africa’s chemical and biological warfare program, known as “Project Coast,” was commenced in the 1980s, in response to the perceived threat of communist regimes flanking the country. The fact that South African troops had been exposed to biowarfare agents in both World Wars, coupled with being privy to British bioweapons secrets, motivated the country to devote resource towards bioweapons research and training and, ultimately, Project Coast. In 1993-1994, South Africa dismantled Project Coast, along with its ballistic missile and nuclear weapons programs.32 Indeed, it was the first country in the world to dismantle all weapons of mass destruction (WMD) programs. But the extent of Project Coast was not publicly known until 1998-1999, when the Truth and Reconciliation Commission hearings coerced many scientists to disclose their involvement with the Project in order to gain immunity. The now transparent history serves as a horrific example of how science can be subverted to undermine entire communities and how scientists can be persuaded to participate in the proclaimed national interest. At the time of the Project, research conducted for the sake of the national interest was considered the most important research in the country. At the workshop, three dual-use technologies allegedly produced under the auspices of Project Coast were described: Up to as many as 45 Bacillus anthracis strains, including a penicillin-resistant strain, were bio-engineered. There are disputed claims that South Africa may have played a role in the 1979-1980 anthrax epidemic in Zimbabwe (formerly Rhodesia), which killed more than 80 people and injured thousands (although this occurred before the formal creation of Project Coast). 31   Burgess, S. and H. Purkitt. 2001. “The Rollback of South Africa’s Chemical and Biological Warfare Program,” USAF Counterproliferation Center, Air War College, Air University, Maxwell Air Force Base, Alabama; April. 32   Ibid.

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An International Perspective on Advancing Technologies and Strategies for Managing Dual-Use Risks: Report of a Workshop There is no proof that race-targeting bacterial bioweapons were actually produced, but significant sums of money were spent on the effort and the intent existed. Acquisition of a peptide synthesizer was ostensibly for the purposes of AIDS research, but court testimony indicated that the synthesizer was in fact being used for research on behavior-changing peptides absorbed through the nasal mucus membranes (e.g., they could make a person either more aggressive or more passive). Again, although it’s not clear whether this approach was ever tested or used on humans, the malicious intent existed. Although South Africa has dismantled Project Coast and its other weapons programs, and post-apartheid legislative initiatives address the need to regulate dual-use technologies with WMD potential, it is interesting to note that the Non-Proliferation Council does not fall under the Ministry of Defense, presumably because of the realization that such technologies have commercial use. It is also interesting to note and of concern that apartheid bioweapons expertise still exists and may be “at large,” that is for sale to the highest bidder. As recommended by the international community, the South African government has attempted to keep many of these experts employed under its watch rather than have them take their expertise elsewhere.