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The International Perspective on the Biotechnology Landscape

The global technology landscape is shifting dramatically and rapidly, both in terms of the types of technological advances being made and the geographical spread and distribution of these advances. Some of the most prominent technological features of today’s landscape are derived from recent advances in genomic sequencing, computing, and bioinformatic technologies. As highlighted during the workshop, these include the establishment of national genomic medicine platforms; high throughput microbial sequencing; the research and development of plant-based manufacturing of vaccines, antibodies, and other pharmaceuticals; and advances in transgenic crop bioengineering. This chapter provides a summary of workshop presentations and discussion on these topics.

One of the most prominent features of today’s global advancing technology landscape is the range of biomedical possibilities afforded by the 2001 completion of the draft human genome—from the discovery of molecular mechanisms of disease to the development of a new generation of diagnostic tools.1 The biomedical applications of genomic knowledge are expected to culminate ultimately in the personalized practice of medicine. Although many analysts do not expect personalized—or genomic—medicine to become an affordable, widespread reality for another 10 to 20 years, steps are being taken now and plans are being made to accommo-

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The International Human Genome Mapping Consortium. 2001. “A physical map of the human genome.” Nature 409:934-941, February 15; Venter J. C. et al. 2001. “The sequence of the human genome.” Science 291:1304-1351.



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An International Perspective on Advancing Technologies and Strategies for Managing Dual-Use Risks: Report of a Workshop 2 The International Perspective on the Biotechnology Landscape The global technology landscape is shifting dramatically and rapidly, both in terms of the types of technological advances being made and the geographical spread and distribution of these advances. Some of the most prominent technological features of today’s landscape are derived from recent advances in genomic sequencing, computing, and bioinformatic technologies. As highlighted during the workshop, these include the establishment of national genomic medicine platforms; high throughput microbial sequencing; the research and development of plant-based manufacturing of vaccines, antibodies, and other pharmaceuticals; and advances in transgenic crop bioengineering. This chapter provides a summary of workshop presentations and discussion on these topics. One of the most prominent features of today’s global advancing technology landscape is the range of biomedical possibilities afforded by the 2001 completion of the draft human genome—from the discovery of molecular mechanisms of disease to the development of a new generation of diagnostic tools.1 The biomedical applications of genomic knowledge are expected to culminate ultimately in the personalized practice of medicine. Although many analysts do not expect personalized—or genomic—medicine to become an affordable, widespread reality for another 10 to 20 years, steps are being taken now and plans are being made to accommo- 1   The International Human Genome Mapping Consortium. 2001. “A physical map of the human genome.” Nature 409:934-941, February 15; Venter J. C. et al. 2001. “The sequence of the human genome.” Science 291:1304-1351.

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An International Perspective on Advancing Technologies and Strategies for Managing Dual-Use Risks: Report of a Workshop date the new medicine when it does arrive. Both Singapore and Mexico are aggressively developing national genomic medicine platforms. Importantly, the human genome is not the only genome that has been sequenced nor the only one from which society can benefit. Beginning with the first complete genetic map of a free-living organism, the bacterium Haemophilus influenzae, in 1995,2 scientists have sequenced more than 200 complete microbial genomes. Although The Institute for Genomic Research (TIGR), Maryland, and The Sanger Institute, Cambridge, UK, lead the world in genomic sequencing, more than 75 centers worldwide have sequenced at least one microbial genome. Included in this chapter is a summary of TIGR’s high-throughput sequencing capabilities. Another large section of this chapter is devoted to plant-based technology platforms, for example plant-based vaccines and transgenic crop technology. Plant-based pharmaceutical manufacturing and transgenic crop technology promise untold economic and societal benefits, particularly for the developing world. Transgenic crop technology, by requiring little initial capital investment, may provide a low-cost means of vaccine production. Experimental data have established proof-of-concept that plant-based vaccines induce immunity, but technical and regulatory obstacles are preventing the field from moving forward more quickly. By contrast, many of the limiting technical challenges of the transgenic crop industry have been overcome, yet the use of the technology is still limited to only a few countries, crops, plant species, and traits. GENOMIC TECHNOLOGY3 Genomic Medicine in Mexico4 Mexico is in the process of developing one of the first genomic medicine platform in Latin America, one that is expected to serve as a regional model for other countries in their efforts to ease health and financial burdens (see Figure 2-1). Not only does Mexico view its effort as a strategic tool for the development of the country as a whole (i.e., with respect to public health, biomedical sciences, biotechnology, and the economy), but also with respect to strengthening national security and preserving Mexican sovereignty. The present time presents a window of opportunity for investment in this emerging medical technological trend, so as to mini- 2   Fleischmann, R. D. et al. 1995. “Whole-genome random sequencing and assembly of Haemophilus influenzae Rd.” Science 269:496-512. 3   This section is based on the workshop presentations of Gerardo Jimenez-Sanchez, Patrick Tan Boon Ooi, and Jacques Ravel. 4   This subsection based on the workshop presentation of Gerardo Jimenez-Sanchez.

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An International Perspective on Advancing Technologies and Strategies for Managing Dual-Use Risks: Report of a Workshop FIGURE 2-1 Chronology of the development of genomic medicine in Mexico. Mexico is in the process of developing one of the first genomic medicine platforms in Latin America. NOTE: Adapted from Gerardo Jimenez-Sanchez’s PowerPoint presentation, September 21, 2004. mize the likelihood of needing to depend on foreign aid and sources in the future and to improve economic growth and social welfare now. The platform will be concentrated at The National Institute of Genomic Medicine (Instituto de Medicina Genómica, or INMEGEN). INMEGEN, which was created in July 2004 by the Mexican Congress was promoted by the National Autonomous University of Mexico (UNAM), the Secretary of Health (SSA), the National Council of Science and Technology (CONACYT), and the Mexican Health Foundation (FUNSALUD). It is now the eleventh National Institute of Health of Mexico in the realm of the Ministry of Health. Primary goals of the Mexico City and Cuernavaca-based institution are to incorporate genomics into the prevention, diagnosis, and treatment of disease; enhance genomics training and research (e.g., 150 Mexican scientists are ready to be incorporated into the Institution; and a Ph.D. program in genomic medicine has been initiated); develop biotechnology and intellectual property; and educate the public (e.g., through lectures, publications, a Web portal,5 and extra- 5   See http://www.inmegen.gob.mx.

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An International Perspective on Advancing Technologies and Strategies for Managing Dual-Use Risks: Report of a Workshop mural pursuits). Research areas include characterizing the genetic variation of and developing pharmacogenomic strategies for the Mexican people; and studying the ethical, legal, and social implications of genomic medicine in the Mexican cultural framework. With over 100 million inhabitants (Mexico is the eleventh most populated country in the world) and 65 different ethnic groups, the modern Mexican population has a unique characteristic genetic structure (i.e., as evident by polymorphisms in blood group proteins, serum proteins, major histocompatibility complex genes, and microsatellites) that may preclude importing genome-specific pharmaceuticals. Mexico also has a unique epidemiology that includes emerging infectious diseases, malnutrition, and a wide range of chronic health problems (e.g., cardiovascular disease, obesity, diabetes, and certain cancers). One might question the cost of developing a genomic medicine platform in a country still challenged with basic needs like clean water, maternal health, and nutrition. Importantly, many of the diseases that genomic medicine would target bear a significant economic and public health cost to Mexico. Direct costs of diabetes, for example, account for 4 to 6 percent of the total annual health budget.6 As also recognized by the Mexican government, ethnic- and population-based variation raises questions about the dual-use risk of technologies that exploit such variation. For example, although sarin is considered a chemical weapon, not a bioweapon, the human body’s ability to defend itself against sarin is ethnic-specific. The active ingredient in sarin is an organophosphate that binds to cholinesterase. When bound, cholinesterase cannot metabolize acetylcholine, which then accumulates in synapses and causes symptoms associated with sarin poisoning. In order to get rid of the sarin, the body uses an enzyme called PON1. There are two allelic variants of PON1 in the human population: the R allele, which is associated with slow inactivation of sarin, and the Q allele, which causes rapid inactivation. As it turns out, the former occurs at a much higher frequency among Asians, suggesting that Asians might be more susceptible to a sarin attack. A Mexican genomic platform is considered key to discouraging non-Mexican research and development of Mexican-specific products and services. Anecdotal reports indicate that U.S. field workers have, in the past, collected blood samples from Mexican indigenous populations and taken the samples back to the United States. Presumably, polymorphisms could be identified and genomic-specific medicines made and sold at U.S. prices. If this were to happen, Mexicans would likely not be able to afford the 6   Jimenez-Sanchez, G. 2003. “Developing a platform for genomic medicine in Mexico.” Science 300:295-296.

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An International Perspective on Advancing Technologies and Strategies for Managing Dual-Use Risks: Report of a Workshop drugs, thereby worsening economic and inequity problems that already exist. Moreover, it has been realized that the same knowledge and technology could be used to make Mexican-specific bioweapons. While the dual-use risk is for the most part considered only hypothetical, it has raised a security issue and prompted action. At the national level, the country is also very aware of how biotechnology developments can and should proceed within the Mexican social context, as the country has an ancient tradition of laws, religion, and traditions that make it difficult to introduce new knowledge and technology. In addition to its work on genomic medicine, the newly established INMEGEN will also be focusing on several other research areas, including metabolism, cardiovascular disease, infectious diseases, and cancer. The Institute is developing several support units, including scientific and ethic committees, high throughput genotyping facilities, gene expression facilities, bioinformatics units, intellectual property units, and a business “incubator.” The business incubator is designed to maximize bench-to-bedside applications, for example by working on intellectual property issues, identifying new markets, developing the commercialization process, scaling up technology, etc. INMEGEN is concentrating its efforts both internally and externally, with a goal of building national networks in academic research, bench-to-bedside applications, and industrial production. As of September 2004, collaboration agreements had been signed with several U.S. institutions, including the National Institutes of Health, Johns Hopkins University, and the Translational Genomic Research Institute in Phoenix. Recently, in collaboration with the University of Toronto Joint Centre for Bioethics, the Institute held a joint meeting on Latin American genomic medicine. The meeting was held in Venezuela and attracted attendees from throughout Latin America and the Caribbean. The Mexican Society of Genomic Medicine (SOMEGEN) comprises another component of the effort to build this new national biotechnology platform in personalized health care. The rapidly growing SOMEGEN, which was founded in June 2003, by 35 members of the academic community from various scientific and educational institutions, currently has five chapters. As of September 2004, its Spanish-based Web site7 had received over 700,000 hits in the previous ten months, and more than 30,000 documents had been downloaded over the same time period. More than 80 percent of the downloads were from Latin America, and more than 52 percent from industrial affiliates. 7   http://www.somegen.org.mx. 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 FIGURE 2-2A Singapore’s current focus on biotechnology is a natural outgrowth of its already high-tech manufacturing and financial service-based economy. NOTE: Adapted from Patrick Tan Boon Ooi’s PowerPoint presentation, September 21, 2004. Biotechnology Growth in Singapore8 Recent biotechnology growth in Singapore promises to push that country to the fore as a regional and global biotechnology hub. At least that is the vision: to create infrastructure and industry pipelines that will serve both upstream basic research and the health delivery system. With a focus on genomic medicine, this will include the development of pharmaceuticals, the manufacture and marketing of pharmaceuticals, and the development of regional headquarters for pharmaceutical companies. Singapore’s primary interest in genomic medicine is economic. Already, high tech manufacturing and financial services serve as the fulcrum of the Singaporean economy (see Figure 2-2A and B). Strengthening biotechnology capacity is expected to slow or stop the outsourcing of high tech jobs to India and China. In addition to the economic potential of genomic medicine, Singapore recognizes the need to understand and address ethnic-specific differences 8   This subsection 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 FIGURE 2-2B Singapore invests in high tech. Singapore’s current focus on biotechnology is a natural outgrowth of its already high-tech manufacturing and financial service-based economy. NOTE: Adapted from Patrick Tan Boon Ooi’s PowerPoint presentation, September 21, 2004. in disease. This is particularly true given the ethnic diversity of Singapore9 (i.e., 98 percent of Singapore’s 4 million people are Chinese, Malay, or Indian), despite its small country size (i.e., roughly the size of Washington, DC). Accumulating evidence indicates patients respond to drugs in ethnic- and population-specific ways (see Table 2-1A and B). For example, only certain polymorphisms in the gene that encodes acetylcholinesterase (ACE) are associated with the renal-protective effects of various ACE inhibitors. In its efforts to become a global genomic hub with strong ties to the international community, the Singapore government took a major step forward when it established Biopolis, which is already considered a 9   The majority of Singapore’s population is ethnic Chinese.

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An International Perspective on Advancing Technologies and Strategies for Managing Dual-Use Risks: Report of a Workshop TABLE 2-1A Ethnic Differences in Drug Effects? Drug Year ADR Common in Rare in Chlorpromazine 1950s Generality White Caucasiana in West Africa Nigerians and Ghanaians Ibufenac 1968 Hepatotoxicity UK Japan Clioquinol 1970s Neuropathy Japan Western world Perhexiline 1980s Neuropathy UK India Terodiline 1990-1991 Cardiotoxocity UK Japan NOTE: Adapted from Patrick Tan Boon Ooi’s PowerPoint presentation, September 21, 2004.. TABLE 2-1B Genetics Influences Drug Effects Gene Medications Drug Effects Linked to Polymorphism Ace Enalapril, lisinopril, captopril Renoprotective effects, cardiac indices, blood pressure, immunoglobulin A nephropathy Potassium channels HERG Quinidine Cisapride Drug-induced long QT syndrome Drug-induced torsade de pointes KvLQT1 Terfenadine, disopyramide, mefloquine Drug-induced long QT syndrome hKCNE2 Clarithromycin Drug-induced arrhythmia NOTE: Adapted from Patrick Tan Boon Ooi’s PowerPoint presentation, September 21, 2004.. world-class biomedical research and development hub. Comprised of five different research institutes, Biopolis serves as a site for both public and corporate R&D (e.g., including Novartis and soon GlaxoSmithKline). Remarkably, the facilities went from initial groundbreaking to official opening within a single year. In November 2004, Biopolis hosted the 5th Human Genome Organization (HUGO) Pacific Meeting and the 6th Asia-Pacific Conference on Human Genetics. Additionally, in partnership with the U.S. Centers for Disease Control and Prevention, the Singapore government recently opened the Regional Emerging Diseases Intervention Center (REDI) to conduct research on new viruses and bioterrorist threats and to establish public health policies for emerging infectious diseases. REDI is already beginning to serve as a regional reference center for molecular diagnostics. For example, in one instance, when the U.S. Embassy in Thailand received a white powder-filled envelope, rather than send it to the CDC, the Embassy sent it to Singapore for analysis.

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An International Perspective on Advancing Technologies and Strategies for Managing Dual-Use Risks: Report of a Workshop In response to a question about whether Singapore is engaged in regional training, it was pointed out that the country’s top priority is to train persons from Singapore, often through collaborations with the United States. For example, Johns Hopkins University has recently opened a campus in Singapore, from which students are awarded Johns Hopkins degrees upon graduation. A Duke-affiliated medical school is being established, from which students will receive joint degrees. Eventually, training for persons from the rest of the region may become possible, although obviously there is a strong economic incentive not to create regional competition. Again, economics is the major driver in Singapore’s pursuit to become a global hub. Much of the funding for these efforts comes from the Ministry of Trade and Industry, not the Ministry of Health. Challenges to Genomic Medicine10 Integrating personalized, or genomic, medicine into routine health care—whether in Singapore, Mexico, the United States, or elsewhere—will require overcoming two major challenges. First, it will be necessary to make the “$1000 genome” a reality (see Figure 2-3A-C). The $1000 genome refers to the cost of determining an individual’s entire genomic sequence and, although somewhat arbritrary, has come to represent the point at which the technology is finally affordable enough for widespread use. It is not clear how the $1000 genome hurdle will be met, although major biotech companies are trying. Some experts believe it will require a new technology. The second and arguably more significant challenge will be making the philosophical jump from the highly interventional, British-style school of medicine to a preventative, predictive health care paradigm. Genomic medicine is expected to revolutionize human medicine by altering the nature of diagnosis, treatment, and prevention. In traditional medicine, diagnosis is based on clinical criteria; treatment is population-based; and intervention is based on the late-stage identification of disease. In genomic medicine, diagnosis is based on molecular criteria (e.g., the use of microarrays in cancer diagnosis); treatment is highly individualized (i.e., genomic-based); and prevention is based on early-stage identification of who is at risk. Microbial Genomics11 If The Institute for Genomic Research (TIGR), Maryland, is any indication, genomic sequencing, per se, is no longer a science—it’s an industry. 10   This subsection is based on comments by Patrick Tan Boon Ooi and Jacques Ravel. 11   This subsection is based on the presentation by J. Ravel.

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An International Perspective on Advancing Technologies and Strategies for Managing Dual-Use Risks: Report of a Workshop FIGURE 2-3A The $1000 genome. As sequencing technology has improved, production has increased and cost has gone down, but not enough to meet the $1000 mark. The $1000 genome represents a somewhat arbitrary “industry standard” when personalized genome sequencing, and personalized medicine, will be an affordable, widespread reality. NOTE: Adapted from Patrick Tan Boon Ooi’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 FIGURE 2-3B Sequencing efficiency 1997–2004 NOTE: Adapted from Jacques Ravel’s PowerPoint presentation, September 21, 2004. FIGURE 2-3C Number of base pairs read 1997–2004 NOTE: Adapted from Jacques Ravel’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 isolated. Yeast-derived manufacturing involves inserting the isolated gene into yeast cells such that they produce the protein, growing the yeast cells, lysing them, and then purifying the antigen through a multi-step process.17 Social vs. economic value of vaccines Infectious diseases cause 25 percent of all deaths, 45 percent of deaths in low-income countries, and 63 percent of deaths in children worldwide. However, very few companies focus on vaccines against infectious disease; greater returns on investment are likely from vaccines to prevent cancer and other chronic diseases.18 HBsAg is now a mandatory component of childhood immunization in the United States. But several countries, including the United Kingdom, do not required hepatitis B vaccination, primarily because it is not cost-effective. For this and other reasons, the vaccine is only being administered throughout about 60 percent of the world. Several years ago, researchers at Arizona State University, Tempe, AZ, questioned whether plant-derived HBsAg and other antigens, rather than yeast-derived antigen, might confer certain advantages that would make the hepatitis B and other vaccines more affordable and accessible. In places like Mexico, for example, where over 40 million vaccine doses are purchased every year (mostly by the government) at a cost of about U.S. $30 per person, a more cost-effective vaccine production system would be a boon. Expenditure for vaccines comprises approximately 1 percent of Mexico’s GNP. The advantages of plant-based manufacturing stem from the totipotency of plant cells, which allows for the ready regeneration of plant tissue for harvesting; the fact that plant-based vaccines do not require a multi-step antigen purification process; and the oral administration of plant-derived vaccines (as opposed to intramuscularly). However, the use of plant-derived vaccines will require overcoming several technical, regulatory, and other challenges. One of the main perceived challenges is the degradation of purified product and loss of activity that occur as antigens pass through the stomach and into the intestine. The gut and liver are designed in many ways to prevent a systemic immune response to food allergens and proteins, yet protection against hepatitis B probably requires a systemic response. Because of this, 17   Sitrin et al. 1993. “Survey of licensed hepatitis B vaccines and their production processes.” In: Hepatitis B Vaccines in Clinical Practice, R. W. Ellis, ed., Marcel Dekker Inc., NY. 18   Adapted from Charles Arntzen’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 there is concern that plant-derived vaccines either would not work (at least not for all infectious diseases) or would require administering multiple doses. However, researchers have shown that in murine model studies, plant-derived HBsAg vaccines do elicit an immune response; and potato-based products currently in human clinical trial show significant positive results for average mean IgG following the administration of three doses of vaccine (at baseline, week 2, and week 4), serving as proof of principle for plant-derived immunization. Significant results depend on much higher dosages—about 100 times greater—than intramuscular injections do. They also rely on antigens being in the form of virus-like particles recognizable by the immune system. It has been suggested that one delivery strategy worth exploring is the anchoring of domains onto mucosa-targeting protein subunits, which has resulted in very good mucosal immunization with HIV.19 Another option is an oral adjuvant, such as Quillaja saponeria extract, which is used in the food industry (and is what gives root beer its suds); Q. saponeria has been tested as an adjuvant with freeze-dried plant vaccines. In addition to the technical challenge of bypassing GI tolerance, the eventual widespread use of plant-derived vaccines faces an uphill battle with respect to similar societal issues that GM (genetically modified) foods face. It will be very important that there is not even a single instance of accidental genetic transfer from a plant vaccine crop to a food crop. If this were to happen, not only might it have unpredictable crop-related and human health consequences, it could kill the entire industry. To avoid such a catastrophe, crop stewardship is a critically important in the development of a plant-based manufacturing system. Neither the USDA nor the FDA have established rules for the production of plant-derived vaccines, but necessary restrictions will likely include growing all materials in physically isolated greenhouses (i.e., separated, sealed buildings that prevent bees and pollen from entering and exiting); and using non-food crops, like tobacco and alfalfa. With regards to the latter, because raw potatoes would not likely be well received in immunization programs in the developing world, ASU researchers have also been experimenting with other modes of delivery, including freeze-drying of tomato and leaf tissue using readily available technology from the food processing industry. The dried, ground-up tissue is put into capsules for easy consumption. Importantly, these tomato-based experimental vaccines come from a 19   Matoba, N. et al. 2004. “A mucosally targeted subunit vaccine candidate eliciting HIV-1 transcytosis-blocking Abs.” Proceedings of the National Academy of Sciences 101(37):13584-13589.

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An International Perspective on Advancing Technologies and Strategies for Managing Dual-Use Risks: Report of a Workshop tasteless, seedless tomato variety that stands no chance of becoming a food crop and would not likely ever be transported to a grocery store. Given these difficult delivery and regulatory challenges, one might question the rationale for moving from yeast-based to plant-based vaccine manufacturing. The single most obvious answer is economics. Compared to producing protein pharmaceuticals (which are mostly fermentation-based recombinant proteins, such as monoclonal antibodies), plant-based manufacturing requires considerably less initial capital investment. In the case of protein pharmaceuticals, of which there are currently 99 in late clinical trials, companies must decide fairly early on whether to spend the U.S. $200-500 million to build a production facility. Plant-based production does not require that very tough economic decision. Greenhouses cost a mere U.S. $20 per square foot, which is practically nothing compared to the cost of building a fermentation facility. The materials for the technology can be purchased from a food industry technology catalogue. Not only is it cheap, it is scalable. It is easy to build another greenhouse or another freeze-drier as the market expands. Other advantages of plant-derived vaccines include the fact that they are needle-free; they are heat-stable and do not require refrigeration; and, since they are oral, they are easier to dispense and do not cause the same contamination problems that needles do. Why use crops? Prepare a strategic reserve of plague vaccine Prepare a strategic reserve of post-Ebola exposure therapeutic antibodies20 Academic researchers have been investigating plant-based vaccines for about a decade and, despite the apparent promise of the technology, very little venture capital interest has been expressed. The technology still lies within the relatively early assembly phase of the technological development process (i.e., discovery is complete, but now all the various components of the technology platform need to be assembled before the plant-based vaccine manufacturing can be transferred and production begun). Work still needs to be done in the areas of molecular technique development, antigen design, down-stream processing under GMP (good manufacturing process), product formulation, and perhaps most importantly, regulatory clarification. 20   Adapted from Charles Arntzen’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 It is interesting to note that when the hepatitis B injectable vaccine was announced in 1986, it was not quickly embraced either. A WHO-affiliated global task force spent several years convincing various governments, organizations, etc., to adopt the vaccine.21 Plant-based vaccines will require a similar public education effort. Plant-Derived Proteins22 Not only does plant-based manufacturing have the potential to increase global immunization coverage for hepatitis B and other diseases, the development of the platform serves as a component of U.S. biodefense research efforts. Funded by the U.S. Army and in collaboration with scientists at USAMRIID, Ft. Detrick, the ASU group conducting the plant-based hepatitis B vaccine work described herein is also conducting research on plant-derived antibodies for use against potential biowarfare agents. The scientists are running animal clinical trials with plant-derived antigen protection against Yersinia pestis; and they are researching the capacity to use plant-derived antibodies for protection against Ebola virus. In both cases, the goal is to build a strategic reserve of what might be post-event prophylactic agents or post-exposure therapeutic agents in the event of a bioterrorist attack. Because of the high initial investments associated with traditional monoclonal antibody manufacturing, coupled with the large list of potential bioterrorist agents, the relatively inexpensive and scalable plant harvesting is considered a cost-effective approach. In contrast to plant-derived vaccines, several companies have expressed interest in plant-derived proteins. These include both large companies, such as Syngenta and Dow Chemical Company, as well as small biotech companies. Monsanto reportedly spent several years and hundreds of millions of dollars demonstrating the ease of purifying monoclonal antibodies from corn but then withdrew its efforts, presumably because of the costs in investing in a downstream processing facility. The company was also keenly aware of crop stewardship and gene transfer issues. Four Latin American countries have invested in plant-based protein manufacture: Mexico, Cuba, Brazil, and Argentina. A question was raised about the technical limitations of so-called biopharming. A major technical problem facing the development of such products is low protein expression levels. As with plant-based vaccines, a second major problem is delivering the product to the right tissue at the 21   Mahoney, R. in Muraksin, W. 1995. The War Against Hepatitis B: A History of the International Task-Force on Hepatitis B Immunization. University of Pennsylvania Press. 22   This subsection based on the presentations of Charles Arntzen and Miguel Gomez Lim.

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An International Perspective on Advancing Technologies and Strategies for Managing Dual-Use Risks: Report of a Workshop right time and in the right amount. A third set of technical/scientific problems relates to the immunological challenge that food-derived products pose (i.e., as with vaccines, in terms of being recognized as foreign and eliciting an immune response). And fourth, as of September 2004, there had been only one human clinical trial of plant-derived monoclonal antibodies and thus practically no precedence with regards to the extent to which products will need to be purified. That first trial was for use against Streptococcus mutans (a causal agent of dental caries). The material used was not highly purified—antibiotics were used to cleanse the mouth, and then the material was simply swabbed on. Limited research funding was cited as one of the challenges to addressing these various technical problems, which may reflect a general public perception that this type of technology is not beneficial or worthwhile. TRANSGENIC CROPS23 Bio-pharming for vaccines, antibodies, and other protein pharmaceuticals may be only an emerging technology, wrought with technical and crop stewardship challenges. Transgenic food crops, on the other hand, have already entered and flourished in the global marketplace. The main producers of transgenic crops are the United States (63 percent of the market), Argentina (21 percent), Canada (6 percent), China and Brazil (4 percent each), and South Africa (1 percent). China is expected to become the largest market in the world over the next 10 to 20 years. With one-quarter of the world’s population and only 7 percent of the world’s arable land, the country has made a strong commitment to using transgenic technology and has spent U.S. $120 million in the last three years on transgenic rice technology alone. Between 2001 and 2005, China’s investment in transgenic technology was 400 percent greater than between 1996 and 2000. But the country faces several challenges, most notably a strong cultural and historical tradition (which may slow acceptance of the technology) and export complications. With regards to the latter, although China was the first country to produce commercially and export a transgenic plant, tobacco, the transgenic backlash in the European Union forced China to discontinue the program. Brazil and India are expected to become larger sectors of the production market in the near future. Other developed countries involved in transgenic crop production include Australia, Spain, Rumania, and Bulgaria; other developing countries with small but growing shares of the 23   This section is based on the workshop presentation of Luis Herrera-Estrella.

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An International Perspective on Advancing Technologies and Strategies for Managing Dual-Use Risks: Report of a Workshop market include Indonesia, Mexico, Uruguay, Colombia, Honduras, and the Philippines. The potential agricultural and societal benefits of transgenic biotechnology include: disease resistance (particularly with respect to viruses; about 50 different transgenic plant species, with resistance to some 80 different viruses, have been produced although not made available commercially); reduced pesticide use (because of effective insect resistance); enhanced nutritive composition of foods; herbicide tolerance; longer shelf life of fruits; more rapid growth of crops; and improvements in taste and quality. Together, these benefits reduce production costs and lead to the production of more and better quality products and ultimately to fewer human health problems (e.g., associated with chemical use, etc.). Currently, approximately 45 percent of the world’s crops are lost to disease, insects, drought, etc. In the United States alone, $20 billion worth of crops are lost annually (i.e., one-tenth of production), which represents a large margin that could potentially be impacted by this technology. The situation per hectare is worse in other parts of the world. For example, while the United States produces about 6 tons of rice per hectare, Europe produces about 5 tons per hectare, Africa only 1.7 tons, and Latin America only 2.3 tons per hectare. Likewise with corn (maize), of which the United States produces 7 tons per hectare, Europe produces about 6 tons per hectare, Latin America 2.1, and Africa only 1.7. Main areas of research on transgenic technology include: mechanisms of disease resistance, including how plants recognize pathogens and trigger defense mechanisms; drought and salinity tolerance, both of which are major global problems (i.e., about 40 percent of the world’s arable land is affected by drought); photosynthesis efficiency; apomixis (i.e., the ability to reproduce asexually through seeds, so that hybrid performance can be inherited); nutrient uptake and utilization efficiency (i.e., to reduce fertilizer use; fertilizer use is considered a major problem not only because of environmental contamination but because of the limited supply of fertilizer); yield components;

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An International Perspective on Advancing Technologies and Strategies for Managing Dual-Use Risks: Report of a Workshop development of metabolic profiling (i.e., with the goal of modifying plants to produce desirable metabolites); and functional genomics for gene discovery (including proteomic analysis). The research and development of transgenic crops are associated with a wide range of technological tools: Routine gene transfer protocols, which exist for most major crops (e.g., Agrobacterium-mediated and particle bombardment) Technology for producing transgenic plants without antibiotic-resistant genes Technology for suppressing the expression of undesirable genes (or activating the expression of desirable genes) Genomic information, which is available for many crops (e.g., the complete genome sequences are available for Arabidopsis thaliana, a widespread model plant system, as well as rice) Technology for using transgenic plants as bioreactors Gene knock-outs (e.g., in A. thaliana, knock-outs are available for every single gene, so any one gene can be chosen for study) Activation of random genes (i.e., using mobile elements that activate transcription) Microarrays and gene expression analysis Metabolic profiling Genome-wide, high density single nucleotide polymorphism (SNP) maps available for QTL (quantitative trait loci, such as those associated with yield and other major traits) isolation Despite the potential benefits of transgenic crop technology and the many tools available to build upon and improve the technology, the use of the technology is still limited to a few countries (as mentioned above), a few crops, a few plant species, and a few traits (see Figure 2-5). Major transgenic crops include soja (i.e., Glycine soja, wild soybean; 61 percent of global market), maize (23 percent), cotton (11 percent), and colza (i.e., rapeseed oil; 5 percent). Major traits include glyphosate resistance (73 percent of global market), Bt (Bacillus thuringiensis, the bacterium from which most biopesticides are derived; 18 percent), or both (9 percent). A question was raised about whether the “growing” use of transgenic plants might make crops more vulnerable to either natural or intentional disease outbreaks, by virtue of reducing the genetic diversity in a fixed land space. In resposnse, it was pointed out that, in fact, the opposite would likely occur. The problems of reduced genetic variation and increased vulnerability to disease are not a transgenic problem per se.

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An International Perspective on Advancing Technologies and Strategies for Managing Dual-Use Risks: Report of a Workshop FIGURE 2-5 The limited use of GM agricultural crops. Despite the potential benefits of transgenic crop technology and the many tools available to build upon and improve the technology, the use of the technology is still limited to a few countries (as mentioned above), a few crops, a few plant species, and a few traits. NOTE: Adapted from Luis Herrera-Estrella’s PowerPoint presentation, September 21, 2004. They became problems in monoculture situations long before transgenic technology emerged, and farmers started sacrificing natural biodiversity for higher productivity varieties decades ago. The use of transgenic technology could, in theory, encourage the preservation of genetic diversity (and thus the reduced risk of disease wiping out an entire crop) by engineering local varieties that are as productive as, if not more productive than, commercial varieties.

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An International Perspective on Advancing Technologies and Strategies for Managing Dual-Use Risks: Report of a Workshop Public Opinion and Other Obstacles to Transgenic Technology24 The primary obstacle to the broader dissemination of transgenic technology is public opinion, coupled with a lack of trust in government agencies. This stems in large part from controversy in the European Union regarding genetically modified (GM) foods. As an example of how turbulent public opinion about technology can be, two very different, opinionated articles appeared on the same date in the same issue of the Mexican newspaper La Jornada.25 In one, “Biosafety Law a Threat to Food Sovereignty,” a number of non-governmental organizations (NGOs) declared to the newspaper that biosafety laws, which the Mexican government is considering as a way to regulate the use of transgenic crops, were a threat to food sovereignty. In the second article, “Farmers Demand Access to Transgenic Plants,” the Mexican corn farmers union demanded access to transgenic plants. It will be interesting to see how public opinion in Mexico—and throughout Latin America—is swayed by recent decisions in the European Union to grow GM maize. On September 8, 2004, the European Commission approved 17 different transgenic varieties of Monsanto-engineered maize for growth throughout Europe. The approval is the first inscription of GM varieties in the EU Seed Catalogue.26 Opinion in Latin America with regards to this issue typically reflects European, not U.S. opinion, because of a lack of trust in the U.S. government. It is believed that the origins of the unfavorable public opinion largely reflect a lack of awareness of the potential benefits of transgenic technology which, in turn, is due partly to the fact that the first generation GM crops were introduced using traits with improved agronomical characteristics rather than features that directly benefited consumers The next generation GM crops will have consumer value-added traits, for example fruits with more nutrients or with neutraceuticals, which presumably will increase public awareness of the potential benefits of GM crops. However, the nature of these second generation transgenic products, particularly foods enhanced with nutraceuticals, raises yet another consumer-benefit issue. Nutraceuticals are components of food that are not directly nutrient-related but can prevent disease or minimize other 24   This subsection based on the presentation of Luis Herrera-Estrella. 25   Perez, M. 2004. “Biosafety law as a threat to food sovereignty.” La Jornada, Society and Justice section, September 13:43. Gomez Mena, Carolina. 2004. “Farmers demand access to transgenic plants.” La Jornada, Society and Justice section, September 13:45. 26   Inscription of MON 810 GM Maize Varieties in the Common EU Catalogue of Varieties, http://europa.eu.int/comm/dgs/health_consumer/library/press/i04_1083.en.pdf. Accessed on November 16, 2004.

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An International Perspective on Advancing Technologies and Strategies for Managing Dual-Use Risks: Report of a Workshop health problems. If efforts are directed to these presumably higher market value traits, will this lead to a lower investment in input and productivity traits? If a company were, for example, to invest in tomatoes with anti-carcinogenic properties, will this compromise the much more urgent need to increase food production? In addition to public perception, another obstacle to the global proliferation of transgenic technology is the lack of technology transfer to small farmers throughout the developing world. Most products currently being commercialized, whether for nutraceuticals or not, are aimed at the U.S. market—not as a solution to any sort of food-security problems but because the U.S. market is the largest in the world. Transferring the technology to smaller farmers with domestic agendas will require the political and economic will of governments and a strong exchange between the public and private sectors. There are signs that this is happening. For example, Monsanto and Mexico are collaborating to produce virus-resistant potatoes. Since Mexico neither imports nor exports potatoes and relies mostly on a single domestic variety, presumably this technology transfer does not pose any sort of market threat to Monsanto. Likewise with avocado, another important Mexican food; 80 percent of the Mexican market for avocado relies on a single variety, and modifying that variety would benefit Mexico without incurring competition for Monsanto. Other obstacles include restrictive or unclear legislation; lack of infrastructure for biosafety evaluation; patent issues; and a general lack of consensus on ethical aspects of transgenic technology. For example, in Mexico, although transgenic plants were first field-tested some 20 years ago, the country still does not have clear legislation for the commercial use of such plants. The problem is confounded by a widespread lack of infrastructure for biosafety evaluation (i.e., to monitor the environmental and public health impacts of the commercial use of transgenic crops). Patent restrictions limit opportunities for transgenic technological growth. For example, Monsanto controls 80 percent of the transgenic seed market. Most of the remainder is controlled by four other large companies. This domination of intellectual property is a significant deterrent for smaller, local companies to become involved. If a developing world company wanted to use the technology to produce viral- and insect-resistant local crops but had to pay royalties, its product would have little market value, despite the potential positive impact of such products. This situation does not appear to be improving. In 2001, the United States filed about 9000 patents for the use of various plant genes. That same year, Japan filed about 11,000. Mexico filed only three.

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