Agricultural Biotechnology Research Paper PDF

© 1999 Nature America Inc. http://biotech.nature.com RESOURCES INDUSTRY TRENDS Agricultural biotechnology...

© 1999 Nature America Inc. http://biotech.nature.com RESOURCES INDUSTRY TRENDS Agricultural biotechnology Aris Persidis It has been said that the genetic manipulation coat protein4. This work was aided by the production6, and confirming the potential of of plants is the reason why the Genomics development of another key tool in plant plants as carriers for the production of novel Revolution—touted as the third technologi- transgenics: the Ti plasmid of Agrobacterium materials. This and other work has led to cal revolution following the Industrial tumefaciens, used as a workhorse of plant experiments to produce textile fibers, fuel oil, Revolution and the Computer Revolution— genetic engineering to shuttle foreign genes plastics, vaccines, nonplant enzymes, and will have a major global impact1. Genomics into plant cells. other materials in plants. Transgenic varieties will certainly influence new drug discovery to The use of tobacco plants and TMV as a of major crops, such as corn, soybean, cotton, treat human diseases, but through its appli- platform on which to try different approaches and canola were first planted on a commercial cation to agricultural biotechnology, a signif- to the genetic engineering of desirable traits scale in the last decade, and Calgene’s (Davis, icant proportion of our needs for fuel, fiber, has continued unabated. By the late 1980s, CA) groundbreaking Flavr-Savr transgenic food, and some medicines will soon be plants were being engineered that expressed tomato was introduced in 1996, albeit for a obtained from genetically modified plants. antisense RNA against TMV coat protein and short period of time. Major chemical and pharmaceutical com- were resistant to disease progression5. Also, panies, including Rohm and Haas the first monoclonal antibodies (Mabs) were Current state © 1999 Nature America Inc. http://biotech.nature.com (Philadelphia, PA), Dow Chemical (Midland, produced in transgenic plants, paving the way According to ISAAA, the world market for MI), DuPont (Wilmington, DE), Monsanto for a low-cost, high-yield alternative for Mab genetically engineered plants will be $3 bil- (St. Louis, MO), and Novartis (Basel, Switzerland) are investing heavily in agbiotech—specifically, genetic engineering Table 1. Selected recent agbiotech deals. of plants—both in-house and also through major collaborations with genomics compa- Companies Date Deal size ($M) Area nies. The US market for genetically engi- Axys Pharmaceuticals (S. San Francisco, 4/99 N/A Acquisition of Global Agro neered seeds, both transgenic and nontrans- CA) / Global Agro (Encinitas, CA) genic, was $1.5 billion in 1998, making up 5% of the global agrochemical market, Novartis (Basel, Switzerland) / 1/99 N/A Crop enhancement according to the International Service for the Diversa (San Diego, CA) Acquisition of Agri-Biotech Applications (ISAAA; Nairobi, Kenya). It is not surprising, Pioneer Hi-Bred (Des Moines, IA) / 1/99 $90 Genomics for agbiotech Maxygen (Redwood City, CA) therefore, that with a market this size, agri- cultural biotechnology is a centerpiece of Novartis Crop Protection 12/98 N/A Combinatorial library modern biotechnology applications. (Basel, Switzerland) / generation and screening Pharmacopeia (Princeton, NJ) for agbiotech Historical perspective Numerous developments over a century or Bayer (Leverkusen, Germany) / Paradigm 11/98 $40 Herbicide novel gene Genetics (Research Triangle Park, NC) targets more have contributed to the current progress of agricultural biotechnology and DuPont (Wilmington, DE) / 11/98 $60 Genomics for agbiotech transgenic plants. One focus of current plant Lynx Therapeutics (Hayward, CA) genetic engineering is the use of plant virus- es, such as tobacco mosaic virus (TMV), to Pioneer Hi-Bred (Des Moines, IA) / 9/98 $27 Proteomics for agbiotech carry foreign genes and ensure their expres- Oxford GlycoSciences (Oxford, UK) sion in the plant. The existence of plant Hoechst Schering AgrEvo (Berlin, 6/98 $45 Genomics for agbiotech viruses was postulated in 1898 by Beijerinck, Germany) / GeneLogic (Gaithersburg, MD) but did not gain wide acceptance until much later. First isolated in the form of particles of Monsanto (St. Louis, MO) / 5/98 $2,500 Acquisition of DeKalb an enzyme-like protein in 1935, TMV was DeKalb Genetics (Dekalb, IL) characterized as a nucleoprotein in 1937 Monsanto (St. Louis, MO) / 10/97 $343.0 Genomics for agbiotech (reviewed in ref. 2). Research on TMV’s Millennium (Cambridge, MA) structural aspects continued through the 1960s3, and by the mid-1980s it was shown Novartis Crop Protection 9/97 N/A Combinatorial library that tobacco plants could be genetically (Basel, Switzerland) / generation and screening transformed to resist virus disease develop- Chiron (Emeryville, CA) for crop protection ment, for example, by expressing the TMV Monsanto (St. Louis, MO) / 12/96 $65 Screening for agrochemi- ArQule (Medford, MA) cals by Directed Array Aris Persidis is vice president for business AgrEvo (Berlin, Germany) / Plant 8/96 $500 Acquisition of PGS development at Argonex Inc., 2044 India Genetic Systems (Ghent, Belgium) Road, Charlottesville, VA 22901 Source: Biovista (www.biovista.com). ([email protected]). 612 NATURE BIOTECHNOLOGY VOL 17 JUNE 1999 http://biotech.nature.com  © 1999 Nature America Inc. http://biotech.nature.com RESOURCES Table 2. Genomic and screening programs of selected agrochemical and pharma- ceutical companies in agbiotech. Company Program BASF (Ludwigshafen, Germany) Functional genomics of plants Bayer (Leverkusen, Germany) Target screening in model organisms Dow Chemical (Midland, MI) Functional genomics of plants DuPont (Wilmington, DE) Genomics and target screening Monsanto (St. Louis, MO) Combinatorial screening and plant genomics Novartis (Basel, Switzerland) Functional genomics and combinatorial screening Rhône-Poulenc (Lyon, France) Functional genomics of plants Rohm and Haas (Philadelphia, PA) Gene switching and plant genomics Zeneca (Wilmington, DE) Combinatorial screening and plant genomics Source: Adapted from Thayer, A.M. Chem. Eng. News, April 1999, p. 21. lion in 2000 and will reach $25 billion by On the technology front, present expe- 2010. Transgenic plants will take the majori- rience collected from transgenic plants ty of the largest crop seed markets, and will suggests that simplicity in attempting to be planted on about 60 million hectares engineer a desired trait is the key factor for annually, mostly in the US. Herbicide-resis- success. For example, introducing just one © 1999 Nature America Inc. http://biotech.nature.com tant soybeans and insect-resistant corn and or a few foreign genes into a plant, with cotton have already proved to be successful minimal effects on its physiology, is the products, both in the field and on the bot- best way forward. A case in point is the tom line of the agrochemical companies that engineering of glyphosate herbicide resis- make the seeds. tance in plants. Glyphosate is a major her- The large agrochemical and pharmaceuti- bicide, and achieving resistance to it in the cal companies that want to exploit the vast desired plant crop enhances the herbicide’s and lucrative agbiotech markets have realized selectivity. Glyphosate-resistant plants are that the key technological driver behind created by engineering into them a single transgenic plants is genomics. Genomics bacterial enzyme that is highly resistant to arose as part of the effort to sequence the the herbicide. entire human genome. The efficient DNA- Another example is the engineering of sequencing capabilities and gene expression insect-resistant plants by the addition of the assays it spawned are traditionally used to gene for one of the insecticidal toxins of screen for drugs for human use, but these Bacillus thuringiensis (Bt). The financial companies are now focusing these technolo- returns that result from these simple proto- gies on the identification of novel plant and cols are significant. For example, in the US in plant pathogen targets, against which they 1997, transgenic corn expressing a Bt toxin can screen their vast compound libraries. In had a 7% increase in yield per acre and an order to achieve these aims, they are turning increased net return per acre of $16.887. their attention to biotech companies orient- ed toward genomics, combinatorics, and Industry challenges bioinformatics, whose primary interest is not Manipulating the plant genome to achieve agbiotech, but whose tools can find a ready desirable traits is aided by tremendous application there. advances in genetic engineering, but it is by Table 1 lists a selection of recent deals no means without challenges. For example, involving large agrochemical or pharmaceu- it cannot be predicted a priori whether the tical companies and biotech companies. It best way to engineer a trait into a plant is can be seen that agbiotech deals can be very conventional breeding and transgenic substantial, as illustrated by the acquisitions methodology or the use of plant virus gene of DeKalb Genetics (DeKalb, IL) and Plant vectors. Virus-based transient RNA and Genetic Systems (Ghent, Belgium) and the DNA gene expression is rapid, convenient, Monsanto/Millennium collaboration, and and widely applicable, whereas conventional that the whole gamut of high-throughput crossbreeding is not. However, instability of target and lead identification and validation the foreign gene in the viral genome can pre- are involved. This is very important from the sent problems, and expression efficiency perspective of smaller biotech companies may not always be under tight control. There whose technologies may be suffering from is, however, a great deal of work being done too much competition in the human health- to improve plant viruses as the main tools care arena—their technologies can be easily for the engineering of transgenic plants, applied to the agbiotech field. Table 2 lists the including gene replacement, gene insertion, genomic and screening efforts of some of the antisense approaches, epitope presentation, largest agrochemical and pharmaceutical use of gene expression cassettes, comple- companies. mentation, and others8. NATURE BIOTECHNOLOGY VOL 17 JUNE 1999 http://biotech.nature.com 613  © 1999 Nature America Inc. http://biotech.nature.com RESOURCES Another technical challenge is that, irre- Another interesting prospect is the spective of the mode of novel gene intro- increasing availability of plant genomic duction, it is not sufficient merely to intro- knowledge. As plant genomes begin to duce a gene into a plant. The gene should become fully known, the same types of exist in single copy, and the vector carrier advances that knowledge of the genomes of should not be integrated into the plant human or other organisms have led to will genome. In addition, it is necessary to be be enabled in plants as well. For example, able to predict the quantitative expression the variation in plant microsatellite DNA is of transgenes to ensure that the traits do now being explored in a systematic fash- not “jump” between species, and also that ion13. Understanding this variability and its no unwanted gene expression occurs9. implications may lead to the plant equiva- These challenges are akin to the ones faced lent of pharmacogenomics, whereby genet- by human gene therapy, which is confront- ic variation in a plant population is exploit- ed with the requirement to deliver and ed in order to target specifically certain express genes very precisely and in a con- treatments, or where this variation leads to trolled manner. In both instances, these are a better understanding of the underlying issues of which the industry is well aware, molecular mechanism of plant disease. and concerted efforts are being made to address them. Conclusions It may be surprising, but it is certainly the The future case that at present more than half of the © 1999 Nature America Inc. http://biotech.nature.com Transgenic plants are being engineered with world’s soybean crop and about one-third a variety of useful traits that do not always of the corn crop is transgenic, with genes fall within the typical categories of higher that confer herbicide or disease resistance. yield, insect or herbicide resistance, longer Soybeans and corn are part of hundreds of shelf-life, and the like. A particularly inter- everyday foods such as cereals, cooking esting application of transgenic plants to oils, corn syrup, soft drinks, and sweets. look out for is their use for bioremediation, Nevertheless, the public has considerable specifically the reclaiming of metal-conta- reservations about transgenic plants. In minated soils. Europe, attitudes are much stricter than in Phytoremediation is a potentially cheap the US. Agricultural biotechnology is way to achieve soil remediation, and it may already enjoying tremendous success, and even be possible to recycle metals from these its future is bright. If it is to realize its full plants. For example, plants are often able to potential as an integrated part of society’s accumulate metals such as selenium and technology background, however, its devel- mercury and tolerate them, both of which opers and practitioners will need to make are important traits if they are to be used as an even more concerted effort to share bioremediators. In addition, soil lead and their knowledge with the public, showing chromium may be inactivated in the soil how all relevant concerns are being itself by plants. However, there is at present addressed. Achieving this balance of tech- little understanding of the molecular mech- nological progress and education will anisms by which plants achieve these effects ensure the ultimate success of this major naturally. Progress has been reported technology revolution. recently on the uptake of iron, zinc, and cadmium by Arabidopsis and yeast mutants, and this information will be used in the Acknowledgments The author would like to thank Lorraine Keller of future to develop commercially viable Rohm and Haas for providing some background plants used for metal phytoremediation10. information and materials. The future will see continued efforts to use transgenic plants as factories for vac- cine production, including even immuno- 1. Abelson, P.H. Science 279, 2019 (1998). 2. Bos, L. Phil. Trans. R. Soc. Lond. B. Biol. Sci. 354, contraceptive vaccines, something that is 675–685 (1999). extremely important in the context of 3. Warner, D.T. J. Theor. Biol. 6, 118–136 (1964). 4. Abel, P.P. et al. Science 232, 738–743 (1986). eradicating disease from the developing 5. Powell, P.A. et al. Proc. Natl. Acad. Sci. USA 86, world while also providing food11. 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