Czech J. Genet. Plant Breed., 2014, 50(1):1-10 | DOI: 10.17221/187/2013-CJGPB

Molecular farming: strategies, expression systems and bio-safety considerationsReview

Kafeel AHMAD
Department of Biology, University of Leicester, Leicester, United Kingdom

Molecular farming is an experimental application of biotechnology that involves the genetic modification of crops for the production of proteins and chemicals for medicinal and commercial purposes. The vast majority in the developing world cannot afford the high cost of therapeutics produced by existing methods. We need to produce not only new therapeutics but also cheaper versions of the existing ones. Molecular farming could offer a viable option for this growing need for biopharmaceuticals. Plant made therapeutics are cheaper, safer, can be abundantly produced and easily stored. Here, strategies and approaches utilized in plant molecular farming are discussed. Furthermore, the bio-safety considerations related to this emerging field are also discussed.

Keywords: biopharmaceuticals; recombinant proteins; rhizosecretion; therapeutics; transformation

Published: March 31, 2014  Show citation

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AHMAD K. Molecular farming: strategies, expression systems and bio-safety considerations. Czech J. Genet. Plant Breed.. 2014;50(1):1-10. doi: 10.17221/187/2013-CJGPB.
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    References

    1. Akerele O. (1993): Nature's medicinal bounty: don't throw it away. World Health Forum, 14: 390-395.
    2. Allera-Moreau C., Chomarat P., Audinot V., Cogé F., Gillard M., Martineau Y., Boutin J.A., Prats A.C. (2006): The use of IRES-based bicistronic vectors allows the stable expression of recombinant G-protein coupled receptors such as NPY5 and histamine 4. Biochimie, 88: 737-746. Go to original source... Go to PubMed...
    3. Bakker H., Bardor M., Molthoff J.W., Gomord V., Elbers I., Stevens L.H., Bosch D. (2001): Galactoseextended glycans of antibodies produced by transgenic plants. Proceedings of the National Academy of Sciences of the United States of America, 98: 2899-2904. Go to original source... Go to PubMed...
    4. Barta A., Sommergruber K., Thompson D., Hartmuth K., Matzke M.A., Matzke A.J.M. (1986): The expression of nopaline synthase human growth hormone chimaeric gene in transformed tobacco and sunflower callus tissue. Plant Molecular Biology, 6: 347-357. Go to original source... Go to PubMed...
    5. Boehm R. (2007): Bioproduction of therapeutic proteins in the 21st century and the role of plants and plant cells as production platforms. Annals of the New York Academy of Sciences, 1102: 121-134. Go to original source... Go to PubMed...
    6. Cabanes-Macheteau M., Fitchette-Laine A.C., Loutelier-Bourhis C., Lange C., Vine N., Ma J., Lerouge P., Faye L. (1999): N-Glycosylation of a mouse IgG expressed in transgenic tobacco plants. Glycobiology, 9: 365-372. Go to original source... Go to PubMed...
    7. Carter J.E., Langridge W.H. (2002): Plant-based vaccines for protection against infectious and autoimmune diseases. Critical Reviews in Plant Sciences, 21: 93-109. Go to original source...
    8. Cavener D.R., Ray S.C. (1991): Eukaryotic start and stop translation sites. Nucleic Acids Research, 19: 3185-3192. Go to original source... Go to PubMed...
    9. Chen M., Liu X., Wang Z., Song J., Qi Q., Wang P.G. (2005): Modification of plant N-glycans processing: the future of producing therapeutic protein by transgenic plants. Medicinal Research Reviews, 25: 343-360. Go to original source... Go to PubMed...
    10. Christensen A.H., Quail P.H. (1996): Ubiquitin promoter-based vectors for high-level expression of selectable and/or screenable marker genes in monocotyledonous plants. Transgenic Research, 5: 213-218. Go to original source... Go to PubMed...
    11. Conrad U., Fiedler U. (1998): Compartment-specific accumulation of recombinant immunoglobulins in plant cells: An essential tool for antibody production and immunomodulation of physiological functions and pathogen activity. Plant Molecular Biology, 38: 101-109. Go to original source...
    12. Cramer C.L., Boothe J.G., Oishi K.K. (1999): Transgenic plants for therapeutic proteins: linking upstream and downstream strategies. Current Topics in Microbiology and Immunology, 240: 95-118. Go to original source... Go to PubMed...
    13. Daniell H. (2006): Production of biopharmaceuticals and vaccines in plants via the chloroplast genome. Biotechnology Journal, 1: 1071-1079. Go to original source... Go to PubMed...
    14. Daniell H., Dhingra A. (2002): Multigene engineering: dawn of an exciting new era in biotechnology. Current Opinion in Biotechnology, 13: 136-141. Go to original source... Go to PubMed...
    15. Daniell H., Kumar S., Dufourmantel N. (2005): Breakthrough in chloroplast genetic engineering of agronomically important crops. Trends in Biotechnology, 23: 238-245. Go to original source... Go to PubMed...
    16. Datla R.S.S., Bekkaoui F., Hammerlindl J.K., Pilate G., Dunstan D.I., Crosby W.L. (1993): Improved high-level constitutive foreign gene expression in plants using an AMV RNA4 untranslated leader sequence. Plant Science, 94: 139-149. Go to original source...
    17. De Cosa B., Moar W., Lee S.B., Miller M., Daniell H. (2001): Over-expression of the Bt cry2Aa2 operon in chloroplasts leads to formation of insecticidal crystals. Nature Biotechnology, 19: 71-74. Go to original source... Go to PubMed...
    18. Drake P.M., Barbi T., Sexton A., Mcgowan E., Stadlmann J., Navarre C., Ma J.K.C. (2009): Development of rhizosecretion as a production system for recombinant proteins from hydroponic cultivated tobacco. The FASEB Journal, 23: 3581-3589. Go to original source... Go to PubMed...
    19. European Parliament (2003): Regulation (EC) No 1829/2003 of the European Parliament and of the Council of 22 September 2003 on Genetically Modified Food and Feed. Official Journal of the European Union, L268: 1-23.
    20. Evangelista R.L., Kusnadi A.R., Howard J.A., Nikolov Z.L. (1988): Process and economic evaluation of the extraction and purification of recombinant glucouronidase from transgenic corn. Biotechnology Progress, 14: 607-614. Go to original source... Go to PubMed...
    21. Finnegan J., McElroy D. (1994): Transgene inactivation: plants fight back. Bio/Technology, 12: 883-888. Go to original source...
    22. Fischer R., Emans N. (2000): Molecular farming of pharmaceutical proteins. Transgenic Research, 9: 279-299. Go to original source... Go to PubMed...
    23. Fischer R., Stoger E., Schillberg S., Christou P., Twyman R.M. (2004) Plant-based production of biopharmaceuticals. Current Opinion in Plant Biology, 7: 152-158. Go to original source... Go to PubMed...
    24. Franken E., Teuschel U., Hain R. (1997): Recombinant proteins from transgenic plants. Current Opinion in Biotechnology, 8: 411-416. Go to original source... Go to PubMed...
    25. Fu H., Machado P.A., Hahm T.S., Kratochvil R.J., Wei C.I., Lo Y.M. (2010): Recovery of nicotine-free proteins from tobacco leaves using phosphate buffer system under controlled conditions. Bioresource Technology, 101: 2034-2042. Go to original source... Go to PubMed...
    26. Gallie D. (1998): Controlling gene expression in transgenics. Current Opinion in Plant Biology, 1: 166-172. Go to original source... Go to PubMed...
    27. Georgiou G., Bowden G.A. (1991): Inclusion body formation and the recovery of aggregated recombinant proteins. In: Ho C., Prokop A., Bajpaj R. (eds): Recombinant DNA Technology and Applications. McGraw-Hill, New York, 333-356.
    28. Giddings G., Allison G., Brooks D., Carter C. (2000): Transgenic plants as factories for biopharmaceuticals. Nature Biotechnology, 18: 1151-1155. Go to original source... Go to PubMed...
    29. Goderis I.J.W.M., De Bolle M.F.C., Francois I.E.J.A., Wouters P.F.J., Broekaert W.F., Cammue B.P.A. (2002): A set of modular plant transformation vectors allowing flexible insertion of up to six expression units. Plant Molecular Biology, 50: 17-27. Go to original source... Go to PubMed...
    30. Harashima S. (1994): Heterologous protein production by yeast host-vector systems. Bioprocess Technology, 19: 137-158. Go to original source...
    31. Helenius A., Aebi M. (2001): Intracellular functions of N-linked glycans. Science, 291: 2364-2369. Go to original source... Go to PubMed...
    32. Hellen C.U.T., Sarnow P. (2001): Internal ribosome entry sites in eukaryotic mRNA molecules. Genes and Development, 15: 1593-1612. Go to original source... Go to PubMed...
    33. Herbers K., Sonnewald U. (1999): Production of new/ modified proteins in transgenic plants. Current Opinion in Biotechnology, 10: 163-168. Go to original source... Go to PubMed...
    34. Hood E.E. (2004): Plants as enzyme factories. In: Christou P., Klee H. (eds): Handbook of Plant Biotechnology, Wiley-VCH, Chichester, 791-800. Go to original source...
    35. Houdebine L.M., Attal J. (1999): Internal ribosome entry sites (IRESs): reality and use. Transgenic Research, 8: 157-177. Go to original source... Go to PubMed...
    36. Hunt A.G. (1994): Messenger RNA 38 end formation in plants. Annual Review of Plant Physiology and Plant Molecular Biology, 45: 47-60. Go to original source...
    37. Ingelbrecht I.L.W., Herman L.M.F., Dekeyser R.A., Van Montagu M.C., Depicker A.G. (1989): Different 38 end regions strongly influence the level of gene expression in plant cells. Plant Cell, 1: 671-680. Go to original source...
    38. Johansen L.K., Carrington J.C. (2001): Silencing on the spot. Induction and suppression of RNA silencing in the Agrobacterium-mediated transient expression system. Plant Physiology, 126: 930-938. Go to original source... Go to PubMed...
    39. Kapila J., Rycke R.D., Montagu M.V., Angenon G. (1996): An Agrobacterium mediated transient gene expression system for intact leaves. Plant Science, 122: 101-108. Go to original source...
    40. Kaufman R.J., Davies M.V., Wasley L.C., Michnick D. (1991): Improved vectors for stable expression of foreign genes in mammalian cells by use of the untranslated leader sequence from EMC virus. Nucleic Acids Research, 19: 4485-4490. Go to original source... Go to PubMed...
    41. Khoudi H., L aberge S., Ferullo J.M., Bazin R., Darveau A., Castonguay Y., Allard G., Lemieux R., Vézina L.P. (1999): Production of a diagnostic monoclonal antibody in perennial alfalfa plants. Biotechnology and Bioengineering, 64: 135-143. Go to original source...
    42. Kleiner S.M. (1995): The true nature of herbs. Physician and Sports Medicine, 23: 13-14. Go to original source... Go to PubMed...
    43. Krebbers E., Bosch D., Vandekerckhove J. (1992): Prospects and progress in the production of foreign proteins and peptides in transgenic plants. In: Shewry P.R., Gutteridges S. (eds): Plant Protein Engineering. Cambridge University Press, London, 315-325.
    44. Kusnadi A.R., Hood E.E., Witcher D.R., Howard J.A., Nikolov Z.L. (1998): Production and purification of two recombinant proteins from transgenic corn. Biotechnology Progress, 14: 149-155. Go to original source... Go to PubMed...
    45. Li L., Zhou Y., Cheng X., Sun J., Marita J.M., Ralph J., Chiang V.L. (2003): Combinatorial modification of multiple lignin traits in trees through multigene cotransformation. Proceedings of the National Academy of Sciences of the United States of America, 100: 4939-4944. Go to original source... Go to PubMed...
    46. Loos A., Steinkellner H. (2012): IgG-Fc glycoengineering in non-mammalian expression hosts. Archives of Biochemistry and Biophysics, 526: 167-173. Go to original source... Go to PubMed...
    47. Lubon H., Paleyanda R.K., Velander W.H., Drohan W.N. (1996): Blood proteins from transgenic animal bioreactors. Transfusion Medicine Reviews, 10: 131-143. Go to original source... Go to PubMed...
    48. Lutcke H.A., Chow K.C., Mickel F.S., Moss K.A., Kern H.F., Scheele G.A. (1987): Selection of AUG initiation codons differs in plants and animals. EMBO Journal, 6: 43-48. Go to original source... Go to PubMed...
    49. Ma J.K.C., Lehner T., Stabila P., Fux C.I., Hiatt A. (1994): Assembly of monoclonal antibodies with IgG1 and IgA heavy chain domains in transgenic tobacco plants. European Journal of Immunology, 24: 131-138. Go to original source... Go to PubMed...
    50. Ma J.K.C., Hiatt A., Hein M., Vine N.D., Wang F., Stabila P., van Dolleweerd C., Mostov K., Lehner T. (1995): Generation and assembly of secretory antibodies in plants. Science, 268: 716-719. Go to original source... Go to PubMed...
    51. Ma J.K.C., Drake P.M.W., Christou P. (2003): The production of recombinant pharmaceutical proteins in plants. Nature Reviews Genetics, 4: 794-805. Go to original source... Go to PubMed...
    52. Ma J.K.C., Drake P.M.W., Chargelegue D., Obregon P., Prada A. (2005): Antibody processing and engineering in plants, and new strategies for vaccine production. Vaccine, 23: 1814-1818. Go to original source... Go to PubMed...
    53. Maas C., Laufs J., Grant S., Korfhage C., Werr W. (1991): The combination of a novel stimulatory element in the first exon of the maize Shrunken-1 gene with the following intron 1 enhances reporter gene expression up to 1000-fold. Plant Molecular Biology, 16: 199-207. Go to original source... Go to PubMed...
    54. Mason H.S., Warzecha H., Mor T., Arntzen C.J. (2002): Edible plant vaccines: applications for prophylactic and therapeutic molecular medicine. Trends in Molecular Medicine, 8: 324-329. Go to original source... Go to PubMed...
    55. Matthews B.F., Hughes C.A. (1993): Nutritional improvement of the aspartate family of amino acids in edible crop plants. Amino Acids, 4: 21-34. Go to original source... Go to PubMed...
    56. Matzke A.J.M., Matzke M.A. (1998): Position effects and epigenetic silencing of plant transgenes. Current Opinion in Plant Biology, 1: 142-148. Go to original source... Go to PubMed...
    57. Menassa R., Nguyen V., Jevnikar A., Brandle J. (2001): A self-contained system for the field production of plant recombinant interleukin-10. Molecular Breeding, 8: 177-185. Go to original source...
    58. Mewett O., Johnson H.S., Holtzapffel R. (2007): Plant Molecular Farming in Australia and Overseas. Bureau of Rural Sciences, Canberra, 1-63.
    59. Meyer P., Saedler H. (1996): Homology-dependent gene silencing in plants. Annual Review in Plant Physiology and Plant Molecular Biology, 47: 23-48. Go to original source... Go to PubMed...
    60. Moravec T., Schmidt M.A., Herman E.M., WoodfordThomas T. (2007): Production of Escherichia coli heat labile toxin (LT) B subunit in soybean seed and analysis of its immunogenicity as an oral vaccine. Vaccine, 25: 1647-1657. Go to original source... Go to PubMed...
    61. Nagels B., Weterings K., Callewaert N., Van Damme E.J.M. (2012): Production of plant made pharmaceuticals: from plant host to functional protein. Critical Reviews in Plant Sciences, 31: 148-80. Go to original source...
    62. Pelletier J., Sonenberg N. (1988): Internal initiation of translation of eukaryotic mRNA directed by a sequence derived from poliovirus RNA. Nature, 334: 320-325. Go to original source... Go to PubMed...
    63. Perrin Y., Vaquero C., Gerrard I., Sack M., Drossard J., Stöger E., Christou P., Fischer R. (2000): Transgenic pea seeds as bioreactors for the production of a single-chain Fv fragment (scFV) antibody used in cancer diagnosis and therapy. Molecular Breeding, 6: 345-352. Go to original source...
    64. Qian B., Shen H., Liang W., Guo X., Zhang C., Wang Y., Li G., Wu A., Cao K., Zhang D. (2008): Immunogenicity of recombinant hepatitis B virus surface antigen fused with preS1 epitopes expressed in rice seeds. Transgenic Research, 17: 621-631. Go to original source... Go to PubMed...
    65. Rademacher T., Sack M., Arcalis E., Stadlmann J., Balzer S., Altmann F., Quendler H., Stiegler G., Kunert R., Fischer R. (2008): Recombinant antibody 2G12 produced in maize endosperm efficiently neutralizes HIV-1 and contains predominantly single-GlcNAc N-glycans. Plant Biotechnology Journal, 6: 189-201. Go to original source... Go to PubMed...
    66. Ramessar K., Capell T., Twyman R.M., Quemada H., Christou P. (2008): Trace and traceability - a call for regulatory harmony. Nature Biotechnology, 26: 975-978. Go to original source... Go to PubMed...
    67. Rigano M.M., Walmsley A.M. (2005): Expression systems and developments in plant-made vaccines. Immunology and Cell Biology, 83: 271-277. Go to original source... Go to PubMed...
    68. Ruf S., Hermann M., Berger I.J., Carrer H., Bock R. (2001): Stable genetic transformation of tomato plastids and expression of a foreign protein in fruit. Nature Biotechnology, 19: 870-875. Go to original source... Go to PubMed...
    69. Ruhlman T., Ahangari R., Devine A., Samsam M., Daniell H. (2007): Expression of cholera toxin B-proinsulin fusion protein in lettuce and tobacco chloroplasts-oral administration protects against development of insulitis in non-obese diabetic mice. Plant Biotechnology Journal, 5: 495-510. Go to original source... Go to PubMed...
    70. Sainsbury F., Thuenemann E.C., Lomonossoff G.P. (2009): pEAQ: versatile expression vectors for easy and quick transient expression of heterologous proteins in plants. Plant Biotechnology Journal, 7: 682-693. Go to original source... Go to PubMed...
    71. Sandhu J.S., Krasnyanski S.F., Domier L.L., Korban S.S., Osadjan M.D., Buetow D.E. (2000): Oral immunization of mice with transgenic tomato fruit expressing respiratory syncytial virus-F protein induces a systemic immune response. Transgenic Research, 9: 127-35. Go to original source... Go to PubMed...
    72. Sasaki Y., Sone T., Yahata K., Kishine H., Hotta J., Chesnut J.D., Honda T., Imamoto F. (2008): Multigene gateway clone design for expression of multiple heterologous genes in living cells: Eukaryotic clones containing two and three ORF multi-gene cassettes expressed from a single promoter. Journal of Biotechnology, 136: 103-112. Go to original source... Go to PubMed...
    73. Schillberg S., Twyman R.M., Fischer R. (2005): Opportunities for recombinant antigen and antibody expression in transgenic plants-technology assessment. Vaccine, 23: 1764-1769. Go to original source... Go to PubMed...
    74. Sexton A., Harman S., Shattock R.J., Ma J.K.C. (2009): Design, expression, and characterization of a multivalent, combination HIV microbicide. The FASEB Journal, 23: 3590-3600. Go to original source... Go to PubMed...
    75. Sharma A.K., Sharma M.K. (2009): Plants as bioreactors: recent developments and emerging opportunities. Biotechnology Advances, 27: 811-832. Go to original source... Go to PubMed...
    76. Singh B.K., Matthews B.F. (1994): Molecular regulation of amino acid biosynthesis in plants. Amino Acids, 7: 165-174. Go to original source... Go to PubMed...
    77. Slater S., Mitsky T.A., Houmiel K.L., Hao M., Reiser S.E., Taylor N.B., Tran M., Valentin H.E., Rodriguez D.J., Stone D.A. (1999): Metabolic engineering of Arabidopsis and Brassica for poly (3-hydroxybutyrateco-3-hydroxyvalerate) copolymer production. Nature Biotechnology, 17: 1011-1016. Go to original source... Go to PubMed...
    78. Sparrow P.A.C., Twyman R.M. (2009): Biosafety, risk assessment and regulation of plant-made pharmaceuticals. Methods in Molecular Biology, 483: 341-353. Go to original source... Go to PubMed...
    79. Stoger E., Vaquero C., Torres E., Sack M., Nicholson L., Drossard J., Williams S., Keen D., Perrin Y., Christou P., Fischer R. (2000): Cereal crops as viable production and storage systems for pharmaceutical scFv antibodies. Plant Molecular Biology, 42: 583-590. Go to original source... Go to PubMed...
    80. Sullivan M.L., Green P.J. (1993): Post-transcriptional regulation of nuclear-encoded genes in higher plants: the roles of mRNA stability and translation. Plant Molecular Biology, 23: 1091-1104. Go to original source... Go to PubMed...
    81. Taylor C.B., Green P.J. (1995): Identification and characterization of genes with unstable transcripts (GUTs) in tobacco. Plant Molecular Biology, 28: 27-38. Go to original source... Go to PubMed...
    82. Trevelyan J. (1993): Herbal medicine. Nursing Times, 89: 36-38.
    83. Trivedi P.K., Nath P. (2004): MaExp1, an ethylene-induced expansin from ripening banana fruit. Plant Science, 167: 1351-1358. Go to original source...
    84. Tsuboi T., Takeo S., Iriko H., Jin L., Tsuchimochi M., Matsuda S., Han E.T., Otsuki H., Kaneko O., Sattabongkot J. (2008): Wheat germ cell-free system-based production of malaria proteins for discovery of novel vaccine candidates. Infection and Immunity, 76: 1702-1708. Go to original source... Go to PubMed...
    85. Twyman R.M., Stoger E., Schillberg S., Christou P., Fischer R. (2003): Molecular farming in plants: host systems and expression technology. Trends in Biotechnology, 21: 570-578. Go to original source... Go to PubMed...
    86. Van Den Elzen P.J.M., Jongedijk E., Melchers L.S., Cornelissen B.J.C. (1993): Virus and fungal resistance: From laboratory to field. Philosophical Transactions: Biological Sciences, 342: 271-278. Go to original source...
    87. Verma D., Daniell H. (2007): Chloroplast vector systems for biotechnology applications. Plant Physiology, 145: 1129-1143. Go to original source... Go to PubMed...
    88. Verwoerd T.C., van Paridon P.A., van Ooyen A.J.J., van Lent J.W.M., Hoekema A., Pen J. (1995): Stable accumulation of Aspergillus niger phytase in transgenic tobacco leaves. Plant Physiology, 109: 1199-1205. Go to original source... Go to PubMed...
    89. Whitelam G.C. (2000): Vaccine production in plants. In: Andrew P.W., Oyston P., Smith G.L. Stewart-Tull D.E. (eds): Fighting Infection in the 21st Century. Blackwell Science Ltd., Oxford, 133-142. Go to original source...
    90. Whitelam G.C., Cockburn B., Gandecha A.R., Owen M.R.L. (1993): Heterologous protein production in transgenic plants. Biotechnology and Genetic Engineering Reviews, 11: 1-29. Go to original source... Go to PubMed...
    91. Winslow L.C., Kroll D.J. (1998): Herbs as medicines. Archives of Internal Medicine, 158: 2192-2199. Go to original source... Go to PubMed...
    92. Yusibov V., Hooper D.C., Spitsin S.V., Fleysh N., Kean R.B., Mikheeva T., Deka D., Karasev A., Cox S., Randall J. (2002): Expression in plants and immunogenicity of plant virus-based experimental rabies vaccine. Vaccine, 20: 3155-3164. Go to original source... Go to PubMed...
    93. Zhang S., Fauquet M. (1998): Expression and inheritance of multiple transgenes in rice plants. Nature Biotechnology, 16: 1060-1064. Go to original source... Go to PubMed...
    94. Zhou Y., Aran J., Gottesman M.M., Pastan I. (1998): Co-expression of human adenosine deaminase and multidrug resistance using a bicistronic retroviral vector. Human Gene Therapy, 9: 287-293. Go to original source... Go to PubMed...
    95. Ziegler M., Thomas S., Danna K. (2000): Accumulation of a thermostable endo-1,4-β-d-glucanase in the apoplast of Arabidopsis thaliana leaves. Molecular Breeding, 6: 37-46. Go to original source...

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