Production of Medicines from Engineered Proteins in Plants: Proteins for a New Century



Recombinant proteins have already delivered major benefits to human health in the relatively short time they have been available. Plant-based production strategies for these proteins—sometimes called molecular pharming—are becoming widespread and offer major utility, as well as overcoming some of the drawbacks of microbial and mammalian production systems. Flexible and rapid engineering methods, combined with benefits of high volume expression for protein isolation, or seed-based long-term storage, offer many options for medically-relevant protein production with direct benefits for people who need to use them. Metabolic and infectious disease treatments are among the early targets, but cancer treatment, circulatory aliments, allergy reduction, and wound repair and tissue regeneration support may result from proteins produced in plant systems. Selected samples of projects are provided to illustrate the current directions, including the first FDA approved recombinant plant drug to treat a disease. Other examples of projects aimed at communicable diseases, cancer, heart disease, and wound repair are included. When safety and efficacy are demonstrated, and with adherence to appropriate regulatory and biosafety frameworks, plant-derived recombinant proteins may offer high-volume and cost-effective delivery systems for many medical applications in this century.


Molecular pharming Enzymes GMO Vaccines Bioreactors 


  1. Ammann K (2013) Genomic misconception: a fresh look at the biosafety of transgenic and conventional crops. A plea for a process agnostic regulation. N Biotechnol 31:1PubMedCrossRefGoogle Scholar
  2. Belhaj K, Chaparro-Garcia A, Kamoun S, Nekrasov V (2013) Plant genome editing made easy: targeted mutagenesis in model and crop plants using the CRISPR/Cas system. Plant Methods 9(1):39PubMedCentralPubMedCrossRefGoogle Scholar
  3. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TH, Weissig H, Shindyalov IN, Bourne PE (2000) The protein data bank. Nucleic Acids Res 28:235–242, PubMedCentralPubMedCrossRefGoogle Scholar
  4. Bliss M (2013) The Discovery of Insulin. University of Chicago Press, Chicago. ISBN 022607563XGoogle Scholar
  5. Boothe J, Nykiforuk C, Shen Y, Zaplachinski S, Szarka S, Kuhlman P, Murray E, Morck D, Moloney MM (2010) Seed-based expression systems for plant molecular farming. Plant Biotechnol J 8(5):588–606PubMedCrossRefGoogle Scholar
  6. Boseley S Anti-HIV drug made by GM plants begins trials in humans. The Guardian. July 19, 2011. Accessed on the web:
  7. Both L, van Dolleweerd C, Wright E, Banyard AC, Bulmer-Thomas B, Selden D, Altmann F, Fooks AR, Ma JK (2013) Production, characterization, and antigen specificity of recombinant 62-71-3, a candidate monoclonal antibody for rabies prophylaxis in humans. FASEB J 27(5):2055–2065PubMedCentralPubMedCrossRefGoogle Scholar
  8. Bruce TJ (2012) GM as a route for delivery of sustainable crop protection. J Exp Bot 63(2):537–541PubMedCrossRefGoogle Scholar
  9. Chang X, Jorgensen AM, Bardrum P, Led JJ (1997) Solution structures of the R6 human insulin hexamer. Biochemistry 36(31):9409–9422PubMedCrossRefGoogle Scholar
  10. Cox TM (2010) Gaucher disease: clinical profile and therapeutic developments. Biologics 4:299–313PubMedCentralPubMedGoogle Scholar
  11. Danigelis A (2012) Tobacco: more efficient flu vaccine-maker? Sept 25. Accessed on the web:
  12. De Muynck B, Navarre C, Boutry M (2010) Production of antibodies in plants: status after twenty years. Plant Biotechnol J 8(5):529–563PubMedCrossRefGoogle Scholar
  13. Domon E, Takagi H, Hirose S, Sugita K, Kasahara S, Ebinuma H, Takaiwa F (2009) 26-Week oral safety study in macaques for transgenic rice containing major human T-cell epitope peptides from Japanese cedar pollen allergens. J Agric Food Chem 57(12):5633–5638PubMedCrossRefGoogle Scholar
  14. Dormitzer PR, Suphaphiphat P, Gibson DG, Wentworth DE, Stockwell TB, Algire MA, Alperovich N, Barro M, Brown DM, Craig S, Dattilo BM, Denisova EA, De Souza I, Eickmann M, Dugan VG, Ferrari A, Gomila RC, Han L, Judge C, Mane S, Matrosovich M, Merryman C, Palladino G, Palmer GA, Spencer T, Strecker T, Trusheim H, Uhlendorff J, Wen Y, Yee AC, Zaveri J, Zhou B, Becker S, Donabedian A, Mason PW, Glass JI, Rappuoli R, Venter JC (2013) Synthetic generation of influenza vaccine viruses for rapid response to pandemics. Sci Transl Med 5(185):185ra68PubMedCrossRefGoogle Scholar
  15. Gerritsen VB (2001) Protein of the 20th century. Protein spotlight, vol 9, April. Accessed on the web:
  16. Goeddel DV, Kleid DG, Bolivar F, Heyneker HL, Yansura DG, Crea R, Hirose T, Kraszewski A, Itakura K, Riggs AD (1979) Expression in Escherichia coli of chemically synthesized genes for human insulin. Proc Natl Acad Sci U S A 76(1):106–110PubMedCentralPubMedCrossRefGoogle Scholar
  17. Goldstein DA, Thomas JA (2004) Biopharmaceuticals derived from genetically modified plants. QJM 97(11):705–716PubMedCrossRefGoogle Scholar
  18. Greenham T, Altosaar I (2013) Molecular strategies to engineer transgenic rice seed compartments for large-scale production of plant-made pharmaceuticals. Methods Mol Biol 956:311–326PubMedCrossRefGoogle Scholar
  19. Guan ZJ, Guo B, Huo YL, Guan ZP, Dai JK, Wei YH (2013) Recent advances and safety issues of transgenic plant-derived vaccines. Appl Microbiol Biotechnol 97(7):2817–2840PubMedCrossRefGoogle Scholar
  20. Hauptmann V, Weichert N, Rakhimova M, Conrad U (2013) Spider silks from plants—a challenge to create native-sized spidroins. Biotechnol J 8(10):1183–1192PubMedCrossRefGoogle Scholar
  21. Heuser S (2009) One girl’s hope, a nation’s dilemma. Boston Globe, BostonGoogle Scholar
  22. Hood G (2013) Finding an all-natural alternative to DEET. KUNC Radio 91.5. Accessed on the web 19 Oct 2013.
  23. Huskens D, Schols D (2012) Algal lectins as potential HIV microbicide candidates. Mar Drugs 10(7):1476–1497PubMedCentralPubMedCrossRefGoogle Scholar
  24. Jones DS, Podolsky SH, Greene JA (2012) The burden of disease and the changing task of medicine. N Engl J Med 366(25):2333–2338PubMedCrossRefGoogle Scholar
  25. Kumar CS, Deepesh G, Mahavir Y, Archana T (2012) Edible vaccine: a new platform for the development of malaria vaccine. Crit Rev Eukaryot Gene Expr 22(3):243–248PubMedCrossRefGoogle Scholar
  26. Landry N, Ward BJ, Trépanier S, Montomoli E, Dargis M, Lapini G, Vézina LP (2010) Preclinical and clinical development of plant-made virus-like particle vaccine against avian H5N1 influenza. PLoS One 5(12):e15559PubMedCentralPubMedCrossRefGoogle Scholar
  27. Lössl AG, Clarke JL (2013) Conference scene: molecular pharming: manufacturing medicines in plants. Immunotherapy 5(1):9–12PubMedCrossRefGoogle Scholar
  28. Maxmen A (2012) Drug-making plant blooms. Nature 485(7397):160PubMedCrossRefGoogle Scholar
  29. McCormick AA (2011) Tobacco derived cancer vaccines for non-Hodgkin’s lymphoma: perspectives and progress. Hum Vaccin 7(3):305–312, Epub 2011 Mar 1PubMedCrossRefGoogle Scholar
  30. Mehrotra S, Goyal V (2013) Evaluation of designer crops for biosafety—a scientist’s perspective. Gene 515(2):241–248PubMedCrossRefGoogle Scholar
  31. Nochi T, Takagi H, Yuki Y, Yang L, Masumura T, Mejima M, Nakanishi U, Matsumura A, Uozumi A, Hiroi T, Morita S, Tanaka K, Takaiwa F, Kiyono H (2007) Rice-based mucosal vaccine as a global strategy for cold-chain- and needle-free vaccination. Proc Natl Acad Sci U S A 104(26):10986–10991PubMedCentralPubMedCrossRefGoogle Scholar
  32. Nochi T, Yuki Y, Katakai Y, Shibata H, Tokuhara D, Mejima M, Kurokawa S, Takahashi Y, Nakanishi U, Ono F, Mimuro H, Sasakawa C, Takaiwa F, Terao K, Kiyono H (2009) A rice-based oral cholera vaccine induces macaque-specific systemic neutralizing antibodies but does not influence pre-existing intestinal immunity. J Immunol 183(10):6538–6544PubMedCrossRefGoogle Scholar
  33. Paul M, van Dolleweerd C, Drake PM, Reljic R, Thangaraj H, Barbi T, Stylianou E, Pepponi I, Both L, Hehle V, Madeira L, Inchakalody V, Ho S, Guerra T, Ma JK (2011) Molecular pharming: future targets and aspirations. Hum Vaccin 7(3):375–382PubMedCentralPubMedCrossRefGoogle Scholar
  34. Paul MJ, Teh AY, Twyman RM, Ma JK (2013) Target product selection—where can molecular pharming make the difference? Curr Pharm Des 19(31):5478–5485PubMedCrossRefGoogle Scholar
  35. Rosales-Mendoza S (2012) Can a plant-based vaccine treat hypertension? Med Hypotheses 79(5):555–559PubMedCrossRefGoogle Scholar
  36. Rosales-Mendoza S, Govea-Alonso DO, Monreal-Escalante E, Fragoso G, Sciutto E (2012) Developing plant-based vaccines against neglected tropical diseases: where are we? Vaccine 31(1):40–48PubMedCrossRefGoogle Scholar
  37. Rosenberg Y, Sack M, Montefiori D, Forthal D, Mao L, Hernandez-Abanto S, Urban L, Landucci G, Fischer R, Jiang X (2013) Rapid high-level production of functional HIV broadly neutralizing monoclonal antibodies in transient plant expression systems. PLoS One 8(3):e58724PubMedCentralPubMedCrossRefGoogle Scholar
  38. Salazar-González JA, Rosales-Mendoza S (2013) A perspective for atherosclerosis vaccination: is there a place for plant-based vaccines? Vaccine 31(10):1364–1369PubMedCrossRefGoogle Scholar
  39. Shaaltiel Y, Bartfeld D, Hashmueli S, Baum G, Brill-Almon E, Galili G, Dym O, Boldin-Adamsky SA, Silman I, Sussman JL, Futerman AH, Aviezer D (2007) Production of glucocerebrosidase with terminal mannose glycans for enzyme replacement therapy of Gaucher’s disease using a plant cell system. Plant Biotechnol J 5(5):579–590PubMedCrossRefGoogle Scholar
  40. Shilo S, Roth S, Amzel T, Harel-Adar T, Tamir E, Grynspan F, Shoseyov O (2013) Cutaneous wound healing after treatment with plant-derived human recombinant collagen flowable gel. Tissue Eng Part A 19(13–14):1519–1526PubMedCentralPubMedCrossRefGoogle Scholar
  41. Shoseyov O, Posen Y, Grynspan F (2013) Human collagen produced in plants: more than just another molecule. Bioengineered 5(1):2165Google Scholar
  42. Sinclair D, Abba K, Zaman K, Qadri F, Graves PM (2011) Oral vaccines for preventing cholera. Cochrane Database Syst Rev 16(3):CD008603Google Scholar
  43. Stöger E (2013) Editorial: from plant biotechnology to bio-based products. Biotechnol J 8(10):1122–1123PubMedCrossRefGoogle Scholar
  44. Tokuhara D, Yuki Y, Nochi T, Kodama T, Mejima M, Kurokawa S, Takahashi Y, Nanno M, Nakanishi U, Takaiwa F, Honda T, Kiyono H (2010) Secretory IgA-mediated protection against V. cholerae and heat-labile enterotoxin-producing enterotoxigenic Escherichia coli by rice-based vaccine. Proc Natl Acad Sci U S A 107(19):8794–8799PubMedCentralPubMedCrossRefGoogle Scholar
  45. Tokuhara D, Álvarez B, Mejima M, Hiroiwa T, Takahashi Y, Kurokawa S, Kuroda M, Oyama M, Kozuka-Hata H, Nochi T, Sagara H, Aladin F, Marcotte H, Frenken LG, Iturriza-Gómara M, Kiyono H, Hammarström L, Yuki Y (2013) Rice-based oral antibody fragment prophylaxis and therapy against rotavirus infection. J Clin Invest 123(9):3829–3838PubMedCentralPubMedCrossRefGoogle Scholar
  46. WHO (2012) The top 10 causes of death. World Health Organization, Geneva. Fact sheet no. 318. Accessed 15 Oct 2013
  47. Xu X, Gan Q, Clough RC, Pappu KM, Howard JA, Baez JA, Wang K (2011) Hydroxylation of recombinant human collagen type I alpha 1 in transgenic maize co-expressed with a recombinant human prolyl 4-hydroxylase. BMC Biotechnol 11:69PubMedCentralPubMedCrossRefGoogle Scholar
  48. Zimran A, Brill-Almon E, Chertkoff R, Petakov M, Blanco-Favela F, Muñoz ET, Solorio-Meza SE, Amato D, Duran G, Giona F, Heitner R, Rosenbaum H, Giraldo P, Mehta A, Park G, Phillips M, Elstein D, Altarescu G, Szleifer M, Hashmueli S, Aviezer D (2011) Pivotal trial with plant cell-expressed recombinant glucocerebrosidase, taliglucerase alfa, a novel enzyme replacement therapy for Gaucher disease. Blood 118(22):5767–5773PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  1. 1.OpenHelix, LLCBainbridge IslandUSA

Personalised recommendations