Pharming (genetics)

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For pharming in internet, see pharming. For pharming in drug abuse, see pharming parties.

Pharming is a portmanteau of farming and "pharmaceutical" and refers to the use of genetic engineering to insert genes that code for useful pharmaceuticals into host animals or plants that would otherwise not express those genes, thus creating a genetically modified organism (GMO).[1][2] Pharming is also known as molecular farming, molecular pharming[3] or biopharming.[4]

The products of pharming are recombinant proteins or their metabolic products. Recombinant proteins are most commonly produced using bacteria or yeast in a bioreactor, but pharming offers the advantage to the producer that it does not require expensive infrastructure, and production capacity can be quickly scaled to meet demand, at greatly reduced cost.[5]

History[edit source | edit]

The first recombinant plant-derived protein (PDP) was human serum albumin, initially produced in 1990 in transgenic tobacco and potato plants.[6] Open field growing trials of these crops began in the United States in 1992 and have taken place every year since. While the United States Department of Agriculture has approved planting of pharma crops in every state, most testing has taken place in Hawaii, Nebraska, Iowa, and Wisconsin.[7]

In the early 2000s, the pharming industry was robust. Proof of concept has been established for the production of many therapeutic proteins, including antibodies, blood products, cytokines, growth factors, hormones, recombinant enzymes and human and veterinary vaccines.[8] By 2003 several PDP products for the treatment of human diseases were under development by nearly 200 biotech companies, including recombinant gastric lipase for the treatment of cystic fibrosis, and antibodies for the prevention of dental caries and the treatment of non-Hodgkin's lymphoma.[9]

Several proteins were brought to market as research and bioproduction reagents, mostly by Sigma-Aldrich. ProdiGene struck agreements with Sigma to distribute ProdiGene's corn-produced aprotinin, trypsin,[10] beta-glucuronidase (GUS), and avidin. Large Scale Biology and SIgma agreed that Sigma would distribute LSBC's tobacco-produced aprotinin. Sigma also agreed to distribute Ventria's rise-produced Lactoferrin and Lysozyme.

However in late 2002, just as ProdiGene was ramping up production of trypsin for commercial launch[11] it was discovered that volunteer plants (leftover from the prior harvest) of one of their GM corn products were harvested with the conventional soybean crop later planted in that field.[12] ProdiGene was fined $250,000 and ordered by the USDA to pay over $3 million in cleanup costs. This raised a furor and set the pharming field back, dramatically.[5] Many companies went bankrupt as companies faced difficulties getting permits for field trials and investors fled.[5] In reaction, APHIS introduced more strict regulations for pharming field trials in the US in 2003.[13] In 2005, Anheuser-Busch threatened to boycott rice grown in Missouri because of plans by Ventria Bioscience to grow pharm rice in the state. A compromise was reached, but Ventria withdrew its permit to plant in Missouri due to unrelated circumstances.

The industry has slowly recovered, by focusing on pharming in simple plants grown in bioreactors and on growing GM crops in greenhouses.[14] Some companies and academic groups have continued with open-field trials of GM crops that produce drugs. In 2006 Dow AgroSciences received USDA approval to market a vaccine for poultry against Newcastle disease, produced in plant cell culture - the first plant-produced vaccine approved in the U.S.[15][16]

Pharming in mammals[edit source | edit]

Milk is presently the most mature system to produce recombinant proteins from transgenic organisms. Blood, egg white, seminal plasma, and urine are other theoretically possible systems, but all have drawbacks. Blood, for instance, as of 2012 cannot store high levels of stable recombinant proteins, and biologically active proteins in blood may alter the health of the animals.[17] Expression in the milk of a mammal, such as a cow, sheep, or goat, is a common application, as milk production is plentiful and purification from milk is relatively easy. Hamsters and rabbits have also been used in preliminary studies because of their faster breeding.

One approach to this technology is the creation of a transgenic mammal that can produce the biopharmaceutical in its milk (or blood or urine). Once an animal is produced, typically using the pronuclear microinjection method, it becomes efficacious to use cloning technology to create additional offspring that carry the favorable modified genome.[18] In February 2009 the US FDA granted marketing approval for the first drug to be produced in genetically modified livestock.[19] The drug is called ATryn, which is antithrombin protein purified from the milk of genetically modified goats. Marketing permission was granted by the European Medicines Agency in August 2006.[20]

Pharming in plants[edit source | edit]

Plant-Made Pharmaceuticals (PMPs), also referred to as pharming, is a sub-sector of the biotechnology industry that involves the process of genetically engineering plants so that they can produce certain types of therapeutically important proteins and associate molecules such as peptides and secondary metabolites. The proteins and molecules can then be harvested and used to produce pharmaceuticals.

Recently, several non-crop plants such as the duckweed Lemna minor or the moss Physcomitrella patens have shown to be useful for the production of biopharmaceuticals. These frugal organisms can be cultivated in bioreactors (as opposed to being grown in fields), secrete the transformed proteins into the growth medium and, thus, substantially reduce the burden of protein purification in preparing recombinant proteins for medical use.[21][22][23] In addition, both species can be engineered to cause secretion of proteins with human patterns of glycosylation, an improvement over conventional plant gene-expression systems.[24][25] Biolex Therapeutics developed a duckweed-based expression platform; it sold that business to Synthon and declared bankruptcy in 2012.

Additionally, an Israeli company, Protalix, has developed a method to produce therapeutics in cultured transgenic carrot or tobacco cells.[26] Protalix and its partner, Pfizer, received FDA approval to market its drug, a treatment for Gaucher's Disease, in 2012.[27]

Arabidopsis is often used as a model organism to study gene expression in plants, while actual production may be carried out in maize, rice, potatoes, tobacco, flax or safflower. The advantage of rice and flax is that they are self-pollinating, and thus gene flow issues (see below) are avoided. However, human error could still result in pharm crops entering the food supply. Using a minor crop such as safflower or tobacco, avoids the greater political pressures and risk to the food supply involved with using staple crops such as beans or rice. Despite these risks, corn and soybeans are currently the most common crops that are being used in field trials to produce pharmaceuticals.[citation needed]

Regulation[edit source | edit]

The regulation of genetic engineering concerns the approaches taken by governments to assess and manage the risks associated with the development and release of genetically modified crops. There are differences in the regulation of GM crops - including those used for pharming - between countries, with some of the most marked differences occurring between the USA and Europe. Regulation varies in a given country depending on the intended use of the products of the genetic engineering. For example, a crop not intended for food use is generally not reviewed by authorities responsible for food safety.

Controversy over pharming[edit source | edit]

There are controversies around GMOs generally on several levels, including whether making them is ethical, issues concerning intellectual property and market dynamics; environmental effects of GM crops; and GM crops' role in industrial agricultural more generally. There are also specific controversies around pharming.

Advantages[edit source | edit]

Plants do not carry pathogens that might be dangerous to human health. Additionally, on the level of pharmacologically active proteins, there are no proteins in plants that are similar to human proteins. On the other hand, plants are still sufficiently closely related to animals and humans that they are able to correctly process and configure both animal and human proteins. Their seeds and fruits also provide sterile packaging containers for the valuable therapeutics and guarantee a certain storage life.[28]

Global demand for pharmaceuticals is at unprecedented levels. Expanding the existing microbial systems, although feasible for some therapeutic products, is not a satisfactory option on several grounds.[8] Many proteins of interest are too complex to be made by microbial systems or by protein synthesis.[6][28] These proteins are currently being produced in animal cell cultures, but the resulting product is often prohibitively expensive for many patients. For these reasons, science has been exploring other options for producing proteins of therapeutic value.[2][8][16]

These pharmaceutical crops could become extremely beneficial in developing countries. The World Health Organization estimates that nearly 3 million people die each year from vaccine preventable disease, mostly in Africa. Diseases such as measles and hepatitis lead to deaths in countries where the people cannot afford the high costs of vaccines, but pharm crops could help solve this problem.[29]

Disadvantages[edit source | edit]

While molecular farming is one application of genetic engineering, there are concerns that are unique to it. In the case of genetically modified (GM) foods, concerns focus on the safety of the food for human consumption. In response, it has been argued that the genes that enhance a crop in some way, such as drought resistance or pesticide resistance, are not believed to affect the food itself. Other GM foods in development, such as fruits designed to ripen faster or grow larger, are believed not to affect humans any differently from non-GM varieties.[2][16][28][30]

In contrast, molecular farming is not intended for crops destined for the food chain. It produces plants that contain physiologically active compounds that accumulate in the plant’s tissues. Considerable attention is focused, therefore, on the restraint and caution necessary to protect both consumer health and environmental biodiversity.[2]

The fact that the plants are used to produce drugs alarms activists. They worry that once production begins, the altered plants might find their way into the food supply or cross-pollinate with conventional, non-GM crops.[30] These concerns have historical validation from the ProdiGene incident, and from the StarLink incident, in which GMO corn accidentally ended up in commercial food products. Activists also are concerned about the power of business. According to the Canadian Food Inspection Agency, in a recent report, says that U.S. demand alone for biotech pharmaceuticals is expanding at 13 percent annually and to reach a market value of $28.6 billion in 2004.[30] Pharming is expected to be worth $100 billion globally by 2020.[31]

List of originators (companies and universities) and research projects and products[edit source | edit]

Please note that this list is by no means exhaustive.

Projects known to be abandoned

See also[edit source | edit]

References[edit source | edit]

  1. ^ "Molecular farming". Retrieved 2008-09-11. 
  2. ^ a b c d Sonya Norris (4 July 2005). "Molecular farming". Science and Technology Division Canadian Library of Parliament. Retrieved 2008-09-11. 
  3. ^ Humphreys, John M; Chapple, Clint (2000). "Molecular 'pharming' with plant P450s". Trends in Plant Science 5 (7): 271–2. doi:10.1016/S1360-1385(00)01680-0. PMID 10871897. 
  4. ^ Miller, Henry I. (2003). "Will we reap what biopharming sows?". Nature Biotechnology 21 (5): 480–1. doi:10.1038/nbt0503-480. PMID 12721561. 
  5. ^ a b c Jocelyn Kaiser for Science Magazine 25 April 2008 Is the Drought Over for Pharming?
  6. ^ a b Sijmons, Peter C.; Dekker, Ben M. M.; Schrammeijer, Barbara; Verwoerd, Theo C.; Van Den Elzen, Peter J. M.; Hoekema, André (1990). "Production of Correctly Processed Human Serum Albumin in Transgenic Plants". Bio/Technology 8 (3): 217–21. doi:10.1038/nbt0390-217. PMID 1366404. 
  7. ^ Kimbrell, Andrew (2007). Your right to know: Genetic engineering and the secret change in your food. California: Earth Aware Editions. [page needed]
  8. ^ a b c Twyman, Richard M.; Stoger, Eva; Schillberg, Stefan; Christou, Paul; Fischer, Rainer (2003). "Molecular farming in plants: Host systems and expression technology". Trends in Biotechnology 21 (12): 570–8. doi:10.1016/j.tibtech.2003.10.002. PMID 14624867. 
  9. ^ Ma, Julian K-C.; Drake, Pascal M. W.; Christou, Paul (2003). "Genetic modification: The production of recombinant pharmaceutical proteins in plants". Nature Reviews Genetics 4 (10): 794–805. doi:10.1038/nrg1177. PMID 14526375. 
  10. ^ a b SIgma Info Sheet
  11. ^ a b "ProdiGene Launches First Large Scale-Up Manufacturing of Recombinant Protein From Plant System" (Press release). ProdiGene. February 13, 2002. Retrieved March 8, 2013. 
  12. ^ a b News of contamination[unreliable source?]
  13. ^ Biotechnology Regulatory Services Factsheet [Internet]: US Department of Agriculture; c2006. Available from:
  14. ^ Boehm, Robert (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: 121–34. doi:10.1196/annals.1408.009. PMID 17470916. 
  15. ^ FDA Approval News
  16. ^ a b c Ma, Julian K -C.; Barros, Eugenia; Bock, Ralph; Christou, Paul; Dale, Philip J.; Dix, Philip J.; Fischer, Rainer; Irwin, Judith et al. (2005). "Molecular farming for new drugs and vaccines". EMBO reports 6 (7): 593–9. doi:10.1038/sj.embor.7400470. PMC 1369121. PMID 15995674. 
  17. ^ Houdebine, Louis-Marie (2009). "Production of pharmaceutical proteins by transgenic animals". Comparative Immunology, Microbiology and Infectious Diseases 32 (2): 107–21. doi:10.1016/j.cimid.2007.11.005. PMID 18243312. 
  18. ^ Dove, Alan (2000). "Milking the genome for profit". Nature Biotechnology 18 (10): 1045–8. doi:10.1038/80231. PMID 11017040. 
  19. ^ Staff (2008) FDA Approves First Human Biologic Produced by GE Animals US Food and Drug Administration, from the FDA Vetenarian Newsletter 2008 Volume XXIII, No VI, Retrieved 10 December 2012
  20. ^ "Go-ahead for 'pharmed' goat drug". BBC News. June 2, 2006. Retrieved 2006-10-25. 
  21. ^ Büttner-Mainik, Annette; Parsons, Juliana; Jérôme, Hanna; Hartmann, Andrea; Lamer, Stephanie; Schaaf, Andreas; Schlosser, Andreas; Zipfel, Peter F. et al. (2011). "Production of biologically active recombinant human factor H in Physcomitrella". Plant Biotechnology Journal 9 (3): 373–83. doi:10.1111/j.1467-7652.2010.00552.x. PMID 20723134. 
  22. ^ Gasdaska, John R.; Spencer, David; Dickey, Lynn (2003). "Advantages of Therapeutic Protein Production in the Aquatic Plant Lemna". BioProcessing Journal 2 (2): 49–56. 
  23. ^ Baur, Armin; Reski, Ralf; Gorr, Gilbert (2005). "Enhanced recovery of a secreted recombinant human growth factor using stabilizing additives and by co-expression of human serum albumin in the moss Physcomitrella patens". Plant Biotechnology Journal 3 (3): 331–40. doi:10.1111/j.1467-7652.2005.00127.x. PMID 17129315. 
  24. ^ Cox, Kevin M; Sterling, Jason D; Regan, Jeffrey T; Gasdaska, John R; Frantz, Karen K; Peele, Charles G; Black, Amelia; Passmore, David et al. (2006). "Glycan optimization of a human monoclonal antibody in the aquatic plant Lemna minor". Nature Biotechnology 24 (12): 1591–7. doi:10.1038/nbt1260. PMID 17128273. 
  25. ^ Decker, Eva L.; Reski, Ralf (2007). "Current achievements in the production of complex biopharmaceuticals with moss bioreactors". Bioprocess and Biosystems Engineering 31 (1): 3–9. doi:10.1007/s00449-007-0151-y. PMID 17701058. 
  26. ^ Protalix website - technology platform
  27. ^ Gali Weinreb and Koby Yeshayahou for Globes May 2, 2012. FDA approves Protalix Gaucher treatment
  28. ^ a b c "Molecular Farming – Plant Bioreactors". BioPro. Retrieved 2008-09-13. 
  29. ^ Thomson, JA (2006). Seeds for the future: The impact of genetically modified crops on the environment. Australia: Cornell University Press. [page needed]
  30. ^ a b c Mandel, Charles (2001-11-06). "Molecular Farming Under Fire". wired. Retrieved 2008-09-13. 
  31. ^ "Protein Products for Future Global Good". Retrieved 2008-09-11. 
  32. ^ Retrieved on 15 May 2007
  33. ^ Margret Engelhard, Kristin Hagen, Felix Thiele (eds). (2007) Pharming A New Branch of Biotechnology [1]
  34. ^ Farming for Pharma
  35. ^ Frauenhofer website
  36. ^ Pharma Planta website
  37. ^ FAQ page
  38. ^ GTC website
  39. ^ Press release on opening Halle facility
  40. ^ a b Icon press release on clinical trial launch
  41. ^ Iowa State Ag School 2006 Newsletter
  42. ^ APHIS approval
  43. ^ Iowa State plant scientists tweak their biopharmaceutical corn research project
  44. ^ Kentucky Bioprocessing website
  45. ^ Vezina, Louis-P.; D'Aoust, Marc Andre; Landry, Nathalie; Couture, Manon M.J.; Charland, Nathalie; Barbeau, Brigitte; Sheldon, Andrew J. (2011). "Plants As an Innovative and Accelerated Vaccine-Manufacturing Solution". BioPharm International Supplements 24 (5): s27–30. 
  46. ^ Alfalfa page on Medicago website
  47. ^ Company website
  48. ^ a b Press on Pharming Purchase of PPL assets
  49. ^ Company website
  50. ^ Company website
  51. ^ Press release from internet archive
  52. ^ Bloomberg BusinessWeek Profile
  53. ^
  54. ^ Stine Seeds Website
  55. ^ Trademark listing
  56. ^ Ray, Kevin; Jalili, Pegah R. (2011). "Characterization of TrypZean: a Plant-Based Alternative to Bovine-Derived Trypsin (Peer-Reviewed)". BioPharm International 24 (10): 44–8. 
  57. ^ Sigma Catalog
  58. ^ FAQ page
  59. ^ Arntzen website at UofA
  60. ^ . doi:10.1038/news050214-2.  Missing or empty |title= (help)
  61. ^ "NEPA Decision Summary for Permit #10-047-102r". Animal and Plant Health Inspection Service. March 10, 2010. 
  62. ^ Wettstein lab webpage
  63. ^ COST Action FA0804 Official Website
  64. ^ Published PCT Application
  65. ^ CEO Sam Huttenbauer testified before Congress in 2005 about their GM flax efforts Testimony
  66. ^ Web search on October 6, 2012 found no website for this company and found that executives are all with other companies.
  67. ^ Bloomberg BusinessWeek Profile
  68. ^ Plant production for cancer protein Sept 22, 2003
  69. ^ Press Release
  70. ^ Purchase contract
  71. ^ Press Release
  72. ^ Altor website
  73. ^ NCT00879606 Anti-TF Antibody (ALT-836) to Treat Septic Patients With Acute Lung Injury or Acute Respiratory Distress Syndrome
  74. ^ Jiao, J.-a.; Kelly, A. B.; Marzec, U. M.; Nieves, E.; Acevedo, J.; Burkhardt, M.; Edwards, A.; Zhu, X.-y. et al. (2009). "Inhibition of acute vascular thrombosis in chimpanzees by an anti-human tissue factor antibody targeting the factor X binding site". Thrombosis and Haemostasis 103 (1): 224–33. doi:10.1160/TH09-06-0400. PMC 2927860. PMID 20062929. 
  75. ^ Guardian report Sept 2001
  76. ^ Trelys press release
  77. ^ [Celia] (2006-01-13). "Large Scale files Ch. 11 after closing". Sacramento Business Journal. Retrieved 2007-05-10. 
  78. ^ Biomanufacturing Press Release
  79. ^ Sigma catalog Aprotinin
  80. ^ History of bankrupt biotech companies
  81. ^ Cordis entry on Novoplant
  82. ^ APHIS approval
  83. ^ Kiprijanov biography
  84. ^ UPMC buys PPL assets
  85. ^ Press release May 15, 2012: SemBioSys Announces First Quarter Results and Provides Update on Activities

Further reading[edit source | edit]

External links[edit source | edit]