Pharming (genetics)

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For pharming on the Internet, see Pharming. For pharming in drug abuse, see Pharming parties.

Pharming, a portmanteau of "farming" and "pharmaceutical", 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

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

Historical development

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]

Patentability issues regarding pharming

As indicated above, some mammals typically used for food production (such as goats, sheep, pigs, and cows) have been modified to produce non-food products, a practice sometimes called pharming. Use of genetically modified goats has been approved by the FDA and EMA to produce ATryn, i.e. recombinant antithrombin, an anticoagulant protein drug.[21] These products "produced by turning animals into drug-manufacturing 'machines' by genetically modifying them" are sometimes termed biopharmaceuticals.

The patentability of such biopharmaceuticals and their process of manufacture is uncertain. Probably, the biopharmaceuticals themselves so made are unpatentable, assuming that they are chemically identical to the preexisting drugs that they imitate. Several 19th century United States Supreme Court decisions hold that a previously known natural product manufactured by artificial means cannot be patented.[22] An argument can be made for the patentability of the process for manufacturing a biopharmaceutical, however, because genetically modifying animals so that they will produce the drug is dissimilar to previous methods of manufacture; moreover, one Supreme Court decision seems to hold open that possibility.[23]

On the other hand, it has been suggested that the recent Supreme Court decision in Mayo v. Prometheus[24] may create a problem in that, in accordance with the ruling in that case, "it may be said that such and such genes manufacture this protein in the same way they always did in a mammal, they produce the same product, and the genetic modification technology used is conventional, so that the steps of the process 'add nothing to the laws of nature that is not already present.' "

Use this template to terminate a quote within a quote and the main quote to avoid the appearance of 3 's in a row. Example: He said, "When you enter the room, you must say 'hello.' "[25] If the argument prevailed in court, the process would also be ineligible for patent protection. This issue has not yet been decided in the courts.

Pharming in plants

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.[26][27][28] 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.[29][30] 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.[31] Protalix and its partner, Pfizer, received FDA approval to market its drug, Taliglucerase alfa (Elelyso), treatment for Gaucher's Disease, in 2012.[32]

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

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Main article: Regulation of the release of genetic modified organisms

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

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Main article: Genetically modified food controversies

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

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.[33]

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][33] 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.[34]

Disadvantages

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][33][35]

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.[35] 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.[35] Pharming is expected to be worth $100 billion globally by 2020.[36]

List of originators (companies and universities), research projects and products

Please note that this list is by no means exhaustive.

  • Dow AgroSciences - poultry vaccine against Newcastle disease virus (first PMP to be approved for marketing by the USDA Center for Veterinary Biologics[37] Dow never intended to market the vaccine.[38] "'Dow Agrosciences used the animal vaccine as an example to completely run through the process. A new platform needs to be approved, which can be difficult when authorities get in contact with it for the first time', explains the plant physiologist Stefan Schillberg, head of the Molecular Biology Division at the Fraunhofer Institute for Molecular Biology and Applied Ecology Aachen."[39]
  • Fraunhofer Institute for Molecular Biology and Applied Ecology, with sites in Germany, the US, and Chile[40] is the lead institute of the Pharma Planta consortium of 33 partner organizations from 12 European countries and South Africa, funded by the European Commission.[41] Pharma Planta is developing systems for plant production of proteins in greenhouses in the European regulatory framework.[42] It is collaborating on biosimilars with Plantform and PharmaPraxis (see below).[43]
  • Genzyme - antithrombin III in goat milk
  • GTC Biotherapeutics - ATryn (recombinant human antithrombin) in goat milk[44]
  • Icon Genetics produces therapeutics in transiently infected Nicotiana benthamiana (relative of tobacco) plants in greenhouses in Halle, Germany[45][46] or in fields. First product is a vaccine for a cancer, non-Hodgkin's lymphoma.[46]
  • Iowa State University - immunogenic protein from E. coli bacteria in pollen-free corn as a potential vaccine against E. coli for animals and humans[47][48][49]
  • Kentucky Bioprocessing took over Large Scale Biology's facilities in Owensboro, Kentucky, and offers contract biomanufacturing services in tobacco plants, grown in greenhouses or in open fields.[50]
  • Medicago Inc. - Pre-clinical trials of Influenza vaccine made in transiently infected Nicotiana benthamiana (relative of tobacco) plants in greenhouses[51] Medicago has a system for pharming in alfalfa that their website says is "not suited for the production of vaccines"[52]
  • PharmaPraxis - Developing biosimilars in collaboration with PlantForm (see below) and Fraunhofer.[43]
  • Pharming - C1 inhibitor, human collagen 1, fibrinogen (with American Red Cross), and lactoferrin in cow milk[53] The intellectual property behind the fibrinogen project was acquired from PPL Therapeutics when PPL went bankrupt in 2004.[54]
  • Phyton Biotech uses plant cell culture systems to manufacture active pharmaceutical ingredients based on taxanes, including paclitaxel and docetaxel[55]
  • Planet Biotechnology - antibodies against Streptococcus mutans, antibodies against doxorubicin, and ICAM 1 receptor in tobacco[56]
  • PlantForm Corporation - biosimilar trastuzumab in tobacco[57] - It is developing biosimilars in collaboration with PharmaPraxis (see above) and Fraunhofer.[43]
  • ProdiGene - was developing several proteins, including aprotinin, trypsin and a veterinary TGE vaccine in corn. Was in process of launching trypsin product in 2002[11] when later that year its field test crops contaminated conventional crops.[12] Unable to pay the $3 million cost of the cleanup, it was purchased by International Oilseed Distributors in 2003[58][59] International Oilseed Distributors is controlled by Harry H. Stine,[60] who owns one of the biggest soybeans genetics companies in the US.[61] ProdiGene's maize-produced trypsin, with the trademark TrypZean[62] is currently sold by Sigma-Aldritch as a research reagent.[10][63][64]
  • Syngenta - Beta carotene in rice (this is "Golden rice 2"), which Syngenta has donated to the Golden Rice Project[65]
  • University of Arizona - Hepatitis C vaccine in potatoes[66][67]
  • Ventria Bioscience - lactoferrin and lysozyme in rice
  • Washington State University - lactoferrin and lysozyme in barley[68][69]
  • European COST Action on Molecular Farming - COST Action FA0804 on Molecular Farming provides a pan-European coordination centre, connecting academic and government institutions and companies from 23 countries.[70] The aim of the Action is to advance the field by encouraging scientific interactions, providing expert opinion and encouraging commercial development of new products. The COST Action also provides grants allowing young scientists to visit participating laboratories across Europe for scientific training.
  • Mapp Biopharmaceutical in San Diego, California was reported in August 2014 to be developing ZMapp, an experimental cure for the deadly Ebola virus disease. Two Americans who had been infected in Liberia were reported to be improving with the drug. ZMapp was made using antibodies produced by GM tobacco plants.[71][72]

Projects known to be abandoned

See also

References

  1. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  2. ↑ 2.0 2.1 2.2 2.3 Lua error in package.lua at line 80: module 'strict' not found.
  3. ↑ Lua error in package.lua at line 80: module 'strict' not found.Closed access
  4. ↑ Lua error in package.lua at line 80: module 'strict' not found.Closed access
  5. ↑ 5.0 5.1 5.2 Lua error in package.lua at line 80: module 'strict' not found.
  6. ↑ 6.0 6.1 Lua error in package.lua at line 80: module 'strict' not found.Closed access
  7. ↑ Lua error in package.lua at line 80: module 'strict' not found.[page needed]
  8. ↑ 8.0 8.1 8.2 Lua error in package.lua at line 80: module 'strict' not found.Closed access
  9. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  10. ↑ 10.0 10.1 SIgma Info Sheet
  11. ↑ 11.0 11.1 Lua error in package.lua at line 80: module 'strict' not found.
  12. ↑ 12.0 12.1 News of contamination[unreliable source?]
  13. ↑ Biotechnology Regulatory Services Factsheet [Internet]: US Department of Agriculture; c2006. Available from: http://www.aphis.usda.gov/publications/biotechnology/content/printable_version/BRS_FS_pharmaceutical_02-06.pdf
  14. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  15. ↑ FDA Approval News
  16. ↑ 16.0 16.1 16.2 Lua error in package.lua at line 80: module 'strict' not found.
  17. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  18. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  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. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  21. ↑ Andre Pollack for the New York Times. February 6, 2009 F.D.A. Approves Drug From Gene-Altered Goats
  22. ↑ Richard H. Stern. Mayo v Prometheus: No Patents on Conventional Implementations of Natural Principles and Fundamental Truths, [2012] Eur. Intell. Prop. Rev. 502, 517. See Cochrane v. Badische Anili11 & Soda Fabrik, 111 U.S. 293, 311 (1884) (holding invalid claim to artificially made plant dye; "the product itself could not be patented, even though it was a product made artificially for the first time"); American Wood-Paper Co. v. Fibre Disintegrating Co., 90 U.S. 566, 596 (1874) (holding invalid claim to artificially manufactured paper-pulp because "whatever may be said of their process for obtaining it, the product was in no sense new").
  23. ↑ The American Wood-Paper case invalidated the product patent but left open the patentability of the process, saying "whatever may be said of their process for obtaining it...." 90 U.S. at 596.
  24. ↑ Mayo Collaborative Services v. Prometheus Labs., Inc., 566 U.S. __, 132 S. Ct. 1289 (2012).
  25. ↑ Richard H. Stern. Mayo v Prometheus: No Patents on Conventional Implementations of Natural Principles and Fundamental Truths, [2012] Eur. Intell. Prop. Rev. 502, 517-18 (quoting Mayo v. Prometheus; see also Alice v. CLS Bank, 573 U.S. __, 134 S. Ct. 2347 (2014) (to similar effect).
  26. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  27. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  28. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  29. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  30. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  31. ↑ Protalix website - technology platform
  32. ↑ Gali Weinreb and Koby Yeshayahou for Globes May 2, 2012. FDA approves Protalix Gaucher treatment
  33. ↑ 33.0 33.1 33.2 Lua error in package.lua at line 80: module 'strict' not found.
  34. ↑ Lua error in package.lua at line 80: module 'strict' not found.[page needed]
  35. ↑ 35.0 35.1 35.2 Lua error in package.lua at line 80: module 'strict' not found.
  36. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  37. ↑ Retrieved on 15 May 2007
  38. ↑ Margret Engelhard, Kristin Hagen, Felix Thiele (eds). (2007) Pharming A New Branch of Biotechnology [1]
  39. ↑ Farming for Pharma
  40. ↑ Fraunhofer website
  41. ↑ Pharma Planta website
  42. ↑ FAQ page
  43. ↑ 43.0 43.1 43.2 Brennan, Zachary. Brazilian JV looks to tap plant-based manufacturing system for biosimilars. BioPharma-Reporter.com, 23-Jul-2014.
  44. ↑ GTC website
  45. ↑ Press release on opening Halle facility
  46. ↑ 46.0 46.1 Icon press release on clinical trial launch
  47. ↑ Iowa State Ag School 2006 Newsletter
  48. ↑ APHIS approval
  49. ↑ Iowa State plant scientists tweak their biopharmaceutical corn research project
  50. ↑ Kentucky Bioprocessing website
  51. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  52. ↑ Alfalfa page on Medicago website
  53. ↑ Company website
  54. ↑ 54.0 54.1 Press on Pharming Purchase of PPL assets
  55. ↑ Phyton Biotech Official Website
  56. ↑ Company website
  57. ↑ Company website
  58. ↑ Press release from internet archive
  59. ↑ Bloomberg BusinessWeek Profile
  60. ↑ http://investing.businessweek.com/research/stocks/private/snapshot.asp?privcapId=6741964
  61. ↑ Stine Seeds Website
  62. ↑ Trademark listing
  63. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  64. ↑ Sigma Catalog
  65. ↑ FAQ page
  66. ↑ [2]
  67. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  68. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  69. ↑ Wettstein lab webpage
  70. ↑ COST Action FA0804 Official Website
  71. ↑ Ward, Andrew (8 August 2014) Biotech groups face ethical dilemmas in race for Ebola Cure, Financial Times, Page 4, Internet article retrieved 8 August 2014
  72. ↑ Langreth, Robert, et al (5 August 2014) Ebola Drug Made From Tobacco Plant Saves U.S. Aid Workers Bloomberg News, Retrieved 8 August 2014
  73. ↑ Published PCT Application
  74. ↑ CEO Sam Huttenbauer testified before Congress in 2005 about their GM flax efforts Testimony
  75. ↑ Web search on October 6, 2012 found no website for this company and found that executives are all with other companies.
  76. ↑ Bloomberg BusinessWeek Profile
  77. ↑ Plant production for cancer protein Sept 22, 2003
  78. ↑ Press Release
  79. ↑ Purchase contract
  80. ↑ Press Release
  81. ↑ Altor website
  82. ↑ Clinical trial number NCT00879606 for "Anti-TF Antibody (ALT-836) to Treat Septic Patients With Acute Lung Injury or Acute Respiratory Distress Syndrome" at ClinicalTrials.gov
  83. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  84. ↑ Guardian report Sept 2001
  85. ↑ Trelys press release
  86. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  87. ↑ Biomanufacturing Press Release
  88. ↑ Sigma catalog Aprotinin
  89. ↑ History of bankrupt biotech companies
  90. ↑ Cordis entry on Novoplant
  91. ↑ APHIS approval
  92. ↑ Kiprijanov biography
  93. ↑ UPMC buys PPL assets
  94. ↑ Press release May 15, 2012: SemBioSys Announces First Quarter Results and Provides Update on Activities

Further reading

  • Biotech firm puts off rice crop here But company says it plans to sow next year. St. Louis Post-Dispatch. April 29, 2005. Pg. A3.
  • Biotech potato provides hepatitis vaccine. The Atlanta Journal-Constitution. February 15, 2005. Pg. 3A.
  • Biotechnology Venture Hits Unexpected Snags. New York Times. November 23, 2001. Pg. 5.
  • Canadian scientists make insulin from plants: 'Bio-pharming' poised to meet huge diabetes demand at less cost. The Ottawa Citizen. February 27, 2005. Pg. A1.
  • GM corn set to stop man spreading his seed. The Observer. September 9, 2001. Pg. 1.
  • Pharming plans transgenic first. Financial Times. May 3, 2005. Pg. 18.
  • USDA says bio-crop safeguards are tighter ProdiGene is back in Nebraska with test plot. Omaha World Herald. June 2, 2004 Pg. 01D
  • Release Permits for Pharmaceuticals, Industrials,Value Added Proteins for Human Consumption,or for Phytoremediation Granted or Pending by APHIS as of March 29, 2006. [3]

External links

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es:Agricultura molecular fr:Molecular pharming

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