Pharming (genetics)

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. As a consequence, the host animals or plants then make the pharmaceutical product in large quantity, which can then be purified and used as a drug product. Some drug products and nutrients may be able to be delivered directly by eating the plant or drinking the milk. Such technology has the potential to produce large quantities of cheap vaccines, or other important pharmaceutical products such as insulin.

The products of pharming are recombinant proteins or their metabolic products. Drugs made from recombinant proteins potentially have greater efficacy and fewer side effects than small organic molecules (which are often screened as potential drugs) because their action can be more precisely targeted toward the cause of a disease rather than treatment of symptoms. 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. It is estimated that the expense of producing a recombinant protein drug via pharming will be less than 20% of the current cost.

In the United States, Transgenic plants including but not limited to those which produce pharmaceuticals, are regulated by three government agencies which comprise the Coordinated Framework for Regulation of Biotechnology established in 1986.

• USDA Animal and Plant Health Inspection Service - evaluates potential agricultural impacts such as gene flow and 'weediness'
• EPA - evaluates potential environmental impact intergenic microorganisms under the Toxic Substances Control Act
• DHHS Food and Drug Administration (FDA) - evaluates human health risk if the plant or one of its proteins is intended for human consumption

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Pharming in Mammals

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.^[1] The first such drug manufactured from the milk of a genetically-modified goat was ATryn®, but marketing permission was blocked by the European Medicines Agency in February 2006.^[2] This decision was reversed in June 2006 and approval was given August 2006.^[3]

Pharming in Plants

Arabidopsis is often used as a model organism to study 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 a non-food crop such as tobacco, avoids the greater political pressures and risk to the food supply involved with using staple crops such as maize or rice.

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

There is much debate over the practicality of using plants to produce proteins. Some groups fear that contamination of conventional crops might occur; in several instances, companies have been fined for violating protocols, resulting in potential contamination. This leads to the question of "Why would biotechnology companies use plants to produce proteins?"

Conventional production methods for pharmaceutical proteins involve substantial investments of both time and finances. Not only are there manufacturing challenges involved with conventional production methods, but there are also considerable regulatory challenges that must be met. There are currently about 30 protein-based medicines on the market, and close to 100 in late-stage human trials. Consequently, companies are motivated to provide a wider range of options for production of proteins used in these treatments.

Biopharm proponents claim that using plants can offer an easily controllable, safe, and cost-effective method for manufacturing proteins, provided that proper regulatory safeguards are put into place to insure that no outcrossing can occur. It is also important to note, that the global demand for particular pharmaceutical protein can easily be met from just a few acres of pharma-crop, which can be grown under high containment conditions (e.g. in the greenhouse). Some scientists even think that the term "gardening" is more appropriate than farming. Opponents are concerned that there are too many ways in which contamination of the food supply and the environment can occur to make this form of production socially desirable, or even economically feasible.

Compared to conventional production methods, plant-made pharmaceuticals could save substantial time, money, and provide a system for producing proteins that could solve current production challenges.

Companies in this industry hope that proteins made from plants can be used to develop treatments for some of the most serious diseases and conditions such as cancer, diabetes, HIV, heart disease, Alzheimer's disease, cystic fibrosis, multiple sclerosis, Hepatitis C, and arthritis, but no such products have as yet been approved.

Controversy over Pharming

Those opposed to pharming fear that through either mishandling or gene flow, potentially dangerous pharmacauticals may inadvertently enter the food supply. Precedents involving non-pharmaceutical genetically modified crops include the Starlink controversy, and trade war over genetically modified food between the European union and the USA. A similar reaction to pharmed rice is feared from Japan.

In 2002, ProdiGene was fined $250,000 and ordered by the USDA to pay over $3 million in cleanup costs after allowing a fraction of a bushel of volunteer pharm corn to comingle with the soybean crop later planted in that field. Although the chance of gene flow between species is claimed to be low and there was in this case no threat to consumers, the USDA has a zero tolerance policy. ProdiGene has since revised its protocols and resumed operations in Nebraska. 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 has withdrawn its 2006 permit to plant in Missouri due to unrelated circumstances. The company's field trials in North Carolina are expected to continue.

List of companies and products

Please note that this list is by no means exhaustive.

• Agragen - docosahexaenoic acid and human serum albumin in flax
• Chlorogen, Inc. - cholera, anthrax, and plague vaccines, albumin, interferon for liver diseases including hepatitis C, elastin, 4HB, and insulin-like growth factor in tobacco chloroplasts
• Dow AgroSciences - poultry vaccine against Newcastle disease virus (first PMP to be approved - approved by USDA Center for Veterinary Biologics^[4].)
• Dow Chemical Company - anti-cancer antibodies
• Epicyte - spermicidal antibodies in corn
• Genzyme - antithrombin III in goat milk
• Iowa State University - unknown product in corn
• MacIntosh & Associates, Inc. - unknown product in peas
• Medicago Inc. - Pre-clinical trials of Influenza vaccine in alfalfa ^[5]
• Meristem Therapeutics - Lipase, lactoferrin, plasma proteins, collagen, antibodies (IgA, IgM), allergens and protease inhibitors in tobacco
• Pharming - C1 inhibitor, human collagen 1, fibrinogen (with American Red Cross), and lactoferrin in cow milk
• Planet Biotechnology - antibodies against Streptococcus mutans, antibodies against doxorubicin, and ICAM 1 receptor in tobacco
• PPL Therapeutics - Alpha 1-antitrypsin for cystic fibrosis and emphysema in sheep milk
• ProdiGene - aprotinin, trypsin and a veterinary TGE vaccine in corn
• SemBioSys - insulin in safflower
• Syngenta - Beta carotene in rice (this is "golden rice 2")
• University of Arizona - Hepatitis C vaccine in potatoes
• Ventria Bioscience - lactoferrin and lysozyme in rice
• Washington State University - lactoferrin and lysozyme in barley

Projects known to be abandoned

• Large Scale Biology (bankrupt) ^[6] - using Tobacco mosaic virus to develop patient-specific vaccines for Non-Hodgkin's lymphoma, Papillomavirus vaccine, parvovirus vaccine, alpha galactosidase for Fabry disease, lysosomal acid lipase, aprotinin, interferon Alpha 2a and 2b, G-CSF, and Hepatitis B vaccine antigens in tobacco
• Monsanto - abandoned development of pharmaceutical producing corn

See also

• Biopharmaceutical
• Bioremediation
• Genetically modified organism
• Polly the sheep

References

1. ^ Alan Dove (2000). "Milking the Genome for Profit". Nature Biotechnology 18: 1045-1048.
2. ^ Phillip B. C. Jones. European Regulators Curdle Plans for Goat Milk Human Antithrombin. Retrieved on 2006-06-23.
3. ^ Go-ahead for 'pharmed' goat drug. Retrieved on 2006-10-25.
4. ^ Retrieved on 15 May, 2007
5. ^ Medicago Inc. press release 29 January, 2007. Retrieved on 15 May, 2007
6. ^ [Celia] (2006-01-13). Large Scale files Ch. 11 after closing. Sacramento Business Journal. Retrieved on 2007-05-10.

• 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. [1]