Pharming

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).

The products of pharming are typically recombinant proteins (or their metabolic products), which are proteins that result from the expression of recombinant DNA (molecular cloning in a laboratory brings together genetic material from multiple sources, creating sequences that would not otherwise be found in biological organisms). Recombinant proteins are most commonly produced using bacteria or yeast in a bioreactor.

The first recombinant plant-derived protein (PDP) was human serum albumin (the most abundant protein in human blood plasma), initially produced in 1990 in transgenic tobacco and potato plants. 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. By 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.

However in late 2002, just as the biotech company ProdiGene was ramping up production of trypsin for commercial launch[ 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. ProdiGene ordered by the USDA to pay over $3 million in cleanup costs. This raised a furor and set the pharming field back, dramatically. Many companies went bankrupt as companies faced difficulties getting permits for field trials and investors fled. In reaction, APHIS introduced more strict regulations for pharming field trials in the US in 2003. 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. Some companies and academic groups have continued with open-field trials of GM crops that produce drugs. In 2006 Dow AgroSciences received FDA approval to market a vaccine for poultry against Newcastle disease, produced in plant cell culture – the first plant-produced vaccine approved by the FDA and USDA.

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. 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. In 2009 the FDA granted marketing approval for the first drug to be produced in genetically modified livestock. The drug is called ATryn, which is antithrombin protein purified from the milk of genetically modified goats.

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. Recently, several non-crop plants such as duckweed and moss 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.

PMP production is typically 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 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.

There are controversies around GMOs 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. However, the advantages of pharming are multifaceted as well. 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.

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. Many proteins of interest are too complex to be made by microbial systems or by protein synthesis. These proteins are currently being produced in animal cell cultures, but the resulting product is often prohibitively expensive for many patients. Pharmaceutical crops could be extremely beneficial in developing countries.

Even in light of any alleged benefits, 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. 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. Pharming is expected to be worth $100 billion globally by 2020.

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