Bio-pharming Fact Sheet No. 0.307 Crop Series|Production by P. Byrne* Manufacturing pharmaceutical products Quick Facts in crops has been one of the promised benefits of plant genetic engineering for the • Bio-pharming is the past 20 years. This use of biotechnology, production of pharmaceutical sometimes known as “pharming,” “bio- proteins in genetically pharming,” or “molecular farming,” has engineered plants. migrated from speculation to the testing phase in fields and greenhouses across • Pharmaceuticals can the country. Bio-pharming promises be made in plants at a more plentiful and cheaper supplies of significantly reduced pharmaceutical drugs, including vaccines for cost compared to current All workers involved with PMP crop production infectious diseases and therapeutic proteins must participate annually in an APHIS-approved production methods. for treatment of such things as cancer and training program on the required procedures heart disease. “Plant-made pharmaceuticals” for growing these crops. Photo courtesy of USDA. • Major concerns with (PMPs) are produced by genetically bio-pharming are that engineering plants to produce specific 2003). Another method for obtaining food or feed crops may compounds, generally proteins, which are biopharmaceuticals is to extract them from become contaminated with extracted and purified after harvest. As used animal and human tissues (e.g., insulin from pharmaceutical products, and here, the terms bio-pharming and PMP pig and cow pancreas, or blood proteins from that the products may have do not include naturally occurring plant human blood (Freese, 2002)). However, these negative effects on natural products or nutritionally enhanced foods. are high-cost procedures that carry the risk of ecosystems. Although PMP technology offers transmitting infectious diseases to humans. potential health and economic benefits, Due to advances in plant genetic engineering • Bio-pharm crops are observers agree that it must be strictly over the past two decades, plants can now be regulated by two federal regulated to prevent pharmaceuticals from modified to produce a wide range of proteins. agencies (USDA and FDA) entering the food supply and to avoid It is hoped this will result in therapeutic and by state departments of unintended effects on the environment. products at a price significantly cheaper agriculture. than through current methods. For example, How are biotech drugs currently antibodies that currently cost thousands of manufactured? dollars per gram might be produced in plants Many protein-based drugs are currently for $200 per gram (Ohlrogge and Chrispeels, produced in sterile fermentation facilities 2003). by genetically engineered microorganisms or mammalian cell cultures in stainless What pharmaceuticals could be made steel tanks (Felsot, 2002). Because these in plants? fermentation plants have huge capital For the near-term, PMPs will be proteins construction costs, industry has been unable because proteins are directly encoded to keep up with the growing demand. For by genes. This property makes their example, the biotech company Amgen production through genetic engineering is reportedly unable to meet demand for more straightforward than other types of Enbrel, a protein-based arthritis medicine biochemical compounds that are synthesized made in mammalian cell cultures (Alper, via more complex methods. See Table 1 for examples of potential bio-pharm products. ©Colorado State University Extension. 7/03. Reviewed 4/08. *P. Byrne, Colorado State University Extension agronomy specialist and associate professor, department of soil and www.ext.colostate.edu crop sciences. 4/08 Table 1: Potential plant-made pharmaceuticals. Information compiled from Canadian Food Inspection Service (2001), Ohlrogge and Chrispeels (2003), and the Web sites of the Biotechnology Industry Organization (www.bio.org/healthcare/pmp/), and Ventria Bioscience (www.ventria.com). Product Definition Examples Antibodies Specialized proteins of the immune system that Specific antibodies may be developed to fight cancer, HIV-AIDS, initiate the body’s defense response. hepatitis, malaria, dental caries, and other diseases. Antigens (vaccines) Compounds that elicit the production of Plant-made vaccines are currently under development for protection antibodies that protect against disease. against cholera, diarrhea (Norwalk virus), and hepatitis B. Enzymes Proteins that catalyze biochemical reactions. Enzymes could be used both to treat and to diagnose disease. For example, lipase is an enzyme that breaks down dietary fats and is used to treat symptoms of cystic fibrosis and other diseases. Hormones Chemical messengers active at low Insulin is produced in the pancreas and helps regulate sugar concentrations and produced in specialized metabolism. Diabetics with insulin deficiencies must replace it via cells. shots or pumps. Structural proteins Proteins that provide structural support to cells Collagen is a structural protein found in animal connective tissues and or tissues. used in cosmetics. Anti-disease agents A wide variety of proteins. The anti-infection proteins interferon and lactoferrin, and aprotinin (which controls blood loss during surgery) have been engineered in plants.

What crops are being considered for the plant it is synthesized) are engineered monitored from planting to harvest to pharmaceutical production? into the plant. Two seed-specific promoters pharmaceutical extraction (Felsot, 2002). The most common PMP crops grown used in experimental bio-pharm lines are Seed will be available only to trained in U.S. field trials are corn, tobacco, and the beta-phaseolin promoter of common contract growers, and the harvested rice. Other crops being investigated bean and the oleosin promoter of Brassica product will be delivered in sealed include alfalfa, potato, safflower, soybean, species (Moloney, 2000). The location of containers to the processing facility. sugarcane, and tomato. Suitable host protein accumulation within the cell is also Standard operating procedures developed plants must be easily engineered, capable important to ensure correct folding and for each specific PMP crop will govern of high levels of protein production, and stability of the protein (Moloney, 2000). isolation distances from conventional crops, have appropriate procedures for extracting While synthesis of biopharmaceuticals equipment use, and field inspections during the PMP from plant tissues. Knowing the in seeds has many advantages, not all PMPs the growing season and for at least a year agronomy, physiology, pests, and diseases will be produced there. Leaves are the afterward. Meticulous record-keeping will of a crop is also an advantage. Ideally, the target tissues in some alfalfa and tobacco be required at each step of the process. host plant is a non-food crop that does applications, and tubers are targeted in not have wild relatives in the production potato production systems (Canadian Food When will plant-made environment, and could not survive in the Inspection Service, 2001). A variation of pharmaceuticals reach the market? environment from seeds carried by wind PMP technology involves infecting plants Research on PMP crops has been or wildlife. When food crops are used, with viruses that are engineered with the ongoing for many years in laboratories, complete pollen sterility is desired, since gene for the pharmaceutical protein. Upon greenhouses, and field trials. In 2002, it would prevent nearby fields of the crop infection (for example, of tobacco leaves), PMP crops were grown at 34 field sites from being pollinated by the bio-pharm the plant’s cellular machinery produces the totaling 130 acres in the U.S. Three PMPs crop. While this is not yet technically biopharmaceutical along with other viral currently undergoing evaluation in clinical feasible, using self-pollinating crops or proteins (Freese, 2002). trials are designed to target non-Hodgkins male-sterile crops can minimize pollination lymphoma, cystic fibrosis, andE. coli/ of food crops. How will PMPs be produced? traveler’s diarrhea (Biotechnology Industry To be successful, pharmaceutical What part of the plant produces production in plants must be a highly the PMP? sophisticated and closely regulated Most bio-pharming applications enterprise, and will differ from target production and storage of the conventional crop production in many pharmaceutical protein in seeds, which ways. Bio-pharm crops must be grown, naturally accumulate high concentrations of transported, and processed using proteins and oils. Seeds are also the easiest safeguards designed to ensure a consistent, part of the plant to store and transport to high-quality product and to prevent processing facilities. To achieve production inadvertent mixing with food crops of the pharmaceutical protein in seeds, and other negative consequences. To seed-specific “promoters” (regulatory achieve this goal, a “closed loop identity Equipment for planting and harvesting of preservation” system is envisioned, in bio-pharm crops must be dedicated to that elements of genes that control how much purpose, i.e., the equipment cannot be of a gene product is made and where in which the crop is carefully regulated and used with any other crop. Photo courtesy of USDA. Organization, www.bio.org/healthcare/ micro-organisms may be inhibited by pmp/factsheet2.asp). Assuming their decomposing crop residue or substances effectiveness and safety are demonstrated exuded from roots of PMP plants. and environmental concerns are adequately • Farm workers may be exposed to addressed, therapeutic pharmaceuticals unhealthy levels of a biopharmaceutical from plants may reach the market in the by absorbing products from leaves second half of this decade. through their skin, inhaling pollen, or breathing in dust at harvest. Who is doing bio-pharming? • Unexpected toxins or residues of pesticides used on the crop may Among the companies pursuing Tractors and tillage equipment must be commercial development of PMPs are Dow thoroughly cleaned before being used with contaminate the final drug product. AgroSciences, Meristem Therapeutics, other crops. Photo courtesy of USDA. and Ventria Bioscience. Reflecting the What steps are being taken to prevent or reduce these risks? commercial uncertainty of the industry, the crop is grown. The potential risk factors some companies, including Monsanto, of PMPs are summarized below. Because bio-pharm crops are genetically have discontinued development of PMP • Pollen from plants engineered engineered, they are subject to U.S. federal products, and the biopharmaceutical firms to produce pharmaceuticals may regulations that govern all such crops. CropTech and Large Scale Biology Corp. fertilize nearby food or feed crops of Three federal agencies, the U.S. Department have filed for bankruptcy in recent years. the same species. If this occurs, the of Agriculture - Animal and Plant Health The companies that develop PMPs will pharmaceutical may be produced in Inspection Service (APHIS), the Food most likely contract with a limited number seed of the neighboring crop, with and Drug Administration (FDA), and the of highly skilled farmers to produce bio- potentially negative effects on human Environmental Protection Agency (EPA) pharm crops. or animal consumers of the seed and all play roles in regulating genetically on crop markets. The risk of gene flow engineered crops, though their specific What are the benefits of plant-made via pollen drift is greater in cross- responsibilities vary depending on the type pharmaceuticals? pollinated crops like corn. Methods of application involved. • PMPs can be produced at a significantly to minimize this risk include spatial Besides the standard regulations reduced cost compared to current and temporal isolation, the use of that apply to all genetically engineered production methods. Therefore, the male sterility (i.e., plants that don’t crops, bio-pharm crops are subject to technology has the potential to benefit produce viable pollen), and in the case additional regulatory oversight. One medical patients by providing a more of corn, detasseling (removing tassels major difference between PMP crops and affordable source of vaccines and other before they shed pollen). When male genetically engineered food crops is that pharmaceuticals. However, it is not clear sterility or detasseling are used, fertile the former require perpetual permitting how large the cost reduction will be or male plants that lack the gene for the by APHIS, whereas the latter crops, once how much of the savings will be passed pharmaceutical are planted in the field approved by the three federal agencies, on to consumers. to provide the pollen source. are considered “unregulated” and are • Plants can be engineered to produce • Commingling of PMP crops and food freely available through commercial proteins of greater complexity than is or feed crops may occur. This could channels without permits. In September, possible with microorganisms (Collins, happen through improper labeling, 2002, FDA and USDA issued the draft 2003), and to produce proteins that mixing of seed in planting, harvesting, document “Guidance for Industry: Drugs, cannot be produced in mammalian cell transportation, or processing Biologics, and Medical Devices Derived cultures (Anonymous, 2002). equipment, or the presence of from Bioengineered Plants for Use in • A limited number of growers and “volunteer” PMP plants in subsequent Humans and Animals”, www.fda.gov/cber/ production workers will likely benefit seasons in the same field. In a 2001 economically from this new agricultural case, ProdiGene failed to eliminate enterprise. The number of acres volunteer bio-pharm corn plants from a required to produce a year’s worth of a soybean crop planted later in the same given pharmaceutical will likely be quite field as the PMP corn (Fox, 2003). The small compared to crop acreage for food company was fined $250,000 by USDA and feed use. and was required to reimburse the government $3 million for expenses What are the risks of plant-made related to destruction of 500,000 bushels pharmaceuticals? of potentially contaminated soybeans. • The introduced gene or its product Risks are not uniform for all bio-pharm may have negative effects on the Bio-pharmed fields will be closely monitored applications, but will vary depending on natural environment. For example, during the growing season and in following the nature of the pharmaceutical product, seasons to ensure that required procedures wildlife feeding on the crop may ingest the crop and tissues in which the PMP is are being followed and that volunteer plants harmful levels of the PMP, or soil are found and disposed of properly. Photo produced, and the environment in which courtesy of USDA. gdlns/bioplant.htm#i. In 2003, APHIS with evaluation of this and future permit announced its intentions to impose more applications for PMP crops, the Colorado Websites for Additional stringent conditions for field tests of Department of Agriculture (CDA) formed Information genetically engineered crops that produce a Technical Advisory Committee to The Union of Concerned Scientists pharmaceutical or industrial compounds. evaluate the adequacy of conditions for Several of these proposed conditions gene containment and for minimizing (www.ucsusa.org/food_and_ are listed in the sidebar. The objective environmental impact. Although the environment/genetic_engineering/ of the new regulations is to prevent Meristem application was approved, the Index-pharmaceutical-industrial-crops. contamination of food and feed crops with company decided not to plant the trial html) discusses benefits and risks of the biopharmaceuticals and to minimize because the optimum planting date had pharm crops. environmental impacts. In 2004, APHIS passed. The Biotechnology Industry provided additional guidance for bio- In 2004, APHIS and CDA approved an pharm permit applicants (APHIS, 2004). application from an Iowa State University Organization, www.bio.org/healthcare/ For example, applicants are requested to researcher to grow bio-pharm corn, and pmp/, has a number of fact sheets on provide details on the amount of the gene a small field plot was planted in Logan plant-made pharmaceuticals. product in all plant parts, the results of County. Whether commercial scale bio- The Transgenic Crops website, allergenicity testing, and an assessment of pharm production will occur in Colorado http://cls.casa.colostate.edu/ potential toxicity to non-target organisms. depends on a number of business and TransgenicCrops/what.html, contains FDA has the responsibility to ensure the government policy decisions, the outcomes safety and usefulness of drugs. Therefore, of which are difficult to predict at present. introductory information on the clinical trials and marketing of PMPs The Colorado Institute of Public Policy techniques and regulation of plant will require FDA approval. FDA will also has examined the issues involved in bio- genetic engineering. oversee procedures for manufacturing pharming and published the report “Bio- The Phyto-Pharma Online Community PMPs to guarantee consistent product Pharming in Colorado: A Guide to Issues (www.plantpharma.org) advocates in quality and potency. for Making Informed Choices (www.cipp. favor of PMP’s and has a variety of EPA regulates the environmental effects colostate.edu/cipp_reports.shtml). of proteins engineered for pest resistance news stories and opinion pieces. (such as Bt insecticidal proteins) in a PMP crop. However, EPA does not review Final Thoughts environmental effects of bio-pharm crops at Like many other aspects of crop Test sites must provide the required this time. biotechnology, supporters and critics isolation distances from other fields of the The department of agriculture of the of PMP crops differ strongly over the same crop. For example, bio-pharm corn state in which a PMP crop field test is benefits and risks of this new application. must be isolated by at least 1 mile from proposed, is given the opportunity to Proponents stress the societal benefits other corn fields if it is open-pollinated, review APHIS’ preliminary assessment of of a cheaper and more plentiful source and by 1/2 mile if pollination is controlled applications for field testing of genetically of pharmaceuticals, while opponents through male sterility or detasseling. engineered crops. In the past, this has emphasize the risks of contamination been a routine approval, but with PMP of the food supply and unknown effects A 50 ft. perimeter fallow zone (area not in on ecosystems. Given the uncertainties crops, states are taking a more cautious production) must surround the PMP crop. approach. State departments of agriculture surrounding bio-pharm crops, it is difficult may request additional permit conditions to predict whether and to what extent beyond those imposed by APHIS. this technology will become part of our future agricultural and health care systems. Are bio-pharm crops likely to be Several questions remain to be answered,  grown in Colorado? including: (1) Are PMPs safe and effective The advantages Colorado has for medicines for humans and animals? (2) Will production costs of PMPs, bio-pharming are the ease of achieving Bio-pharm crop recommended isolation distances for many especially for the purification process, be

crops, and the ability to obtain high yields reduced sufficiently to bring the promised under irrigated conditions with relatively economic benefits? (3) What will be the 

little disease and insect pest pressure. appropriate combinations of crop species, The French company Meristem plant parts, growing environments, and  Therapeutics applied to APHIS for a production safeguards that will provide acceptable levels of gene containment permit to grow a field test of PMP corn in No food or feed crops are allowed in the Phillips County, Colorado in 2003. To assist test plot or fallow zone the following year. and environmental protection? (4) Are Canadian Food Inspection Service. 2001. our regulatory structures adequate to the Plant molecular farming discussion task of regulating and monitoring bio- document. www.inspection.gc.ca/ pharm crops, and, if not, what changes english/plaveg/bio/mf/mf_disde.shtml. will be necessary? (5) To what extent will Collins, S. 2003. Potato the medical factory crop-based pharmaceuticals provide new of tomorrow. The New Zealand Herald, economic opportunities for farmers and April 4, 2003. rural ­communities? Felsot, A. 2002. Pharm farming. Agrichemical and Environmental News, no. 195, July 2002, http://aenews.wsu. References edu. Alper, J. 2003. Hatching the golden egg: A Fox, J.L. 2003. Puzzling industry new way to make drugs. Science response to Prodigene fiasco.Nature 300:729-730. Biotechnology 21: 3-4. Anonymous, 2002. Pharming the Field: Freese, B. 2002. Manufacturing drugs and A look at the benefits and risks of chemical crops: Biopharming poses bioengineering plants to produce new threats to consumers, farmers, food pharmaceuticals. The Pew Charitable companies and the environment. www. Trusts. www.pewtrusts.org/our_work_ foe.org/camps/comm/safefood/ report_detail.aspx?id=35424. biopharm/BIOPHARM_REPORT.pdf. APHIS, 2003. USDA strengthens 2003 Moloney, M.M. 2000. Molecular farming permit conditions for field testing using seeds as hosts. pp. 226-253. M. genetically engineered plants. Press Black and J.D. Bewley (eds.) Seed release. http://www.aphis.usda.gov/lpa/ technology and its biological basis. CRC news/2003/03/gepermits_brs.html. Press, Boca Raton, FL. APHIS. 2004. Updated guidance on Ohlrogge, J., and M.J. Chrispeels. 2003. bioengineered plants for producing Plants as chemical and pharmaceutical pharmaceuticals or industrial products factories. pp. 500-527. M.J. Chrispeels for applicants developing these plants and D.E. Sadava (eds.) Plants, genes, for release (January 2004). and biotechnology. Jones and Bartlett Publishers, Sudbury, MA.

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