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Bio-Pharming

Summary
Bio-pharming is the production of pharmaceutical proteins in genetically engineered plants. Proponents of this technology claim that pharmaceuticals can be made in plants at a significantly reduced cost compared to current production methods. Major concerns with bio-pharming are that food or feed crops may become contaminated with pharmaceutical products, and that the products may have negative effects on natural ecosystems. Bio-pharm crops are regulated by two federal agencies (USDA and FDA) and by state departments of agriculture.

Introduction
The manufacture of pharmaceutical products in plants has been among the promised benefits of plant genetic engineering for nearly 20 years. This application of biotechnology, sometimes known as "bio-pharming", "pharming", or "molecular farming," has now moved beyond the realm of speculation into the experimental testing phase in fields, greenhouses, and clinical trials. Bio-pharming promises more plentiful and cheaper supplies of pharmaceutical drugs, including vaccines for infectious diseases and therapeutic proteins for treatment of conditions such as cancer and heart disease.

"Plant-made pharmaceuticals" (PMPs) are produced by genetically engineering plants to produce specific compounds, generally proteins, which are extracted and purified after harvest. (For an introduction to plant genetic engineering, see the "How Do You Make Transgenic Plants" section of this site.) As used here, the terms bio-pharming and PMP do not include naturally occurring plant products or nutritionally enhanced foods.

Although PMP technology offers potential health and economic benefits, all observers agree that it must be strictly regulated to prevent pharmaceuticals from entering the food supply and to avoid unintended effects on the environment. The following information, presented in question and answer format, covers basic information on the production, regulation, risks, and benefits of PMPs.

How are biotech drugs currently manufactured?
Protein-based drugs developed through biotechnology are currently produced in sterile fermentation facilities, where micro-organisms or mammalian cell cultures in stainless steel tanks churn out a range of genetically engineered products (Felsot, 2002). Most human insulin, for example, is now produced in bacterial cultures. Because these fermentation facilities have huge capital construction costs, industry has been unable to keep up with the growing demand. For example, the biotech company Amgen is reportedly unable to meet demand for Enbrel, a protein-based arthritis medicine made in mammalian cell cultures (Alper, 2003). Some biopharmaceuticals are extracted from animal and human tissues (e.g., insulin from pig and cow pancreas, blood proteins from human blood (Freese, 2002)), a high-cost procedure that carries the risk of transmitting infectious diseases. Due to advances in plant genetic engineering over the past two decades, plants can now be modified to produce a wide range of therapeutic products at a price significantly cheaper than through current methods. For example, antibodies that currently cost thousands of dollars per gram might be produced in plants for $200 per gram (Ohlrogge and Chrispeels, 2003).

What pharmaceuticals could be made in plants?
At least for the near-term, PMPs will be proteins. Because proteins are directly encoded by genes [see our brief introduction to DNA], their production through genetic engineering is more straightforward than other types of biochemical compounds, which are synthesized via more complex biochemical pathways. Some potential bio-pharm products are listed in Table 1.

What crops are being considered for pharmaceutical production?
The most common PMP crops that have been grown in U.S. field trials are corn, tobacco, and rice. Other crops being investigated include alfalfa, potato, safflower, soybean, sugarcane, and tomato.

Sugarcane
All images: USDA

Rice

Potato

Tobacco

Tomato

Corn

Soybean

Suitable host plants must be easily engineered, be capable of high levels of protein production, and have appropriate procedures for extracting the PMP from plant tissues. Knowledge of the agronomy, physiology, pests and diseases of a crop is also an advantage. Ideally, the host plant would be a non-food crop that does not have wild relatives present in the production environment and could not survive in the environment from seeds carried by wind or wildlife. Another desirable feature is a biological mechanism (such as self-pollination or male sterility) that minimizes pollen drift to nearby fields of the same crop. The potential consequences of pollen drift to wild relatives or nearby crop fields are discussed in the Risks & Concerns section of this web site.

What part of the plant will produce the PMP?
Most bio-pharming applications target production and storage of the engineered product in seeds, which naturally accumulate of high concentrations of proteins and oils. Seeds are also the easiest part of the plant to store and transport of processing facilities. Seed-specific promoters used in experimental bio-pharm lines include the beta-phaseolin promoter of common bean and the oleosin promoter of Brassica species (Moloney, 2000). The location of protein accumulation within the cell is also important in ensuring correct folding and stability of the protein (Moloney, 2000).

While synthesis of biopharmaceuticals in seeds has many advantages, not all PMPs will be produced there. Leaves are the target tissues in some alfalfa and tobacco applications, and tubers are targeted in potato production systems (Canadian Food Inspection Service, 2001). A variation of PMP technology is to infect plants with viruses that are engineered with the gene for the pharmaceutical protein. Upon infection, the plant's cellular machinery produces the biopharmaceutical along with other viral proteins (Freese, 2002).

How will PMPs be produced?
To be successful, pharmaceutical production in plants must be a highly sophisticated and closely regulated enterprise, rather than just another crop in the rotation. Bio-pharm crops must be grown, transported, and processed using safeguards designed to ensure a consistent, high-quality product and to prevent inadvertent mixing with food crops or other negative consequences. To achieve this goal, a "closed loop identity preservation" system is envisioned, in which the crop is carefully regulated and monitored from planting to harvest to pharmaceutical extraction (Felsot, 2002). Seed will be available only to trained contract growers, and the harvested product will be delivered in sealed containers to the processing facility. Standard operating procedures developed for each specific PMP crop will govern isolation distances from conventional crops, equipment use, and field inspections during the growing season and for at least a year afterward. Meticulous record-keeping will be required at each step of the process. Federal requirements for field testing PMP crops are discussed in the section "How are pharmaceutical crops regulated?"

How soon will plant-made pharmaceuticals reach the market?
Research on PMP crops has been in progress for many years in laboratories, greenhouses, and field trials. A list of permit applications to USDA-APHIS for bio-pharm field tests dates back to 1991. In 2002, PMP crops were grown at 34 field sites totaling 130 acres in the U.S. (Biotechnology Industry Organization, http://www.bio.org/pmp/factsheet2.asp). Three PMPs currently undergoing evaluation in clinical trials are designed to target non-Hodgkins lymphoma, cystic fibrosis, and E. coli/traveler's diarrhea, respectively (Biotechnology Industry Organization, http://www.bio.org/pmp/factsheet2.asp). Assuming their efficacy and safety are demonstrated and environmental concerns are adequately addressed, pharmaceuticals from plants may reach the market as early as 2005 (Ohlrogge and Chrispeels, 2003).

Who is doing bio-pharming?
Several multinational biotechnology firms that produce other types of genetically engineered crops (including Dow Agroscience and Syngenta) are also pursuing commercial development of PMPs. After researching pharm crops for many years, Monsanto decided in October 2003 to terminate its development of PMPs due to concerns about the economic payoff (New York Times, Oct. 16, 2003). A number of smaller companies (including CropTech, Large Scale Biology Corporation, Meristem Therapeutics, and Prodigene Inc.) are also involved in the biopharmaceutical industry. These companies will most likely contract with a limited number of highly skilled farmers to produce PMP crops.

What are the benefits of plant-made pharmaceuticals?

  • PMPs can be produced at a significantly reduced cost compared to current production methods. Therefore, the technology has the potential to benefit medical patients by providing a cheaper source of vaccines and other medicines. However, it is not clear how large the cost reduction will be or how much of the savings will be passed on to consumers.

  • Producing pharmaceuticals in plants is more flexible than current methods, because production can be more easily scaled up or down depending on demand.

  • Plants can be engineered to produce proteins of greater complexity than is possible with micro-organisms (Collins, 2003), and to produce proteins that cannot be produced in mammalian cell cultures (Anonymous, 2002).

  • A limited number of growers and communities will likely benefit economically from this new agricultural enterprise. The number of acres required to produce a year's worth of a given pharmaceutical will likely be quite small compared to crop acreage for food and feed use.

What are the risks of plant-made pharmaceuticals?
Risks will not be uniform for all bio-pharm applications, but will vary depending on the nature of the pharmaceutical product, the crop and tissues in which the PMP is produced, and the environment in which the crop is grown. The major risk factors of PMPs are summarized below. For a more detailed discussion, see documents by the Canadian Food Inspection Service (2001) and Freese (2002).

  • Pollen from plants engineered to produce pharmaceuticals may fertilize nearby food or feed crops of the same species. If this occurs, the pharmaceutical may be produced in seed of the neighboring crop, with potentially negative effects on human or animal consumers of the seed and on crop markets. The risk of gene flow via pollen drift is greater in cross-pollinated crops like corn. Methods to minimize this risk include spatial and temporal isolation, the use of male sterility (i.e., plants that don't produce viable pollen), and in the case of corn, detasseling (removing tassels before they shed pollen). When male sterility or detasseling are used, fertile male plants that do not produce the pharmaceutical are planted in the field to provide the pollen source.

  • Co-mingling of PMP crops and food or feed crops may occur. This could happen through improper labeling, mixing of seed in planting, harvesting, transportation, or processing equipment, or the presence of "volunteer" PMP plants in subsequent seasons in the same field. In a recent case, USDA fined Prodigene $250,000 for failure to eliminate volunteer bio-pharm corn plants from a soybean crop planted later in the same field as the PMP corn (Anonymous, 2003). The company was also required to reimburse the government $3 million for expenses related to destruction of 500,000 bushels of contaminated soybeans.

  • The introduced gene or its product may have negative effects on the natural environment. For example, wildlife feeding on the crop may ingest harmful levels of the PMP, or soil micro-organisms may be inhibited by decomposing crop residue or substances exuded from roots of PMP plants.

  • Farm workers may be exposed to unhealthy levels of a biopharmaceutical by absorbing products from leaves through their skin, inhaling pollen, or breathing in dust at harvest.

How are pharmaceutical crops regulated?
Because bio-pharm crops are genetically engineered, they are subject to the same U.S. federal regulations that govern all such crops. Three federal agencies (U.S. Department of Agriculture - Animal and Plant Health Inspection Service (APHIS), the Food and Drug Administration (FDA), and the Environmental Protection Agency (EPA)) all play roles in regulating genetically engineered crops, though their specific responsibilities vary depending on the type of application involved. For a detailed description of the roles of the three federal agencies, see the Evaluation & Regulation section of this site.

Besides the standard regulations, bio-pharm crops are subject to additional regulatory oversight, which is evolving as the industry develops and the relevant issues become better understood. One major difference between PMP crops and genetically engineered food crops is that the former will require perpetual permitting by USDA, whereas the latter crops, once approved by the three federal agencies, are considered "non-regulated" and are freely available through commercial channels without permits. In September 2002, FDA and USDA issued the draft document "Guidance for Industry: Drugs, Biologics, and Medical Devices Derived from Bioengineered Plants for Use in Humans and Animals", http://www.fda.gov/cber/gdlns/bioplant.htm#i. The public comment period on this document closed in February 2003. In March 2003, APHIS announced its intent to impose more stringent conditions for field tests of genetically engineered crops that produce pharmaceutical or industrial compounds (See APHIS, 2003a for the press release, and the linked PDF file "APHIS Federal Register Highlights" for comparison of the new regulations to the previous ones.) These new regulations were formalized in August 2003 (APHIS, 2003b). Several of these new requirements for PMP crops are listed in the table below. The objective of these regulations is to prevent any contamination of food and feed crops with the bio-pharmaceuticals and to minimize environmental impacts. In recognition of the evolving status of federal regulation of PMP crops, APHIS invited public comment (until May 9, 2003) on ways to make the regulatory process more transparent, improve field test confinement, and enhance monitoring and compliance. A discussion of the adequacy of APHIS' new regulations is available on the web site of the Pew Initiative on Food and Biotechnology (Anonymous, 2003).

USDA-APHIS requirements for field test plots of PMP crops
All workers involved with PMP crop production must participate annually in an APHIS-approved training program on the required procedures for growing these crops.
Equipment for planting and harvesting of bio-pharm crops must be dedicated to that purpose, i.e., the equipment cannot be used with any other crop.
Tractors and tillage equipment must be thoroughly cleaned before being used with other crops.
Dedicated, locked storage facilities are required for the PMP seed and farm equipment used at the test site.
Test sites must provide the required isolation distances from other fields of the same crop. For example, bio-pharm corn must be isolated by at least 1 mile from other corn fields if it is open-pollinated, and by 1/2 mile if pollination is controlled through male sterility or detasseling. A 50 ft. perimeter fallow zone (area not in production) must surround the PMP crop. No food or feed crops are allowed in the test plot or fallow zone the following year.
Bio-pharmed fields will be closely monitored during the growing season and in following seasons to ensure that required procedures are being followed and that volunteer plants are found and disposed of properly.

Photos: USDA-ARS and web site staff.

FDA has the responsibility to ensure the safety and efficacy of drugs. Therefore, clinical trials and marketing of PMPs will require FDA approval. FDA will also oversee procedures for manufacturing PMPs to guarantee consistent product quality and potency. (See link to FDA's guidance document on PMP crops in the previous paragraph.)

EPA regulates the environmental effects of proteins engineered for pest resistance (such as Bt insecticidal proteins) in a PMP crop. However, EPA does not review environmental effects of bio-pharm crops at this time.

The department of agriculture of the state in which a field test of a genetically engineered crop is proposed, is given the opportunity to review APHIS' preliminary assessment of the developer's application. In the past, this has been a routine approval, but with PMP crops, states are taking a much more cautious approach. For example, the Colorado Department of Agriculture has formed a Technical Advisory Committee of university scientists to help evaluate the adequacy of conditions for gene containment and for minimizing environmental impact of PMP crops (Mitch Yergert, Colorado Department of Agriculture, personal communication).

Final thoughts
Like many other aspects of crop biotechnology, supporters and critics of PMP crops differ strongly over the benefits and risks of this new application. Proponents stress the societal benefits of a cheaper and more plentiful source of pharmaceuticals, while opponents emphasize the risks of contamination of the food supply and unknown effect on ecosystems. Given the uncertainties surrounding bio-pharm crops, it is difficult to predict whether and to what extent this technology will become part of our future agricultural and health care systems. Major questions still to be answered include the following:

  • Are PMPs safe and effective medicines for humans and animals?

  • Will production costs of PMPs, especially for the purification process, be reduced sufficiently to bring the promised economic benefits?

  • What will be the appropriate combinations of crop species, plant parts, growing environments, and production safeguards that will provide acceptable levels of gene containment and environmental protection?

  • Are our regulatory structures adequate to the task of regulating and monitoring bio-pharm crops, and, if not, what changes will be necessary?

  • To what extent will crop-based pharmaceuticals provide new economic opportunities for farmers and rural communities?

Additional links
The Union of Concerned Scientists web site discusses benefits and risks of pharm crops (http://www.ucsusa.org/pharm/pharm_open.html). The site includes a list of companies (with web links) that are involved in PMP technology.

Comments of the Consumers Union on FDA and USDA guidance for production of PMP crops are available at http://www.consumersunion.org/food/gef203.htm.

The Biotechnology Industry Organization, http://www.bio.org/pmp/, has a number of Fact Sheets on plant made pharmaceuticals.


Page last updated : March 11, 2004

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