MAY 2003
VOLUME 23
ISSUE 3
INSIDE THIS ISSUE
Bio-Pharming
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 “pharming”,
“bio-pharming”, or “molecular farming,” has now moved
beyond the realm of speculation into the experimental testing phase in
fields and greenhouses. 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, please visit the web site “Transgenic
Crops: An Introduction and Resource Guide,”
http://www.colostate.edu/programs/lifesciences/TransgenicCrops/)
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). 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 drugs currently manufactured?
Many protein-based drugs 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). Because these facilities have huge capital construction costs,
industry has been unable to keep up with the growing demand. Other drugs
are extracted from animal organs, a high-cost procedure that carries the
risk of transmitting infectious diseases to humans. 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 (Ohrlogge 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, 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.
Table 1. Potential plant-made pharmaceuticals.
| Product | Definition | Examples |
| Antibodies | Specialized proteins of the immune system that initiate the body’s defense response. | Specific antibodies could be developed to fight cancer, HIV-AIDS, hepatitis, malaria, dental caries, and other diseases. |
| Antigens (vaccines) | Compounds that elicit the production of antibodies that protect against disease. | Plant-made vaccines are currently under development for protection 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 cystic fibrosis and other diseases. |
| Hormones | Chemical messengers active at low concentrations and produced in specialized cells. | Insulin is produced in the pancreas and helps regulate sugar metabolism. Diabetics with insulin deficiencies must replace it via shots or pumps. |
| Structural proteins | Proteins that provide structural support to cells or tissues. | Collagen is a structural protein found in animal connective tissues and used in cosmetics. |
| Anti-disease agents | A wide variety of proteins. | The anti-infection agents interferon and lactoferrin and the blood anti-coagulant protein hirudin have been engineered in plants. |
What crops are being considered
for pharmaceutical production?
The most commonly mentioned host plants or “Pharm Crops” for
PMP production are corn, tobacco, and potato. Other crops being investigated
include alfalfa, rice, safflower, soybean, and tomato. 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 such
as tobacco that does not have wild relatives present in the production
environment. 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.
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 high concentrations of proteins
and oils. Seeds are also the easiest part of the plant to store and transport
to 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). (Promoters are
regulatory elements of genes that control how much of a gene product is
made and where in the plant it is synthesized.) The location of protein
accumulation within the cell is also important in ensuring correct folding
and stability of the protein (Moloney, 2000). Not all PMPs will be produced
in seeds; leaves are the target tissues in some alfalfa and tobacco applications,
and tubers are targeted in potato production systems (Canadian Food Inspection
Service, 2001).
How will PMPs be produced?
Pharmaceutical production in plants will be a highly sophisticated and
closely regulated enterprise, and will be very different from conventional
crop production in many ways. Bio-pharm crops must be grown, transported,
and processed using safeguards designed to prevent inadvertent mixing
with food or feed crops. Some of the features that will distinguish bio-pharming
from bulk commodity production are listed below and shown in Fig.
1 (Felsot, 2002; APHIS, 2003):
- All workers must receive training in the principles and methods of gene containment.
- 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.
- Production fields will be carefully chosen to provide the required isolation distances from other fields of the same crop. For example, bio-pharm corn must be isolated by at least one mile from other corn fields if it is open-pollinated, and by one-half mile if pollination is controlled through male sterility or detasseling. The one mile distance is eight times the required isolation distance for certified seed corn production.
- Seed will only be available to contract growers.
- Containers used for transportation of seed to the field and harvested products to the processing plant must be labeled, sealed, and thoroughly cleaned after use.
- 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.
 |
|
Figure 1. Some of the safeguards required by USDA-APHIS for the production of bio-pharm crops |
When will plant-made pharmaceuticals
reach the market?
After many years of research in laboratories and greenhouses, a few bio-pharm
crops are now being grown in experimental field plots. Plant-produced
antibodies are currently undergoing evaluation in clinical trials and
may reach the market as early as 2005 (Ohrlogge and Chrispeels, 2003),
assuming their efficacy and safety are demonstrated, and environmental
concerns are adequately addressed.
Who is doing bio-pharming?
Several multinational biotechnology firms that produce other types of
genetically engineered crops (including Dow Agroscience, Monsanto, and
Syngenta) are also pursuing commercial development of PMPs. A number of
smaller companies (including CropTech, Large Scale Biology Corporation,
Meristem Therapeutics, and Prodigene Inc.) are also leaders 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?
- As mentioned previously, PMPs can be produced at a significantly reduced cost compared to current production methods. Therefore, the technology has the potential to benefit medical patients in all countries, and may be especially important for developing countries by providing a more affordable source of vaccines and pharmaceuticals. However, it is not clear how large the cost reduction will be or how much of the savings will be passed on to consumers.
- 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. 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 or by inhaling dust at harvest.
How are pharmaceutical crops regulated?
Because bio-pharm crops are genetically engineered, they are subject to
the U.S. federal regulations that govern all such crops. Three federal
agencies, the 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 the Transgenic Crops web site (http://www.colostate.edu/programs/lifesciences/TransgenicCrops/).
Besides the standard regulations, bio-pharm crops are subject to additional regulatory oversight. In March, 2003 APHIS announced more stringent conditions for field tests of genetically engineered crops that produce pharmaceutical or industrial compounds. Several of these new requirements are listed in the previous section entitled “How will PMPs be produced?” and in Fig. 1. 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 has invited public comment 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 Pew Initiative on Food and Biotechnology web site (Anonymous, 2003)
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.
EPA will become involved in the regulatory process if the PMP crop contains engineered insect resistance, such as Bt insecticidal proteins. If questions arise about the environmental impact of bio-pharming that are not addressed by the other agencies, then EPA has options for intervening on that issue.
The department of agriculture of the state in which a PMP crop field test is proposed, is given the opportunity to review APHIS’ preliminary assessment of applications for field testing of genetically engineered crops. In the past, this has been a routine approval, but with PMP crops, states are taking a much more cautious approach. State departments of agriculture may well request additional permit conditions beyond those imposed by APHIS.
Are bio-pharm crops likely to be grown in Colorado in
the near future?
Among the advantages Colorado has for bio-pharming are the possibility
of achieving greater isolation distances for corn, compared to many midwestern
locations, and the ability to obtain high yields under irrigated conditions
with relatively little disease and insect pest pressure. Apparently recognizing
these advantages, one company has applied to APHIS for a permit to grow
a field test of PMP corn in Colorado in 2003. According to Mitch Yergert
of the Colorado Department of Agriculture (CDA), APHIS has reviewed and
approved the application and forwarded it to his department for review.
To assist with the evaluation of this and future permit applications for
PMP crops, the CDA has formed a Technical Advisory Committee, which will
evaluate the adequacy of conditions for gene containment and for minimizing
environmental impact. At press time, no decision had yet been made by
the CDA on the 2003 application.
Final thoughts
Before bio-pharm crops become a successful commercial venture, several
major hurdles must be overcome. First, the safety and efficacy of drugs
produced in plants need to be demonstrated. Second, the appropriate genes,
crop species, plant parts, and confinement conditions for growing these
crops, both from technical and regulatory points of view, must be determined.
After the StarLink experience (http://www.colostate.edu/programs/lifesciences/TransgenicCrops/hotstarlink.html)
and the recent ProdiGene episode, regulatory agencies will be extremely
wary of the risks of cross-pollination or co-mingling of PMP crops with
food or feed crops, so confinement conditions will be strict. Third, production
costs for PMPs, especially the costs of purification, must be reduced
before bio-pharm crops become economically feasible. Finally, consumers
must be willing to accept this new source of pharmaceutical products.
When, or if, some bio-pharm crops are approved, they will likely provide
new business opportunities for a small number of growers, rather than
an economic bonanza for rural areas.
Anonymous, 2003. Minding the pharm: Are the Feds up to regulating pharmaceutical plants? AgBiotech Buzz Vol. 3, Issue 3, May 14, 2003. Pew Initiative on Food and Biotechnology, http://pewagbiotech.org/buzz/archive.php3.
Anonymous, 2002. On the pharm. AgBiotech Buzz Vol. 2, Issue 7, July 29, 2002. Pew Initiative on Food and Biotechnology, http://pewagbiotech.org/buzz/archive.php3.
APHIS, 2003. USDA strengthens 2003 permit conditions for field testing genetically engineered plants. Press release. http://www.aphis.usda.gov/lpa/news/2003/03/gepermits_brs.html.
Canadian Food Inspection Service. 2001. Plant molecular farming discussion document. http://www.inspection.gc.ca/english/plaveg/pbo/mf/mf_disde.shtml.
Collins, S. 2003. Potato the medical factory of tomorrow. The New Zealand
Herald, April 4, 2003.
Felsot, A. 2002. “Pharm farming.” Agrichemical and Environmental
News, no. 195, July 2002, http://aenews.wsu.edu.
Freese, B. 2002. Manufacturing drugs and chemical crops: Biopharming poses new threats to consumers, farmers, food companies and the environment. Available from GE Food Alert, http://www.gefoodalert.org.
Moloney, M.M. 2000. Molecular farming using seeds as hosts. pp. 226-253. In M. Black and J.D.Bewley (eds.) Seed technology and its biological basis. CRC Press, Boca Raton, FL.
Ohrlogge, J., and M.J. Chrispeels. 2003. Plants as chemical and pharmaceutical factories. pp. 500-527. In M.J. Chrispeels and D.E. Sadava (eds.) Plants, genes, and biotechnology. Jones and Bartlett Publishers, Sudbury, MA.
Additional sites for information on PMP crops:
The Union of Concerned Scientists web site has an interactive feature
that 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.
