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.
