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BIO-PHARMING
6/27/2003
Ron F. Meyer
Area Extension Agent
(Agronomy)
Colorado State University Extension
Golden Plains
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By: Pat Byrne, Colorado State University
The manufacture of
pharmaceutical products from plants has been among the long 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 and into the
experimental testing phase in both 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/TrangenicCrops/)
A
variation of PMP technology is to infect plants with viruses that are
engineered with a 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. |
Callagen 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
disease of a crop is also an advantage. Ideally, the host plant would be
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 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
(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
cornfields 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.
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 small 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 customers.
- Plants can be engineered to produce proteins of greater
complexity than is possible with microorganisms (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 neighboringcrop, 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 microorganisms 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 Production 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
test 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? 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 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.
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 cost 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. |
Page Created and Maintained by: Perry D. Brewer, Area
Extension Agent (Technology Education/Youth)
6/30/2003 |
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