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.
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
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
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
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
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
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
All images: USDA
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
2000). The location of protein accumulation within the
cell is also important in ensuring correct folding and stability
of the protein (Moloney,
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,
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
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
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
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,
- 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
- 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
& 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",
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
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
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 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,
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
- Will production costs of PMPs, especially for the purification
process, be reduced sufficiently to bring the promised economic
- 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?
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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