Transgenic plants used to produce biopharmaceuticals and bioindustrial
products have great potential, but current production practices limit their
cost
Plants have been a source of industrial and pharmaceutical products
for centuries. Transgenically altered plants can be more efficient at
producing these products and hence represent a logical advance in
technology. However, the public has concerns that plant-made nonfood
products, known as plant-made pharmaceuticals (PMPs) and plant-made
industrial compounds (PMICs), may inadvertently mix with the food supply. To
provide for food safety and gain public confidence, the USDA has adopted
stringent guidelines1 for PMPs and PMICs, distinct from those used for other
transgenic crops intended to enter the food supply. The cost of containing
PMPs and PMICs, however, can make production of many of these products
unfeasible. Moreover, the public?s understanding of nonfood production
methods is generally intertwined with the standard practices of food
production, leading to the perception of increased risk. A recent paper
describes an alternative model for growing PMPs and PMICs2 and addresses
safety and economic concerns as well as some public perception issues. This
review summarizes how these new products can be produced in plants
comparably to other transgenic production systems, using a strategy that
also creates a clearer distinction between food and nonfood products.

Safety
Safety concerns about transgenic nonfood products can be divided into
three categories. The first concern relates to the inherent toxicity of the
molecule itself, whether exposure is from direct consumption of a
pharmaceutical product or from indirect contact with a substance intended
for an industrial use. Science-based models can predict the toxicity of any
substance based on dosage. Such models are used by the Food and Drug
Administration (FDA) and the USDA to evaluate pharmaceutical or food
compounds. These evaluations are uniformly applied to all production systems
to provide a baseline safety assessment of the compound.

The second safety aspect pertains to any unintended compounds that may
be introduced into the final product during the purification or production
process, including toxins, allergens, or pathogens, as well as inadvertent
host proteins. These compounds are host specific and dependant on the level
of purification of the final product. It has been argued that production
hosts that are already in the food chain (e.g., eggs, yeast, food crops)
have a distinct safety advantage because they are already generally regarded
as safe (GRAS). In general, there can be significant differences in product
safety depending on the specific organism and purification procedures used
and whether or not the product is produced in plants.

The third safety consideration is for the environmental and health
consequences of inadvertent exposure to these nonfood compounds. Plants used
to make pharmaceutical or industrial compounds differ significantly from
other transgenic platforms (e.g., microbial and cell cultures) in this
regard, because of the concern that an industrial- or
pharmaceutical-producing plant will cross pollinate or intermix with food
crops nearby. Consequently, current regulations are written to restrict the
movement of transgenic products and to confine the host plant in a way that
will limit its ability to reproduce and generate transgenic products
independently.

Yet despite science-based safety analyses and reasonable regulation,
the perception persists that these products may inadvertently end up in the
food supply, most likely because of the similarity between their production
in plants and food production practices. Currently, any level of
contamination of food products is considered unsafe. Biosafety models for
regulated articles are based on tolerances or action levels, which allow
regulators to set the maximum level of a product below which there is no
cause for concern3,4. However, this type of model has not yet been applied
to plants producing pharmaceutical or industrial products.

Plant production systems that can be contained inside a dedicated
facility include plant cell cultures, aquacultures, greenhouse grown plants,
and the use of underground caves. Each of these options is viable for
certain products, though all have a substantial cost premium over field
grown material and have a limited scale of production. Consequently, there
is a need for field grown material. It is because plant-based systems are
grown in fields outside a dedicated production facility, unlike these other
types of transgenic production systems, that confinement measures have
received by far the most regulatory attention.

There are differences of opinion about how best to achieve
confinement, but methods generally include genetic, temporal, physical
and/or geographic barriers to limit the host?s reproduction outside the
production site. An example of physical separation is used when the
cultivation of sexually compatible crops is limited within a prescribed
distance of regulated transgenic crops, as well as the use of border rows.
The USDA guidelines are written with the assumption that in any given season
or location, plants that are intended for food, feed, and industrial
applications may potentially commingle. These strict guidelines may increase
the fear that PMPs or PMICs will easily intermix with food crops.

An alternative model for growing transgenic nonfood products in plants
It is quite costly for producers to adhere to guidelines when using
the same land to grow regulated products one year and commodity crops in
subsequent years. An alternative to using crop land flexibly to grow all
types of products is to dedicate the land solely for the production of
industrial products. The detailed specifics of this approach, with
underlying assumptions, can be found elsewhere2, but in general, a single
location is employed for growing selected industrial products every year. In
addition, all of the equipment, personnel, and practices are dedicated
solely for this purpose as well. This model is similar in concept to that
used with microbial and cell culture systems in that the location is not
used interchangeably for the production of food and nonfood transgenic
products. The only significant difference in this case is that the dedicated
location includes the field as well as the building where the product is
manufactured.

A transgenic crop can be grown amidst an industrial crop and thereby
provide additional segregation and buffer zones from food crops at no
additional cost. In most cases the transgenic crop, which requires a very
small percentage of the total acreage, allows for a greater separation from
potential food crops. A larger separation distance from food crops permits a
greater distinction for the dedicated material and equipment, and thereby
decreases public perception of risk. It also reduces fears of seeds
inadvertently entering the food supply by spilling on the land and
germinating the following season.

While this approach has advantages for pharmaceutical proteins, field
grown production is also suitable for making industrial products that can
only be produced economically in large volumes. Furthermore, this model
integrates the transgenically produced products with the industrial crop. An
example is given in Figure 1, which depicts the production of transgenic
enzymes for the conversion of ethanol from corn stover. In this case, the
transgenic enzyme is collected only from the germ fraction of plants
harvested from the most central growing area and is in turn used for ethanol
conversion with the stover that is growing in the surrounding locations.




In this model, grain and stover, plus the enzymes needed to process
them into ethanol, are all produced from the same acreage. This design
allows for synergies in transportation and coordination, as well as for
efficient utilization of natural resources. The system is self-contained,
having all the necessary components to produce ethanol; there is no
additional input required to provide the raw materials for stover ethanol
over that which is needed to grow corn for grain ethanol. The benefits in
this example go beyond the savings obtained when planting a field that
otherwise would remain fallow and include: 1) more efficient utilization of
raw materials without additional inputs, reducing the environmental impact
of growing separate crops for grain ethanol, lignocellulosic ethanol, and
enzyme; 2) savings from the elimination of the highly capital intensive
fermentation equipment traditionally used for making the vast quantities of
enzyme required for biomass conversion into ethanol; 3) increased revenue
for growers; 4) reduced transportation cost because the grain, stover, and
enzymes required for ethanol production are supplied in one central
location; and 5) lowered unit cost of the enzymes since all unit operations
are similar to existing practices for growing commodity crops, except mixing
the enzyme fraction with the stover. These economic benefits are realized in
tandem with the additional benefit of being able to make the clear
distinction that, in practice, the industrial product (enzyme) is clearly
separated from those practices, locations, and fields used for food
production.

Conclusions
Transgenic plants used to produce biopharmaceuticals and bioindustrial
products have great potential, but current production practices limit their
cost effectiveness in some cases and raise concerns that the use of food
organisms as hosts for nonfood products increases the potential for
inadvertent exposure. This concept, however, is in direct conflict with
other current production practices that use yeast and eggs (food sources) to
produce products such as industrial enzymes, vaccines, and pharmaceuticals.
The food - host argument diverts attention from the real issue, which is to
ensure that transgenic nonfood products remain outside the food system,
rather than which host is used for production.

The proposed model discussed above for production of nonfood products
in transgenic plants may potentially alleviate associated cost constraints
and public concerns. The practice of using a dedicated area for nonfood
production would draw a clear distinction between plants used to produce
food and nonfood applications. This should help put plant-based production
on par with other non-plant production systems used for transgenic products.

References

1.. USDA (2003) Field testing of plants engineered to produce
pharmaceutical and industrial compounds. Available at
[www.aphis.usda.gov] (verified 14 Feb. 2007).
2.. Howard J, Hood E. (2007) Methods for growing nonfood products in
transgenic plants. Crop Science 47, 1255-1262
3.. USEPA (1989) Risk assessment guidance for superfund. Vol. 1,
Human health evaluation manual (Part A): Interim final. Office of Emergency
and Remedial Response, EPA/5409/1-89/002.
4.. USEPA (1992) EPA guidelines for exposure assessment. Federal
Register 57(104):22888?22938. USEPA, Washington, DC.


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