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Plant Physiology 132:1770-1774 (2003) © 2003 American Society of Plant Biologists Going to "Great Lengths" to Prevent the Escape of Genes That Produce Specialty Chemicals1Department of Genetics and Biotechnology Impacts Center, University of California, Riverside, California 92521–0124
In late 2002, the U.S. Department of Agriculture (USDA)'s Animal and Plant
Health Inspection Service (APHIS), the agency that regulates field release of
genetically engineered (transgenic) plants, found that the biotechnology
company ProdiGene, Inc. failed to follow government regulations for growing
genetically modified (GM) corn (Zea mays), engineered to produce a
specialty pharmaceutical protein, in both Iowa and Nebraska. In Iowa, pollen
from the corn designed to produce a pig vaccine might have pollinated nearby
crops, leading to a government order of the incineration of 63 ha of corn
growing near the experimental site. In Nebraska, engineered seed from the
previous year's experiment germinated and grew as "volunteer corn"
in a field of soybeans (Glycine max). The beans were subsequently
harvested and transported to storage. Despite an APHIS inspector's request to
collect/destroy the corn before the harvest of soybeans, some of those corn
plants were harvested as well and ended up mixed with more than 17.5 million L
(a half-million bushels) of stored soybeans. ProdiGene received a fine of
$250,000. In addition, the USDA required it to buy and destroy the soybeans
containing the GM corn at an approximate cost of $3.5 million. A penalty of
this magnitude is the first of its kind for the U.S. government to levy
against an agricultural biotechnology company, and it is not clear that the
relatively small company will be able to pay the entire cost
(Gillis, 2003
Plants have been used by humans for far more than food, fuel, and fiber for millennia. Historically, they have been a major source of medicines (pharmaceuticals) and remain so for millions of people today. Plants are also a source of dyes, lubricants, adhesives, and other industrial compounds. Some of these plant-derived industrial products are toxic (such as certain compounds derived from the opium poppy [Papaver somniferum]), and others, such as the many industrial starches, are not (Simpson and Ogorzaly, 2001  ).
What's the big deal about plants grown to manufacture pharmaceuticals and
other specialty chemicals (also known as "pharm crops")? Using
crops for this purpose is an especially novel and promising application of
agricultural biotechnology. Plants can be engineered to create chemical
products that are free of animal viruses and prions. They can synthesize all
kinds of proteins and store them in a stable form in seeds. Overall, it
appears that plants can produce many specialty biochemicals, such as
monoclonal antibodies for pharmaceutical purposes, in cleaner form, in greater
quantities, and with less expense than current technologies. Theoretically, at
least, a limited acreage (from a fraction of a hectare to a few dozen
hectares) could produce a sufficient quantity of certain pharmaceutical
products (including those for domesticated animals) to meet the annual demand
(Pew Initiative on Food and Biotechnology,
2003
Interest in such plants is increasing. According to APHIS, "In 2002,
approximately 130 acres (53 ha) of pharmaceutical producing plants were
planted in experimental field tests at 34 sites. Most of these test sites were
less than 5 acres (2 ha). It is anticipated, however, that the number of
requests for permits for field tests, and the scale of production, will
increase significantly over the next few years. Very few permits have been
issued to date for plants in which the modification was made for the expressed
intent of producing an industrial compound. However, as with plants engineered
to produce pharmaceutical compounds, we anticipate an increase in requests for
field tests of these types of plants. "Industrial" plants include
those genetically engineered plants that are not intended for use as food or
feed, but rather are intended to produce compounds that will be extracted for
industrial uses. The range of potential uses of such substances includes, for
example, applications in detergent manufacturing, paper production, mineral
recovery, or in purely experimental research"
(Federal Register, 2003
However, no technology is risk-free. Some, but not all, plant-derived
pharmaceutical and industrial compounds will have an impact on human or animal
health if they end up, unintended, in a high enough concentration in the food
or feed stream. And for some people, the idea of corn flakes containing a
drug, toxic or not, at however low concentration, is unacceptable
(Fig. 1). In fact, in February
2003, the National Food Processors Association strongly urged the U.S. Food
and Drug Administration "that there be no use of food or feed crops to
produce plant-made pharmaceuticals or industrial chemicals without a 100%
guarantee against any contamination of the food or feed supply"
(National Food Processors Association,
2003
It isn't easy to keep crop genes from wandering. For example, plant
breeders trying to create corn seed of high genetic purity have recognized
that the physical separation of different corn varieties by 200 m (660 feet)
will still result in "contamination" due to cross-pollination at
levels of about 0.1% (National Academy of
Sciences, 2000 Thus, it might make sense to create pharm products from plants that are not food or feed plants. Regrettably, that is not now the case. Recently, approximately 75% of the pharm field test applications filed in the United States were for a single crop, corn, a major source of both food and feed in both the United States and worldwide (Information Systems for Biotechnology, http://www.n-biap.vt.edu).
There are good reasons why corn is the organism of choice. More is known
about the genetics of corn than any other crop, and it is relatively easily
transferred. Its genetics are probably the best understood of all crop plants.
American farmers have considerable expertise in growing and harvesting corn.
Its seeds are an ideal storage location and vehicle for specialty chemicals
produced by engineered genes (Pew
Initiative on Food and Biotechnology, 2003
How likely is it that corn genes will end up where they shouldn't be?
Without efforts to isolate corn populations so that they don't cross-pollinate
and without efforts to keep seed for different uses separate, inadvertent
mixing of genetic material in corn is so likely that some mixing is a
certainty. The "Starlink" GM corn incident of 2000 illustrates how
easily things can get out of hand, even when some attempts are made to
maintain segregation. This particular variety of GM corn was released
exclusively for animal consumption before the determination of whether it was
also suitable for human consumption. Nonetheless, it rapidly entered the
general corn grain supply of the United States, within a single year turning
up "in nearly one-tenth of 110,000 grain tests performed by U.S. federal
inspectors" (Haslberger,
2001
In the United States, government regulation of field-grown transgenic pharm
plants has always required efforts to prevent the escape of living transgenes.
Over the last several years, plants engineered to create industrial compounds
have been field tested (and in a few cases, grown commercially) under the more
or less streamlined APHIS "Notification" procedure. In this case,
the applicant essentially fills out a brief form and signs a statement
agreeing to follow APHIS "performance standards" to confine
transgenic organisms and their genes. Plants with certain special phenotypes,
including those engineered to create compounds intended for pharmaceutical
use, have been field tested under the more stringent "Permit"
procedure, which requires a more comprehensive application and regular field
visits by APHIS personnel (National
Academy of Sciences, 2002
Recently, things have changed. In spring 2003, APHIS issued a set of new permit conditions for plants producing pharmaceutical and industrial compounds that include significant policy changes (Federal Register, 2003 ). First
is the explicit mention of "industrial" compounds alongside
pharmaceuticals. This mention is significant both because it acknowledges
possible risks associated with specialty chemicals and because it corrects the
prior possibility of field testing a plant that produces a pharmaceutical
compound under Notification rather than Permit because the compound was not
intended to be used for pharmaceutical purposes. This subtle change allows
APHIS to scrutinize plants according to the actual compounds they produce
rather than the intent for which they are being produced. Second, the new conditions focus on explicit procedures designed to prevent the inadvertent mixture of seed. These include: (a) a perimeter fallow zone of 16 m (50 feet); (b) restricting planting food and feed crops in the same location in the following season if there is a chance for volunteer seedlings to be inadvertently harvested with the following crop; (c) dedicated planting, harvesting, and storage facilities; (d) machinery cleaning procedures; and (e) personnel training programs. These conditions are much more detailed than previous guidelines and requirements.
Third, and most important, are the field test permit conditions specific to
pharmaceutical corn. These involve "great lengths" to avoid
problems. APHIS requires that there will be no corn grown within 1.6 km (1
mile) of the field test site throughout the duration of any test involving
open-pollinated corn. When pollen flow is controlled by placing bags over the
corn tassels, APHIS requires that no other corn be grown within 800 m (2,640
feet) of the test site; in addition, the pharmaceutical corn must be planted
at least 28 d before or 28 d after any corn growing in a zone extending from
800 to 1,600 m from the test site, ensuring no overlap in flowering
(Federal Register, 2003 Fourth, APHIS has made changes in compliance enforcement. Now multiple field inspections will be conducted. Furthermore, recordkeeping is required regarding how permit conditions were fulfilled. Finally, APHIS is growing and adapting. It is reviewing its regulatory system. And most importantly, APHIS has announced that it will lead a public dialogue in the near future.
Clearly, these new requirements are a big deal. Nevertheless, in some cases, industrial stewardship has already outpaced the regulators. Even a year ago, industry scientists began to create closed-loop production systems to prevent transgene escape. Some were even calling to move the sites of pharm corn production hundreds of miles from the Corn Belt (Pew Initiative on Food and Biotechnology, 2003 ). This extraordinary level of industrial stewardship is
commendable and smart. To get a good idea of whether such strategies are
excessive, prudent, or inadequate, it is worth looking at what might go
wrong. Consider what might be the "worst case scenario." One can imagine a plant transformed to produce a specialty compound is grown on limited acreage in the United States. The chosen plant is a widespread, outcrossing species, typically grown in dozens of countries and millions of hectares for human food consumption. The compound is innocuous in low concentration but has serious effects on human health if it reaches a certain concentration in food. Suppose the gene for this compound finds its way, by a rare long-distance (say, on the order of a few miles) pollination event, into a field of a variety of the same species intended for producing a food product. Let's further assume that the food-producing variety is a hybrid and, therefore, in the United States, one whose seed is a "terminal" product, that is, typically consumed or processed, but not used for replanting. That's good news at the national scale, because a low level of gene escape won't have any health effects and might not even be detected by a monitoring program. However, a different outcome might be obtained at the global scale. Food, often in the form of living propagules (seeds or other), often moves beyond the borders of the United States—sold, sent as aid, or in the pockets of travelers. Living seeds of an American variety can end up in distant communities. For annual food crops, seeds are saved and replanted as open-pollinated landraces in most of the world. Those farmers may exchange seed with each other and experiment with seed from distant sources. Let's suppose that one or a few seeds bearing the allele for production of that specialty compound are planted into a landrace field in a different country. Finally, let's imagine that, in the landrace environment, that allele confers a substantial fitness boost to plants that bear it so that they produce more pollen, set more seed, or survive better than plants without that allele. Then, the conditions are right for the allele to increase in frequency, undetected, generation by generation. The compound also increases in frequency and in concentration in the food supply until it eventually has serious effects on the health of the humans who consume it.
Seem far-fetched? Each of the components of the scenario has a very low
probability of happening. And yet, each of the steps is represented by real
phenomena with a nonzero probability. For example, despite a multiyear
moratorium on growing transgenic corn in Mexico, transgenes have introgressed,
unintended and undetected, into remote corn landraces in that country
(Alvarez Morales, 2002
Beyond the isolating procedures now required by APHIS, there are other tools for limiting the spread of genes that produce toxic compounds into food and feed streams. One set of tools are called "bioconfinement" mechanisms, ways of altering an organism's biology to prevent the spread of alleles into populations for which they were unintended. Suggested methods for keeping alleles where you want them are increasing, including male sterility, triploidy, chloroplast transformation, constructs that sterilize the seeds produced by engineered plants (also known as "terminator"), and many more (compare with reviews by Gressel, 1999 ; Daniell,
2002). Although these techniques have great promise, each of them
has its limitations. For example, male sterility will prevent pollen, but not
seed, escape. Furthermore, to be effective, the techniques must not be
"leaky." I am not aware that any of them have been tested
thoroughly enough to demonstrate their efficacy in a variety of
environments. Another set of tools are markers that could be used for easy and unambiguous visual identification of seeds that bear compounds not intended for consumption. Such markers would make monitoring easy, especially compared with the test kits and PCR-based methods currently in use. Imagine corn seeds that are neatly striped or phosphorescent orange. APHIS does not require monitoring, but monitoring might be advisable for certain specific products and useful in determining the efficacy of the proposed new containment methods. Crop choice represents another tool. With its abundant pollen and seeds, corn seems a poor choice from a containment point of view. There are other food crops that might cause less concern. A potato (Solanum tuberosum) bouncing off a truck is less likely to establish on a roadside (and many potato varieties are both pollen and seed sterile). A sugar beet (Beta vulgaris) is less likely to hide in the pocket of an international traveler. Likewise, is it always necessary to use food crops to create specialty chemicals, especially if they would have health effects if consumed by accident? There are nonfood crops that are already grown for the production of specialty chemicals—castor bean (Ricinus communis), opium poppy, etc. Likewise, many nonfood crops have been genetically engineered— Arabidopsis, tobacco (Nicotiana tabacum), Begonia semperflorens, belladonna (Atropa belladonna), petunia (Petunia hybrida), etc. What about insect larvae grown in vats or duckweed grown in a bioreactor? If a food crop is a necessary choice for producing a specialty chemical, is it always necessary to grow it in the field? A considerable measure of containment relative to the field could be afforded simply by growing such plants in a greenhouse. Finally, with regards to biosafety, some products just don't make sense. A number of scientists have scrapped projects or not embarked on them because of biosafety concerns. Although APHIS sets the rules, the real regulators are mindful scientists who make the hard decisions to create the products that are the best in every sense of the word.
This essay explicitly and implicitly lays out many more ethical questions than it answers: Should the creators of new crops look beyond the product to how it will be used? Even though APHIS oversight is restricted to the United States, should regulators make decisions—or at least offer an opinion—about what might happen if a certain product ends up in another country where regulation is less stringent or lacking altogether? Do farmers of one crop have an obligation not to genetically contaminate the crops of other farmers who don't want their crops contaminated? Will bioconfinement methods prove another layer of cost without attaining the level of desired containment? Is there an obligation by society to examine these questions in forums broader than the individual laboratory and the regulator's office?
I have purposely not separated the role of science-based information from
the role of nonscience-based values in risk assessment because they cannot be
fully separated (National Academy of
Sciences, 1996 Scientists are researchers, teachers, and citizens of society. As researchers, we have a responsibility for the science that goes out of the doors of our lab. As teachers, we have a responsibility to communicate what we've learned from our science with the society that nourishes us. And as citizens of that society, we have a responsibility to listen to what the rest of society thinks about what we learn and what we teach.
To read more about pharming and pharm crops, see Ohlrogge and Chrispeels
(2003
This article is partly based on a talk I presented at the Pew Initiative on Food and Biotechnology's Workshop "Pharming the Field." That talk and this manuscript benefited from feedback I received from a diverse array of individuals: Beth Burrows, Maarten Chrispeels, Phil Eppard, Mich Hein, Tracy Kahn, Alan McHughen, Margaret Mellon, Tom Nickson, Mike Pauley, and Jane Rissler. Special thanks to the Edmonds Institute's Beth Burrows for suggesting that an article on this topic would be worthwhile and to the Institute's Freida Morris for transcribing the Pew talk. I am also grateful to the Union of Concerned Scientists for sharing their illustration of "pharmaceutical" corn. Received April 22, 2003; returned for revision April 30, 2003; accepted April 30, 2003.
www.plantphysiol.org/cgi/doi/10.1104/pp.103.025908.
1 This work was supported by the Biotechnology Risk Assessment Research
Grants Program of the USDA (grant nos. 00–33120–9801 and
2002–33120–12769). * E-mail ellstrand{at}ucrac1.ucr.edu; fax 909–787–4437.
Alvarez Morales A (2002) Transgenes in maize landraces in Oaxaca: official report on the extent and implications. The 7th International Symposium on the Biosafety of Genetically Modified Organisms: Meeting Proceedings. International Society for Biosafety Research, Beijing, p 78 Daniell H (2002) Molecular strategies for gene containment in transgenic crops. Nat Biotechnol 20: 581–586[ISI][Medline]
Ellstrand NC (2001) When transgenes wander,
should we worry? Plant Physiol
125:
1543–1545 Ellstrand NC (2003) Dangerous Liaisons: When Crops Mate with their Wild Relatives. Johns Hopkins University Press, Baltimore Federal Register (2003) Field testing of plants engineered to produce pharmaceutical and industrial compounds. Federal Register 68: 11337–11340 Gillis J (2003) U.S. will subsidize cleanup of altered corn. Washington Post, Wednesday, March 26, 2003, p E01 Gressel J (1999) Tandem constructs: preventing the rise of superweeds. Trends Biotechnol 17: 361–366[CrossRef][ISI][Medline] Haslberger A (2001) GMO contamination of seeds. Nat Biotechnol 19: 613[Medline] National Academy of Sciences (1996) Understanding Risk: Informing Decisions in a Democratic Society. National Academy Press, Washington, DC National Academy of Sciences (2000) Genetically Modified Pest-Protected Plants: Science and Regulation. National Academy Press, Washington, DC National Academy of Sciences (2002) Environmental Effects of Transgenic Plants. National Academy Press, Washington, DC National Food Processors Association (2003) No use of food or feed crops for plant-made pharmaceutical production without a "100% guarantee" against any contamination, says NFPA. News release. February 5, 2003 Ohlrogge J, Chrispeels MJ (2003) Plants as chemical and pharmaceutical factories. In MJ Chrispeels, D Sadava D, eds, Plants, Genes, and Crop Biotechnology, Ed 2. Jones and Bartlett, Sudbury, MA, pp 500–529 Pessel FD, Lecomte J, Emeriau V, Krouti M, Messean A, Gouyon PH (2001) Persistence of oilseed rape (Brassica napus L.) outside of cultivated fields. Theor Appl Genet 102: 841–846[CrossRef] Pew Initiative on Food and Biotechnology (2003) Pharming the field: a look at the benefits and risks of bioengineering plants to produce pharmaceuticals. Workshop proceedings, July 2002, Washington, DC. Pew Initiative on Food and Biotechnology. http://pewagbiotech.org/events/0717/ConferenceReport.pdf Shalala D (2002) New directions for biomedical science. Science 295: 585[Abstract] Simpson BB, Ogorzaly MC (2001) Economic Botany: Plants in our World, Ed 3. McGraw-Hill, New York This article has been cited by other articles:
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MUCH ADO ABOUT "PHARM"...
GOING TO GREAT LENGTHS
