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Published online: 5 October 2006; | doi:10.1038/nbt1006-1191
Turning plants into protein factories
Companies making proteins in plants are cooking along, while the agbiotech continues to give itself a black eye. Jeff L. Fox reports.
Jeffrey L Fox
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August proved a cruel month for biotech companies pursuing plant-made products (PMPs) such as pharmaceuticals and industrial proteins. On August 10, a federal district judge in Hawaii ruled the US Department of Agriculture (USDA) violated the Endangered Species Act in permitting cultivation of drug-producing genetically engineered crops throughout the state (see News, page 1186). Barely a week later, US Agriculture Secretary Mike Johanns revealed that Bayer CropScience (Research Triangle Park, North Carolina), had informed officials that a genetically modified (GM), herbicide-tolerant rice had shown up in trace amounts in samples of commercial rice in the US.
The Hawaii court ruling could become a major hurdle for biotech companies in the agricultural sector because the state's year-round growing season has made it the leading location for plantings of experimental GM crops, including several dozen PMP trials. And, although those traces of GM rice do not pose a threat to human health or the environment, they are another in a line of embarrassing and costly mishaps that continue to plague the agbiotech sector.
Last year, for example, local political and economic forces stymied Sacramento, California-based Ventria Bioscience's attempts to plant test plots of GM, lactoferrin- and lysozyme-producing rice in Missouri (Nat. Biotechnol. 23, 636, 2005). Some observers saw those events as signaling the impending demise of companies trying to develop PMPs. The collapse last December of another would-be PMP pioneer, Large-Scale Biology of Vacaville, California, added heft to that growing pessimism.
Despite such setbacks, however, several dozen worldwide PMP companies plug along (Table 1), working with plants as vehicles for producing therapeutics, vaccines, food additives or other valuable products. Some of them, however, no longer consider making those materials in field-grown food crops. Instead, they are using inedible plants such as tobacco, duckweed or mosses. Others are growing edible GM plants or tobacco under stricter confinement—in greenhouses or more fully contained indoor facilities—or are using plant cell cultures instead of intact plants. Meanwhile, new technical developments, including recent efforts to build and harness 'mini' chromosomes, eventually could lead to even more ambitious undertakings with PMPs and in production agriculture (see Box 1).
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It takes a village
Ten 'robust' companies are currently developing PMPs and another 30 are 'emerging' worldwide, according to Francois Arcand, director general of Era Biotech (Barcelona, Spain) and president of the Society for Moleculture, a nonprofit organization that promotes the PMP sector. Although these companies "have not yet found what they'll best do with their plant factories," this sector is building an essential "global village of enabling technologies," he says. He predicts that the PMP sector will prove crucial for meeting worldwide demand for high-value biotech products, particularly biopharmaceuticals, because it offers "productivity and cost advantages." He counts Ventria, despite its difficulties, among the PMP leaders.
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Ventria has been conducting field trials in North Carolina and South America, growing GM rice as a means for producing food additives with medical uses. Although thwarted in Missouri, the company seems to be overcoming earlier opposition to its efforts there, according to CEO Scott Deeter. The troubles last year were largely due to a "small group [with] a lot of press," he says. But its main focus lately has been on promising, albeit controversial, results from a clinical trial of its GM rice–produced antidiarrheal products lactoferrin and lysozyme that was conducted in Peru. "We're very excited with those results," he says.
"Plants can deliver more affordable products on a much larger scale, and when we use rice, we can store it at ambient temperatures and still maintain quality," Deeter continues. Because rice is self-pollinating, there is little chance for exchange between GM and ordinary rice. Moreover, proprietary systems enable them to produce value-added proteins in rice at "25-fold higher yields than the next best [plant] system, conferring a significant advantage," he adds. Deeter maintains his optimism amid a barrage of criticisms, including some assailing the clinical trial in Peru by asserting that it exploited children in a developing country. "We're sticking with rice," he says.
Impact on local farming
But more subtle, and perhaps more significant for Ventria and other companies working on PMPs in US states with a strong agricultural base, are several conclusions embedded in a draft report on biotech's impact on local agriculture, based on a workshop held last April entitled "Finding the Fit Between Molecular Farming and Organic Farming Opportunities for North Carolina." The report included "disparate voices" demanding to be heard in a state with a rich "agrarian tradition," whose state and local officials are contemplating changes in how GM plants are regulated, says biologist Claire Williams of Duke University in Durham, convener of the workshop.
One key conclusion is that PMPs, "if grown in food plants, pose more risk to North Carolina's food supply than any type of GM plant to date." Local opposition to Ventria's 335-acre field trial is focused "not so much on ecology as its being a precedent for companies without a local stake in staying here and eating what's grown locally," Williams says.
In North Carolina, locals, including farmers and state officials, voice concerns about PMP materials somehow being fed accidentally to "hogs eaten for barbecue, making PMPs a consumer issue," Williams continues. However, consumers seem to be comfortable with other PMP companies working locally on nonfood crops, such as tobacco, or on plants or plant cells not grown in open fields.
Like Ventria, SemBioSys Genetics of Calgary, Alberta, Canada, is conducting open field trials in the US and South America—in this case, with GM safflower as the vehicle for producing the company's likely first commercial product, a feed additive for boosting disease resistance in farmed shrimp. Also under development are human-type insulin and apolipoprotein AI ('apo'), according to company director Andrew Baum. The feed additive could be marketed as soon as 2008 in Chile, whereas insulin and apo are at least several years beyond that, he notes.
Because its technology platform depends on using edible oil-producing plant species, SemBioSys opted for safflower for both agronomic and containment reasons, according to Baum. "There are no weedy relatives, the pollen is not wind-blown and it's easy to plant where no other safflower is being grown," he says. "We've planted test plots routinely for four years...and put tremendous effort into developing and implementing SOPs [standard operating procedures]...to comply with permits.
"We want [stringent] regulation because it's important for the public to see there is appropriate diligence," he continues. "We've had no problems with confinement issues, which is a real testament to the work of our field groups....We are confident that we'll be able to manage growing [PMPs] outdoors. But practitioners of this technology fully understand what happens if something goes awry. Bad execution beats good science."
No eating or smoking, please
Critics and proponents alike are quick to agree with Baum, particularly when conversations drift to the uncontained GM corn debacle of several years ago involving the now-defunct Prodigene, which was developing a corn-based vaccine for use in farm animals (Nat. Biotechnol. 21, 3, 2003; Nat. Biotechnol. 22, 133, 2004). Although a research group at Iowa State University in Ames is actively developing a nonpollinating GM corn with which to make therapeutic proteins, there is no visible activity with corn as a field-grown vehicle for PMPs—except as a source for biofuels.
"One thing to be aware of is the strong shift away from corn as a platform for pharmaceuticals, and that's a good thing [because of] pollen and seed segregation problems," says plant geneticist Norman Ellstrand of the University of California, Riverside. "A lot of people are taking bioconfinement seriously."
Field permits issued by officials of the USDA Biotechnology Regulatory Services program in Riverdale, Maryland, document this trend away from corn (Fig. 1), as the volume of permits issued for PMP field trials of GM corn has dropped to one or two per year, from a high of 19 in 2001.
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"We don't think PMPs should be developed in food crops at all, whether indoors or outdoors, and this skepticism is not confined to the public interest community," says William Freese, with the Center for Food Safety in Washington, DC, adding, "And if it's in nonfood plants, it should be...contained." Key industry groups voice similar concerns, including the Washington-based Grocery Manufacturers Association and Food Products Association, which informed USDA of its "strong opposition to the use of food crops to produce PMPs in the absence of controls and procedures that ensure essentially 100% protection of the food supply."
Some stalwarts within the biotech umbrella also are questioning the use of food plants for making PMPs, including Charles Arntzen, a one-time champion of plant-made, edible vaccines. Less than a decade ago, Arntzen, codirector of the Center for Infectious Diseases and Vaccinology for the Biodesign Institute at Arizona State University in Tempe, was helping to develop GM potatoes and bananas as vehicles for human vaccines. More recently, however, his views shifted.
There are "many uncertainties with plant manufacturing systems," Arntzen says, noting that he once thought that anything other than "grow it, dry it, eat it" would be "too expensive." However, he now sees that approach as an "error in strategy," conceding that "process technology that works for foods would not be easy to apply to pharmaceuticals [because] the variability of bananas or potatoes adds to the complexity of [making] a reliable vaccine." Furthermore, he adds, "market dynamics conspire against making changes in manufacturing technologies." Important among those dynamics are nagging questions about how regulatory officials might deal with reviews of vaccines delivered in edible fruits or tubers. Such uncertainties inevitably drive investors in other directions, he laments.
One approach is to use inedible tobacco plants. For instance, a group at the Genetic Engineering and Biotechnology Center in Havana, Cuba, recently received approval from local authorities to use monoclonal antibodies produced in GM tobacco as a means for purifying the active ingredient for a widely used hepatitis B vaccine.
Another approach by Chlorogen of St. Louis, is to transform chloroplasts, as a way of preventing any PMPs from spreading in pollen, but also for amplifying the number of gene copies per cell and the amount of protein that can be made, according to spokesman Dan Holman. "We can produce a lot of protein from a very small biomass." In part because leaves are harvested before seeds can be produced, tobacco farmers have not objected to test plots in Missouri and Kentucky, he notes.
Keep a lid on it
Many concerns over mixing PMP and non-PMP plants can be sidestepped by companies working with fully confined plants or plant cell cultures. For instance, Biolex of Pittsboro, North Carolina, is developing PMPs, including -interferon, monoclonal antibodies and plasmin (a protein involved in blood clotting), in GM duckweed, which is grown indoors in a "fully contained format," says COO David Spencer. "It grows very rapidly with great fidelity...similar to tissue culture."
-interferon, monoclonal antibodies and plasmin (a protein involved in blood clotting), in GM duckweed, which is grown indoors in a "fully contained format," says COO David Spencer. "It grows very rapidly with great fidelity...similar to tissue culture."Similarly, Greenovation of Freiberg, Germany, is growing GM mosses indoors in "photobioreactors with simple media" as a means for producing candidate therapeutic agents, including monoclonal antibodies that are appropriately glycosylated, according to CSO Gilbert Gorr. Not only does this avoid outdoor production, but mosses can be quickly genetically reprogrammed for small-scale product-feasibility studies. "The safety profile is excellent, with no plant or animal viruses, no use of antibiotics and no environmental release," he says.
Plant cell cultures provide another alternative. Last January, USDA officials approved the first PMP veterinary vaccine—in this case, for preventing Newcastle disease in chickens—produced by Dow AgroSciences in Indianapolis, Indiana, in a cultured tobacco cell line. Although that product is not being commercialized, it is the prototype for several other vaccines, including some for infections caused by the avian influenza and West Nile viruses, according to Butch Mercer, Dow AgroScience's global business leader in animal health.
More importantly for the PMP sector, Mercer adds, production in tobacco cell lines is "robust," involves no use of contaminating mammalian proteins and seems to yield protein antigens having "extended levels of stability." Furthermore, approval from the USDA provides a well-demarcated—and remarkably uncontroversial—path through federal regulatory review for at least some PMP products.
Although plant cell culture will work in some instances, it will not in others, insists Arcand of the Society for Moleculture in Spain. Thus, some companies will "need" to grow their GM plants in open fields, he says. Although that need leads to a "risk-management situation," it should prove manageable because the scale is small and the risks are relatively low. "For the next five years, even if we had 40 blockbuster [PMP] drugs, there's no way to get to planting more than 5,000 acres," he says. "That's not agriculture, but gardening."
PMPs are being tightly regulated, and "no regulators will let [industry] put something dangerous in the fields," Arcand continues. "Yes, I'm totally in favor of using tobacco for certain things, but eventually we'll need to use rice or other edible biomass. So Ventria, SemBioSys and other companies need to be in fields. They won't survive unless they respect the rules, but they have been."
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