Policy Review Banner

Down on the Biopharm

Monday, December 1, 2003

Try as we might, we cannot seem to control a highly infectious bug called Norwalk virus that annually causes millions of cases of gastric distress in North America alone. Cruise ships and nursing homes endlessly scrub and sanitize and disinfect; staffs, passengers, and patients wear gloves and avoid person-to-person contact; but the epidemics of gastroenteritis continue. In recent months, cruises have been canceled or ruined, and hospital emergency rooms, schools, and nursing homes have closed down.

University of Arizona scientists have come up with a highly unconventional remedy: the first vaccine against Norwalk virus, now awaiting approval for clinical trials in humans. Why unconventional? After all, anti-viral vaccines have been around since British physician Edward Jenner introduced smallpox vaccine in the eighteenth century. The highly innovative Norwalk vaccine, which is grown in tomatoes and administered in pills that contain powder derived from freeze-dried tomatoes, is just the latest development in a mushrooming new field known by the punny name “biopharming.”

Scientists can even use this approach to make vaccines that will prevent certain kinds of cancers that appear to be caused by viral infections. German researchers have engineered tobacco and potato plants to synthesize a protein component from the human papillomavirus, which is thought to cause cervical cancer, the third most common cancer among women worldwide. When the protein is extracted from the tobacco and potato plants, then purified and administered to mice, it induces an immune response. When the potatoes are fed directly to mice, they also trigger an immune response, though not as strong. If bioengineers one day develop a vaccine against cervical cancer, there will be a huge demand, especially if the vaccine can be stored in edible doses without refrigeration.

Biotech companies are using gene-splicing techniques to reprogram crops — mainly corn, initially — to produce significant concentrations of high-value pharmaceuticals. The concept is not new. Many common medicines, such as morphine, codeine, the laxative Metamucil, and the anti-cancer drug Taxol, are all purified from plants. But biopharming’s great promise lies in using gene-splicing techniques to make old plants do radically new things.

There is also great potential for cost-cutting in the process: The energy for product synthesis comes from the sun, and the primary raw materials are water and carbon dioxide. In addition, biopharming offers tremendous flexibility and economy when adjustments in production are necessary. Doubling the acreage of a crop requires far less capital than doubling the capacity of a bricks-and-mortar factory, making biopharmed drugs potentially much less expensive to produce than those made in conventional ways. As little as 2,000 acres can provide the substrate for a year’s supply of some products. Grain from a biopharmed crop can be stored safely for at least a year with no loss of activity. The quality of the final drug can meet the same standards as current fermentation technology using microorganisms.

But storm clouds are gathering on the horizon. The food industry fears that gene transfer or “volunteer” biopharmed plants in the field could cause vaccines, drugs, and other products to contaminate the food supply, triggering costly recalls and presenting thorny liability issues. Therefore, in comments filed with the Food and Drug Administration in early 2003, food producers called for excessively stringent federal regulation. Some of the demands of the Grocery Manufacturers of America and other food trade associations were reasonable, but not their recommendations to the fda that food plants should be off limits for biopharming “unless the company developing the drug product clearly demonstrates that it is not feasible to use non-food crops” and that “land, labor and equipment [be] dedicated solely to growing” biopharmed products. Although these restrictions would offer minimal additional safety, they would severely stigmatize the technology and push the development costs of biopharmed products into the stratosphere, limiting development only to very high value-added substances and inflating the ultimate costs to the consumer of the biopharmed drugs that reach the marketplace.

A harsh fact of life is that not all of those who need expensive conventional drugs can afford them. The drug regimens to treat aids are the prototype, but costs can be prohibitive for state-of-the-art therapies for diseases ranging from arthritis to tuberculosis. If regulation and other aspects of public policy don’t unnecessarily inflate the costs of development, biopharming can revolutionize the pricing structure of many new drugs.

But this prospect is the triumph of hope over experience. Regulators are alert for new opportunities to increase their regulatory responsibilities and budgets. They are also risk averse, especially when confronted by highly innovative products and processes. All this spells bad news for biopharming: In March 2003, the U.S. Department of Agriculture’s Animal and Plant Health Inspection Service announced onerous new restrictions on the cultivation of biopharmed crops. To a great extent, they tracked the demands of the food industry, which, interestingly, were almost indistinguishable from those of the radical environmental lobby.


usda’s imperfect solution

Most of usda’s new restrictions on the cultivation of the biopharmed plants are excessively burdensome. For the most part, they impose highly prescriptive, one-size-fits-all “design” standards — as contrasted with “performance standards,” which specify an end-point that must be achieved. They do not take into account the actual risks of a given situation. Among other things, the new requirements:

  • Demand that separate planting, storage, and harvesting equipment be set aside for biopharmed crops. (usda allows such equipment to be returned to general use, but only after it has been cleaned in accordance with extraordinary, expensive procedures.) Many biopharmers have always used dedicated equipment to avoid quality-control problems that might arise in the development of their plant-based drugs. But given the factors, discussed later, that mitigate the effects of small amounts of contamination that might occur, this level of precaution — with its attendant expense and inconvenience — is not appropriate for all biopharmers.

  • Double, from half a mile to a mile, the buffer zones that biotech companies must maintain between their pharmaceutical corn and non-engineered corn whenever the drug-bearing crops must be openly pollinated. Under the old regime, if biopharmers put bags over the pharmaceutical plants’ pollen-producing tassels (or removed them), then usda required that: 1) ten rows of non-engineered corn be planted as a buffer around the drug-bearing corn; 2) non-engineered corn grown within two-fifths of a mile be planted at least 21 days before or after the pharmaceutical corn so that their flowering times did not overlap; and 3) if non-engineered corn was planted within a quarter mile, it also had to have its ears and silks covered.

    Now biopharmers who cover or remove the tassels of their drug-bearing corn must stay at least half a mile away from other cornfields, and other cornfields between a half and one mile away must be planted at least 28 days before or after the pharmaceutical crops.

    Arguably, companies that take the additional step of planting male-sterile pharmaceutical corn should be allowed to reduce the buffer zone somewhat, but they cannot do so under the current system. These new requirements may rule out many opportunities for drug-bearing varieties in the Midwestern Corn Belt, where large plots of land with no corn growing on them are rare.

  • Require that farmers seek explicit usda authorization before growing food or feed crops on any land that has been used to cultivate biopharmed corn within the previous year. This measure is supposed to guard against the possibility that, after a field has been cultivated with biopharmed corn, drug-producing “volunteer” plants might sprout later and get mixed with a food crop grown in the same soil. The year after a farmer stops growing biomedical corn on his land, usda permits him to plant cover crops to enrich the soil and prevent it from eroding. Such vegetation is not harvested, but is usually plowed under or burned down with herbicide at the end of the season. The farmer may plant whatever type of cover crops he wishes as long as usda inspectors are able to detect and destroy any drug-producing corn volunteers that might spread pollen to neighboring cornfields. But if he wants to grow food crops, his options are much more limited.

Under usda’s new policy, one company has received permission to cultivate two hand-harvested vegetables on some of its former biopharmed plots next year. In a third field, it will also be allowed to grow a food and fiber crop that completely blocks the emergence of drug-bearing volunteer plants. usda will not reveal what these three food crops are because such information could help eco-terrorists to locate the company’s test sites. As of this writing, most biopharm companies have yet to ask usda for permission to cultivate their fields next year, so we cannot know what food crops they will seek to grow or precisely how the new restrictions will affect them. But if a farmer has cultivated pharmaceutical-containing corn on his land this year, usda will prohibit him from planting weedy crops like soybeans there next season. The rationale is that such prolific crops would eventually become confluent over the entire field and obscure any drug-producing corn stalks that might sprout. This marks a significant policy shift from last year.

Under its old system, usda prohibited anyone from planting edible corn in soil that had been used to cultivate drug-producing corn the previous year but otherwise placed no restrictions on the types of food crops that farmers could grow. Instead, it demanded that farmers weed thoroughly whenever they planted food crops on such land, and government inspectors policed this requirement. In 2002, a Nebraska farmer allegedly planted soybeans in a field in which biopharmed corn had grown the previous season but failed to provide adequate weed control to eliminate drug-bearing corn volunteers. During three separate inspections, usda officials found a small number of cornstalks that had not yet produced seed growing among the soybeans and urged the farmer to remedy the situation, but to no avail. After the harvest, the cornstalk-contaminated soybeans were then pooled with other soybeans into a 500,000-bushel shipment before usda finally ordered the entire batch destroyed. Without admitting fault, Texas-based ProdiGene, the company that developed this biopharmed corn, which synthesizes a vaccine intended to prevent E. coli diarrhea in pigs, agreed to cover all the clean-up costs and compensate the farmers whose soybeans were lost. usda also fined the company $250,000.

Representatives of the biotech industry say that usda’s handling of the ProdiGene affair demonstrated how well the old system worked. But since the policy change, usda officials have claimed that this effective policing was a kind of anomaly — that because ProdiGene had been cited for previous violations, federal surveillance of the company was unusually tight. They argue that the department lacks the manpower to give all biopharmers the same level of scrutiny, especially since many of its personnel have been assigned new homeland-security duties. By greatly restricting the types of food crops that may be grown in fields that have previously been cultivated with drug-bearing corn, usda intends to reduce the number and intensity of the inspections that it must perform on such post-biopharmed plots.

In March 2003, usda announced that henceforth it would inspect every biopharmed plot at least five times a growing season, whereas it normally conducted one or two such inspections under its old regime. usda inspectors used to spend more of their time examining post-biopharmed plots that had since returned to food-crop production. But now that the department has greatly limited the types of food crops that farmers may grow in such fields, fewer such post-biopharming inspections should be necessary. During the year in which a post-biopharmed site is returning to normal food-crop production, federal inspectors might need to spot-check it just a couple of times.

Because the cultivation of pharmaceutical corn involves so many regulatory hurdles, some usda officials have suggested that biopharmers should consider using other plant species as platforms for the production of pharmaceuticals. They argue that tobacco is a good choice for several reasons. Tobacco plants must be grown in seedbeds for two or three months before they are transplanted into the field, and their flowers are typically topped (removed) even before they open, so there is essentially no potential for tobacco seed to be produced or for seed to be carried over and sprout in subsequent seasons. Nor does the biopharmer have to establish large buffer zones to separate the biopharmed crops from conventional ones, because when the flowers are either topped or covered with bags, there is little chance that they will hybridize with nearby tobacco fields. Thus, a farmer can potentially grow drug-bearing tobacco on his land one year and then switch back to ordinary tobacco the next without running afoul of government regulators. Moreover, these officials say, tobacco is not used as food or feed and is not typically grazed upon by wildlife.

However, tobacco cannot be grown everywhere and may not be optimal — or even amenable — to the biosynthesis of certain molecules. More fundamentally, the freedom to innovate, and the ingenuity of the developers and farmers of biopharmed plants, should not be constrained unnecessarily by the whims or the personnel problems of government regulators.


Challenging the zero-tolerance mindset

Federal officials have tried to keep residues of biopharmed products out of the food chain, no matter how trivial the amount. They have declined to establish non-zero tolerance levels for these substances, largely out of concern that opponents of biopharming would take advantage of such a move to proselytize against this new technology.

The government’s overly risk-averse approach can be justified on neither scientific nor political grounds. It appeases neither anti-biotech activists nor the food industry, both of which have simply used usda’s zero-tolerance policy as a rationale to impose even greater regulation and other strictures on biopharming. For example, according to Friends of the Earth:

usda’s gene confinement measures are intended to “minimize” rather than prevent contamination. The few environmental assessments conducted by the usda are of poor quality, and show a disturbing willingness to bend the rules. . . . usda is not qualified to evaluate the health risks of biopharm crops, allows commercial use of biopharm plant products, and is too understaffed to exercise adequate on-the-ground oversight, for the most part allowing companies to regulate themselves.

A recent statement by the North American Millers’ Association (nama) offers another case in point:

Plant-made pharmaceuticals and industrial products are not intended to be cultivated for food and feed use, and are not required to seek food and feed approvals. Therefore, their presence at any level is currently not allowed in products meant for consumption by humans or animals. A positive detection of plant-made pharmaceuticals and industrial products in food or feed in any amount, therefore, would require the immediate recall and destruction of all products manufactured from that grain. Under current regulatory standards, this zero tolerance creates an intolerable risk for U.S. food processors.
That is why nama has called for regulations requiring companies producing plant-made pharmaceuticals and industrial products to demonstrate mandatory liability insurance coverage or to indemnify all downstream traders, handlers, processors and food manufacturers for the full cost of recall, destruction and brand deregulation as a result of gene flow or other release of genetic material into the food or feed industries.

The millers’ association seems not to have considered that one way to eliminate the “intolerable risk for U.S. food processors” created by zero tolerance would be to establish non-zero tolerances. And as the group pleads for new burdens on biopharming, it disregards not only the broader context of agriculture and biotechnology, but also salient features of its own industry. The grain industry’s own products are, after all, highly prone to contamination — by poisonous fungi, rodent hair and droppings, and insect parts, among other unpleasant substances. And these noxious leavings are definitely “not intended for food and feed use,” to borrow the millers’ own phrase. If these contaminants were prohibited from grain at any level, the industry would be out of business; instead, farmers, millers, and government cooperatively have designed approaches to risk assessment and risk management in order to handle, store, and process grain in ways that ensure consumer safety. What’s grain for the goose should be grain for the gander. Instead of punishing biopharming to the point of oblivion, we must reject the zero-tolerance mentality and approach safety scientifically and sensibly.

The food industry is not alone in muddying this issue. In 2002, the Biotechnology Industry Organization (bio) and several member companies came out strongly for stringent regulatory oversight of biopharming and agreed to voluntary but draconian restrictions on biopharmed plants. bio went so far as to suggest that companies refrain from growing biopharmed crops in entire regions of the country where the host crop in question is widely grown — for example, corn in the Midwestern Corn Belt. This precipitated a political firestorm, particularly from powerful Iowa Senator Charles Grassley, and within a few months bio had retreated from its position.

The food and biotech industries have failed to heed the important lessons from the introduction of the first gene-spliced veterinary product, bovine somatotropin (bST), or bovine growth hormone (bGH). The drug, a protein that stimulates milk production in cows, generated tremendous (but largely gratuitous) controversy, with some analysts predicting that its introduction would so frighten consumers that milk consumption could drop as much as 20 percent. Although the milk is in no way different from or less wholesome than that obtained from untreated cows, some in the industry, as well as many anti-biotech activists, advocated special regulations, including mandatory labeling of dairy products from bST-treated animals.

However, after a decade of widespread marketing and consumption of milk from bST-treated cows, an analysis from the usda’s Economic Research Service concluded that “scientific evidence about food safety will not prevent controversy. . . . Even intense controversy may have minimal or no effect on total demand [and] the absence of reports of harm from consumption contributes to continued consumption.” The bottom line is that the mere presence of controversy should not cause industry — or government regulators, for that matter — to overreact.


The worst case

Even if biopharmed crops were to contaminate food crops, how likely is it that anyone would find harmful amounts of prescription drugs in his corn flakes, pasta, or tofu? A combination of factors — including natural selection, farmers pursuing their own commercial self-interest, liability concerns, and the vast size of the U.S. food supply — all militate against such a possibility.

Gene flow is a biological fact of life. It is ubiquitous. All crop plants have wild relatives somewhere, and some gene flow commonly occurs if the two populations are grown sufficiently close together. Thus, although genes could be transferred from a crop that has been modified to synthesize a pharmaceutical, the recipient plant is likely to proliferate only if a certain gene that has moved confers a selective advantage. Such occurrences should be uncommon with biopharming because, most often, the added drug-producing gene should not confer on the recipient any selective advantage and could even place it at a selective disadvantage. Thus, if such a gene were to be transferred into a food crop, it might persist at a low level in the affected crop population for many generations, but we would expect its ability to proliferate and to cause significant contamination of the food crop to be limited.

Another relevant question is the persistence of post-biopharming volunteers. Michael Crawley and his co-workers found in a study published in Nature (February 8, 2001), which compared the performance of four different gene-spliced versus conventional crops (rapeseed, potato, corn, and sugar beet) in natural habitats, that in no case were the gene-spliced plants (which were engineered for traits other than synthesis of pharmaceuticals) found to be more invasive or more persistent than their conventional counterparts. They also found “that arable crops are unlikely to survive for long outside cultivation.” By the end of four years, of all the varieties cultivated in the study, only one variety of conventional potato persisted.

Gene transfer is an age-old consideration for farmers. Farmers in North America and elsewhere, who grow many hundreds of crops virtually all of which (save only wild berries) have been genetically improved in some way, have meticulously developed strategies for preventing pollen cross-contamination in the field — when and if it is necessary for commercial reasons. Traditionally, plant breeders’ guidelines have called for keeping distinct varieties of corn, a wind-pollinated crop, at least 660 feet apart. At this distance, the two corn varieties will not hybridize to any great extent, even if small amounts of pollen might still drift between the fields. Even without government oversight, biopharmers themselves strive to keep their specialty corn sufficiently far from ordinary cornfields, lest their highly valuable drug-producing crops suffer contamination from the food crops.

Canola and rapeseed provide a good example of two crops that are rigorously segregated with minimal government interference. The original rapeseed oil, used as a lubricant, caused heart disease when ingested because of high levels of a chemical called erucic acid. Conventional plant breeding led to the development of rapeseed varieties with low concentrations of erucic acid, which came to be known as canola. In 1985, fda approved canola oil for food use, provided that it contained no more than 2 percent erucic acid. But since rapeseed oil is still used as a lubricant and plasticizer, farmers and processors must carefully segregate these distinct high- and low-erucic acid crops in the field and thereafter, a task they accomplish routinely and without difficulty. What makes these successes particularly compelling is that, unlike certain other crops, such as wheat and barley, which tend to self-fertilize and are less likely to pick up foreign genes, rapeseed/canola is “one of the more problematic in terms of gene flow . . . a worst-case scenario,” according to Danish plant geneticist Rikke Jørgensen of the Riso National Laboratory.

Under this system, small quantities of rapeseed occasionally may get mixed into the canola, but this is of no consequence as long as the finished product meets the federal safety standard. Although it might be politically unrealistic to expect that people will unquestioningly eat tiny quantities of biopharmed crops the way they regularly consume erucic acid, there is no scientific or medical objection to their doing so.

Federal regulators could establish non-zero tolerance levels for biopharmed contaminants in the food supply. In some cases, such as for drugs that are neither orally active nor likely to be allergenic, one might simply conclude that contamination at any level poses negligible risk (not unlike the level of concern about small amounts of pollen from a variety of yellow sweet corn pollinating white sweet corn in a nearby field).

For situations in which risk is uncertain or known to be non-negligible, one would base tolerances on animal toxicology studies, as regulators do for pesticide residues. Before approving a new pesticide, the Environmental Protection Agency requires the manufacturer to examine how much of the chemical mice, rats, rabbits, and chickens can absorb without suffering any observable long-term effects following both acute and chronic exposure. Using highly conservative assumptions about both safety margins and the relevance of extrapolating high dosing of animals to very low exposures in humans, the epa then builds in a safety margin of several orders of magnitude to allow for differences between animals and humans and for possible enhanced susceptibility of children. With these kinds of assumptions, regulators create a huge safety margin — excessively huge, according to many experts — when they determine the maximum safe dose for humans. An analogous approach, which would substitute performance standards — that is, non-zero tolerances for carryover into food — for usda’s current design standards, also could work for pharmaceutical contaminants, at least from a medical standpoint.

Although potentially workable, the outcome of this conservative approach to establishing tolerances — like the epa’s determination of acceptable pesticide residues, from which it is derived — will likely be overly risk-averse. Even in a worst-case scenario, by the time a food contaminated with a biopharmed substance passes a consumer’s lips, it is unlikely to exert a significant effect. Recall that in the ProdiGene case, some 500,000 bushels of ordinary soybeans allegedly came into contact with a very small amount of biopharmed corn stalks and leaves. Not all the data necessary for a detailed analysis of that situation are publicly available, but we do know that for personal injury to occur, several highly improbable events would have to happen.

First, the active drug substance would have to be present in the final food product — say, tofu or salad dressing made with soybean oil — at sufficient levels to exert an adverse effect, the result of either direct toxicity or allergy. But there would have been a huge dilution effect as the tiny amounts of biopharmed corn stalks and leaves were pooled into the massive soybean harvest. With very few exceptions (e.g., peanuts), even an allergic reaction requires more than a minuscule exposure. Second, the active agent would need to survive milling and other processing, and then cooking. Third, it would need to be orally active; to take the example of ProdiGene’s corn, the synthesized “drug” is not pharmacologically active, except in the sense that it elicits antibodies that are intended to confer immunity to E. coli. The probability that all of these events would occur is extremely low.

Moreover, it is essential to consider the broader context of the kinds of chemicals that are commonly in our diet. We routinely consume hundreds of thousands of chemicals of all sorts — proteins, fats, carbohydrates, and minerals, among others. Bruce N. Ames and Lois S. Gold at the University of California at Berkeley have estimated that each day, “on average, Americans ingest roughly 5,000 to 10,000 different natural pesticides and their breakdown products,” as well as about 2,000 milligrams of “burnt material, which is produced in usual cooking practices” and contains many rodent carcinogens and mutagens.

These observations emphasize the primary principle of toxicology — that the dose makes the poison. Unless we have the misfortune to eat something to which we are highly allergic, a poisonous mushroom, or a poorly dissected puffer fish, the chemicals present in food do not cause acute harm. The possible risks of adding one more chemical moiety to the diet, especially in a minuscule amount, must be considered in that context. Except for extraordinary circumstances (for example, biopharming of an extremely potent toxin), there is no scientific justification for the kind of rigorous oversight that usda imposes on biopharmers today.


Lost benefits

On the occasion of usda’s announcement of the new restrictions on biopharmed crops, Agriculture Secretary Ann Veneman told reporters, “It’s very important that we regulate in a way that allows this technology to proceed, so we can reap the benefits of it.” Instead, her department is regulating in a way that will ensure that the field is stigmatized, that biopharming’s research costs are hugely inflated, that only very high-value-added products will be candidates for development, and that consumers ultimately will see few biopharmed drugs in the pharmacy. Moreover, in these circumstances there is little chance that pharmaceutical companies will develop products designed for less developed countries where heat-stable, plant-incorporated drugs and vaccines could revolutionize health care.

Perhaps we should not be surprised to find how far regulators have strayed from a rational, science-based approach to plant-derived pharmaceuticals. The testing and commercialization of gene-spliced plants are over-regulated generally, and it is much too easy for antagonists of biopharming to frighten consumers with images of hazardous drugs floating in children’s breakfast cereals while scientists invariably are careful to qualify their own statements and to refrain from blanket assurances that something is “safe.”

Anti-biotech activists and the food industry are demanding further tightening of the regulatory screws. These pressure groups want food plants to be off limits for biopharming, land once used to grow drug-producing crops to be dedicated solely to that purpose, and biopharmers to be indemnified against any damages they might cause under whatever scenarios their adversaries may dream up. Federal regulators, who are ostensibly committed to science-based regulation that discounts bias and the blandishments of special interests, already have erred on the side of risk-aversion and over-regulation.

If we are to reap what biopharming sows, we need a more reasonable, science-based policy. That’s about as common these days as mango trees in North Dakota. But if we cannot turn back the regulatory clock, at least let’s not make the situation any worse.