Council for Responsible Genetics

There’s a lot wrong with the pharmaceutical industry, no doubt — outrageously priced drugs, overly long patent terms, and the government’s giveaway of taxpayer-funded research. Still, one can usually depend on Pfizer, Bayer and the rest to deliver a pure and consistent product. And this is due in no small part to painstaking control of conditions throughout the production process, from raw materials to finished drug.

A handful of biotechnology firms want to change all this by moving certain kinds of pharmaceutical production from the factory to the fields — from a rigidly controlled environment to the unpredictable world of nature. Put simply, their vision is to replace drug manufacturing plants with plants that manufacture drugs — an experimental process called biopharming. It involves the engineering of genes that mediate the synthesis of medically useful proteins in plants, which are used as “bioreactors” to generate the proteins in their tissues. The plants are grown to maturity, harvested, and the “biopharmaceutical” they contain is then extracted and purified.

There is some precedent for this enterprise. While these sorts of medicinal proteins were once obtained exclusively from animal or human tissue (such as insulin from the pancreas of a cow or pig), in the early 1980s scientists began engineering bacteria, yeast and animal cell cultures to produce biopharmaceuticals in large fermentation tanks. Examples include a bovine growth hormone generated from engineered bacteria, and a protein that stimulates red blood cell production (erythropoietin) produced in hamster ovary cells. Such proteins are often labeled “recombinant” to signify their mixed-species origin, and to warn of subtle differences between them and their natural counterparts.

Such differences can sometimes provoke the body’s immune system to attack recombinant proteins as foreign. This antibody response can render the drug ineffective, disable the body’s own corresponding substance (causing auto-immune dysfunction), or trigger an allergic reaction. Experts agree that plant-produced biopharmaceuticals have an even greater potential to cause such problems than those produced in mammalian cells, because plants attach different types of carbohydrate molecules to proteins than mammals, and some of these carbohydrates have been linked to allergic reactions.

Other factors that could adversely impact the quality and safety of plant-produced drugs include unintended effects of the engineering process, the difficulty of separating the biopharmaceutical from innumerable other plant constituents (tobacco has 4,000), and the ticklish problem of contaminants. Applied or co-engineered pesticides, potent mycotoxins from mold growth on plants, and resident plant viruses (most of which are still uncharacterized) will in many cases be difficult or impossible to remove from the biopharmaceutical.

Contamination of food

Another major challenge is how to keep plant-grown biopharmaceuticals out of the food supply. Modes of contamination include cross-pollination between conventional and biopharm crops, seed dispersal, and unharvested biopharm seed sprouting the next year to contaminate the following season’s crops. This is particularly a problem when one
considers that over 70% of the open-air biopharm field trials conducted to date have utilized corn, a promiscuous pollinator that can send its pollen over a mile on the wind. Iowa farmer Laura Krouse has already seen her open-pollinated corn contaminated with the engineered Bt toxin from neighboring Bt corn fields; she wonders if a drug gene is next. Even the editors of Nature Biotechnology, the industry’s leading journal, admit that such contamination is likely:

Another contamination threat arises from the plans of some companies to make “dual use” of biopharm crops — extracting the drug or chemical and then selling the rest for use as food or animal feed. Incomplete extraction would mean drug or chemical residues in food products, a risk that consumers should not be exposed to.

Substances could harm human health and the environment

Growth factors such as erythropoietin are active at billionths of a gram when injected, and may be harmful by inhalation, ingestion or skin absorption. Aprotonin, a blood clotter grown in several outdoor field trials in corn, belongs to a class of substances known as protease inhibitors (PIs), which are known to cause pancreatic disease in test animals. Some of the industrial enzymes being tested in outdoor field trials, such as trypsin, are known to be inhalant allergens. Other biopharm compounds, including avidin and aprotonin, have been shown to harm insects, including honeybees. Impacts on soil ecology are also an important area of concern, especially since engineered proteins are known to “leak” from the roots of biotech plants. According to Dr. Glynis Giddings et al:

Biopharmaceuticals usually elicit responses at low concentrations, and may be toxic at higher ones. Many have physiochemical properties that might cause them to persist in the environment or bioaccumulate in living organisms, possibly damaging non-target organisms....

In other words, they’re dangerous, they stick around, and they don’t discriminate. If biopharming becomes common, disposal of drug-containing crop residues could become a serious problem.

Self-regulation and secrecy

Given these risks, one would expect the government to tightly regulate biopharming. Unfortunately, oversight of biopharmaceutical-producing crops is little better than regulation of other GE plants. While the USDA has nominal authority, it largely delegates on-the-ground responsibility to the companies themselves. Thus, the USDA rarely visits a field trial site more than once (sometimes never), and its inspectors are often poorly trained. USDA has not even performed an envionmental assessment of a biopharm crop field trial since 1998. In most cases, USDA hides the identity of the drug or chemical as confidential business information of the company, keeps all biopharm crop sites secret from the public and neighboring farmers, and condones biopharm companies’ preferred practice of “anonymously” planting these crops without identification, security measures or notification of neighbors. Joe Jilka of ProdiGene, speaking of his company’s corn, engineered to produce a pig vaccine (TGEV), seems more concerned about theft than public safety:

... the best way to secure it is to grow it just like any other corn. In other words, the anonymity of it just completely hides it. You know, our TGEV corn grown [sic] was up here by Story City right by the interstate, and no one could have ever seen it.

It is small wonder than an expert committee of the National Academy of Sciences strongly criticized the USDA for these and other regulatory deficiencies earlier this year. Surprisingly, it appears that the FDA will not become involved in biopharm regulation until years of field trials have passed and the company is ready to apply for commercial approval of its biopharm compound.

Biopharming does not mean cheaper drugs

At present, there is little to suggest that plant-grown pharmaceuticals would be cheaper than, for instance, those produced in cell cultures. True, companies foresee lower production costs through replacement of high-cost production facilities with the flexibility of low-cost contract farmers and their equipment. However, others believe that biopharming will prove to be expensive and/or non-viable due to difficulties in purifying drugs and chemicals from plants, the costs of mitigating gene flow, and litigation and liability costs from contamination. Barry Holtz of Large Scale Biology, a leading biopharm company, discounts glib predictions of “$5 dollar a gram proteins,” estimating that even high-volume plant-grown drugs would cost “hundreds to thousands of dollars a gram” to produce.

What drug-growing plants mean for farmers

Biopharming is often trumpeted in the farm press as the innovation that will save farmers who are suffering, and in many cases facing bankruptcy, due to low commodity prices. However, like most agricultural innovations, biopharming is geared to larger, more sophisticated farmers. Companies will prefer to hire growers who can afford to implement expensive gene containment measures (such as separate harvesters for biopharm and conventional plots) and who can precisely analyze and amend each plot of their fields for optimal nutrition (precision agriculture). The numerous liability risks associated with biopharm contamination of the food supply, such as loss of export markets, will affect all farmers, whether they choose to grow these crops or not. Farmers and farmworkers will be exposed — through inhalation and skin contact — to biopharmaceutical compounds during harvesting. It is doubtful whether the small premiums being promised for biopharm crops will cover these risks.

Faulty paradigm

In the end, biopharming is likely to fail because it is based on a fundamentally flawed paradigm: the notion that one can consistently produce the uniform, high-quality product demanded from the pharmaceutical industry under conditions that allow for so little control over the production process. As we have seen, even pharmaceutical proteins produced in the rigidly controlled fermentation process sometimes elicit dangerous immune reactions due to subtle, hard-to-detect differences from their natural counterparts. This problem can only be aggravated when the “production platform” is a plant grown in the open air, subject to the vagaries of nature. This, coupled with the equally uncontrollable phenomenon of biopharm gene flow, argues against further experimentation with open-air biopharming (particularly in food crops such as corn). Instead, researchers should further explore contained and controllable alternatives that will keep drug genes indoors and out of our food and environment.

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Bill Freese is a policy analyst for Friends of the Earth (FOE). For a comprehensive treatment of biopharming, see “Manufacturing Drugs and Chemicals in Crops: Biopharming Poses New Threats to Consumers, Farmers, Food Companies and the Environment,” at www.gefoodalert.org.