Stories Farm Fresh Pharmaceuticals

Most genetically modified plants grown today have traits that facilitate production at the farm. The latest GM plants in the development pipeline, however, offer more than just agronomic advantages. Among the new possibilities for plant biotechnology is “biopharming”, or the production of pharmaceuticals or specialty chemicals in genetically modified plants. While progress in the US has been hampered by contamination scandals, European companies seem to have taken the lead by implementing strict safety controls right from the start.

Imagine a field of potato plants. Imagine that each tuber contains proteins from the deadly Cholera bacterium. Although this may sound alarming, the potatoes were actually developed by researchers at the University of Rostock with the goal of delivering life-saving vaccines. The potatoes contain a bacterial protein that researchers hope will make the uptake of orally administered vaccines more efficient. It is hoped the "cholera potato" will help pave the way for the more effective delivery of oral vaccines produced in other transgenic plants. The field trial planted in June 2006 marks the first time that pharma-plants have been grown in Germany outside of a greenhouse.

GM maize for the production of pharmaceuticals. What are the risks? (Photo: Prodigene)

Containment lapses spell trouble for US biopharming projects Commercial production of plant-made pharmaceuticals (PMP) in open fields has yet to be authorised in any country, but many field trials have already taken place in the US. One mismanaged field trial in 2001 exposed the risks involved with biopharming and triggered a serious loss of confidence in US biopharming prospects. The US company ProdiGene conducted field tests with maize engineered to produce trypsin for diabetes and a vaccine for hepatitis B.

When it was found that a few transgenic corn stalks had made their way into half a million bushels of soybeans, the US Department of Agriculture fined Prodiene $250,000 and ordered the company to purchase and destroy the almost $3 million worth of contaminated soybeans. In 2005, Anheuser-Busch, the largest buyer of rice in the US, announced it would not buy rice from Missouri farmers if the biotech company Ventria were to grow PMP rice in the state. Anheuser-Busch retracted its boycott only after Ventria insisted that the company's pharma-rice would be kept nearly 200 kilometres away from the nearest conventional rice field.

Strategies for biocontainment

Secure biocontainment to keep pharmaceutical genes and products out of the environment and the food supply is essential for ensuring the safety and acceptance of biopharming. Some approaches simply involve maintaining wide separation distances between biopharming and food crops. Staggering planting by 25 days is another way of reducing the risk of unwanted out-crossing. In the case of maize, the likelihood of out-crossing can be further reduced by manually removing the pollen-releasing male flowers. Special care must also be taken to reserve farm machinery for biopharming use only. Furthermore, many demand that biopharming projects completely abandon working with food crops to reduce the risk of contaminating food supplies.

Chloroplasts (green structures) in plant cells. In most flowering plants, pollen contains no chloroplasts. If chloroplasts are genetically modified, the pollen from such "transplastomic" plants would not contain foreign genes.

Biological methods for biocontainment offer some additional possibilities. One biological way of preventing out-crossing is to grow male sterile plants, which means plants that are unable to produce viable pollen. One drawback is that without pollen, there is no pollination. Some crops cannot form fruit or grains without adequate pollination. Another approach is to genetically modify the DNA in a plant’s chloroplasts. Since pollen generally does not contain chloroplasts, the transgenes wouldn’t be transmitted by pollen. Genetically transforming chloroplasts, however, is much more difficult than transforming genomic DNA. And plants with GM chloroplasts aren’t always a tight seal. Some plants occasionally let a few chloroplasts slip into their pollen.

The hotly debated “terminator technology”, a genetic technology that makes transgenic seeds unable to grow, could also make for a useful approach. The complexity of germination restriction technologies, however, doesn’t offer 100% assurance that spread will never occur. Besides needing to ensure biocontainment, using plants to produce pharmaceuticals can be problematic because the desired substances are usually produced at low concentrations. In addition, developing a transgenic plant takes much more effort than creating transgenic bacterial strains.

So why use plants for producing pharmaceuticals at all? For one, plants can produce a much wider range of compounds than microbial systems, as plant cells are more similar to human and animal cells. At the same time, there is no risk of contamination with dangerous pathogens, which is often a threat with animal produced pharmaceuticals. Furthermore, using plants can have a cost advantage to producing pharmaceuticals in animals or via more conventional biochemical processes. Production capacity can also be rapidly scaled up. In the case of an epidemic, it would be easier to expand biopharming than to install extra bioreactors or biochemical production facilities. Finally, some protein-based vaccines can be stored longer at room temperature when contained in plant tissue. This would facilitate delivering pharmaceuticals to remote regions in the third world that lack access to refrigeration.

Europe pushes ahead

GM plants have faced major criticism from European consumers. In some ways, however, scepticism among consumers has worked in the biotech industry’s favour. While the US pharmaceutical industry is still recovering from the fallout of ProdiGene and other scandals, European companies have paid attention to consumers and taken a more prudent approach right from the beginning. With very few exceptions, biopharming in Europe has been restricted to greenhouses, thus minimising the risk of food or environmental contamination. The French company Meristem Pharmaceuticals has been an exception, growing 20 hectares of GM maize modified to produce the enzyme lipase in open fields in 2005. The field trial was partially destroyed by activists.

With more positive experience than the US, European governments are generously funding research on PMPs. There are several European companies currently developing plant systems for producing pharmaceuticals. Meristem Pharmaceuticals and the Danish Cobento Biotech are both conducting clinical trials with their PMPs. The range of pharmaceuticals that can now be produced in plants include several vaccines for humans and animals, growth hormones, insulin, blood substitutes, and trypsin inhibitor.
 

Plant cell culture Plant cells in a nutrient solution. Photo: Department of Biological Sciences (Louisiana State University)

Plant cell culture – a promising compromise Demand for PMPs in Europe will likely exceed the capacity of greenhouses. To avoid production in open fields, scientists have been looking into a new possibility. Instead of growing entire plants, it may be useful to extract pharmaceutical products from plant cell cultures. Plant cell cultures would still offer many of the advantages over bacterial and animal production, but would forgo the risks of out-crossing and food supply contamination. Culturing plant cells, however, would necessitate large-scale bioreactors, which presents companies with a technological hurdle. Nevertheless, the promise of plant cell cultures is clear. The US company Dow AgroSciences just received regulatory approval to produce the world’s first plant made vaccine in bioreactors.

See also on GMO-Compass:

• Strategies for Stopping the Spread of Foreign Genes
• Production of Pharmaceuticals, Enzymes and 'Bio' Raw Materials