Green Plants as Biofactories for Drugs

You can custom-design a green plant to produce a desired product in its seed, leaves, fruit, root, or sap to yeild a plant that functions independently as a miniature biofactory.
Aug 01, 2004
Volume 17, Issue 8

Genetic engineering has added a new pathway to the manufacturing of fine and specialty chemicals.1 The idea is as simple as it is overwhelming. Instead of a factory-based chemical or biochemical reactor, you can custom-design a green plant to produce a desired product in its seed, leaves, fruit, root, or sap and grow acres of these in a farm field. Each plant functions independently as a miniature biofactory.

Despite its appeal, this idea has met with considerable opposition from public advocates, environmentalists, and food industry groups over health and safety issues. A major concern is keeping medical crops from contaminating food supplies. Past incidents of food crop contamination by foreign proteins that were not approved for food use (StarLink and Prodigene), resulted in significant costs and liabilities, even when the contamination was not a defined health threat.

These costs are borne not just by the technology developer, but also by businesses in the supply chain between the producer and the consumer. Unless technology developers address these concerns proactively, there is a real likelihood that regulations — rather than what is scientifically doable — will control which plants, technology, or product combinations are to be commercialized, how quickly and at what cost. Fortunately, there is evidence that developers are taking steps to prevent such events.

Plants have long been a source of human therapeutics — prominent examples include morphine from poppies, birth control agents from the Mexican yam, digitalis from the foxglove plant and paclitaxel from the Pacific yew tree. Producing foreign proteins was demonstrated less than 20 years ago, when human growth hormone was expressed in tobacco cells in 1986.2 We now have a host of such proteins and chemical products — antibodies, vaccines, and other metabolites (Table 1).

Human therapeutics comprises the single largest category, by far, of transgenic plant products in development, with somewhat more than 150.4 We will look more closely at the products, technology, and production economics of biopharmaceuticals in green plants and at the risks and liabilities of commercializing the technology.

The advantages of plant biofactories relative to other bioproduction technologies have been detailed elsewhere.5-7 Some of the key ones are:

  • Lower capital and operating costs are possible by avoiding a costly bioreactor.
  • Production can be scaled up with little additional investment by adding acreage.
  • Grain that contains protein can be stored for long periods without loss of activity, thereby eliminating cold-storage maintenance facilities.
  • Protein products fold and assemble correctly, just like their counterparts in mammalian cell culture.
  • Plants do not host human or animal pathogens.

PRODUCTION PLATFORMS There are many production platforms available for manufacturing biopharmaceuticals.8 Microbial fermentation using E. coli or yeast and the culturing of animal (mammalian) cells are the most common for producing recombinant proteins. Transgenic plants and animals (including insects) are in development for producing recombinant proteins. The choice of platform for a given protein revolves around such technical issues as oxidative processing, protein folding, multimeric assembly, and glycosylation.

Recombinant proteins produced by mammalian cell culture are delivered glycosylated. (In the process of their biosynthesis, sugar molecules are added that affect their bioactivity.) This also occurs when plant cells produce proteins, but the resulting glycosylation of the protein produced is structurly different, which can lead to a different immune response and therapeutic activity in humans. Efforts are underway to engineer transgenic plants that yield the same glycosylation pattern as from animal cells, but the desired results have not yet been achieved. Plant Research International, in collaboration with Dow Chemical, is developing therapeutic proteins with mammalian-like glycan structures in transgenic plants.9

The choice of platform also can depend on the commercial volumes planned for a given protein. Microbial fermentation is suitable when the need is for annual volumes in the vicinity of multiple metric tons, whereas animal cell culture is more suitable where the volumes are significantly lower than 1,000 kg/yr. Transgenic plants can span both the low and the high end of the volume spectrum, with significant savings from not building the multiple bioreactors that are required for microbial and animal cell culture technology.

lorem ipsum