Mark S. Lesney

In H. G. Well's 1896 novel, The Island of Dr. Moreau, a mad scientist transforms animals into humans using the then-suspect technology of vivisection. Today's often-feared technology is genetic engineering. This form of genetic "vivisection," when applied to crop plants, produces far less sinister-some might even say mundane-effects. But when human genes are spliced into a tobacco plant, and bacterial proteins appear in restaurant food, it is not necessarily less feared (A Worldwide Controversy) than if the creatures of Wells's island had suddenly come to life.

Genetically engineered plants, in their current form, are designed to integrate into, replace, or enhance the standard practices of modern, chemically driven, industrialized agriculture. It is not surprising, then, that the majority of early transgenic modifications, the first phases that have reached the field, are those of the much-studied, single-gene systems upon which many of our agricultural chemicals have been based. These modifications include changing plant responses to a standard battery of weed-controlling herbicides and inducing the production of pesticides, antiviral, and antifungal compounds for the control of insects and diseases.

Other genetic modifications are just becoming a reality. These involve enhancing or changing nutritional status: for example, improving the oil quality or protein content of traditional crop species. Researchers are attempting to increase vitamin content and natural anticancer compounds of crops.

As for the near future, the unique biology of plant productivity is only now beginning to give up its secrets. These modifications will include changing the genes that affect plant growth in a number of ways, including enhanced photosynthetic partitioning; changes in plant anatomy; enhanced heat, drought, and salt resistance; and a host of other complex traits involved in yield.

Not by Bread Alone
But increasing food yield is not the total story. One of the main goals in biotechnology today is to use botanicals to produce industrial products--turn crop plants into chemical "plants." Rather than adapting to relatively standard agricultural practices, genetic engineering of crop plants is also indulging in transmutations far beyond those Dr. Moreau himself might have dreamed--transforming farm vegetables into our lesser kin with the incorporation of human DNA, merging farming with pharmaceuticals. The goal for the future is to harvest potentially hundreds of pounds of human antibodies, hormones, and vaccines in acres of leaves. Similarly, plants are being transformed with the long-term goal of producing industrial chemicalsÑfeedstocks, not food, the goal being literally tons of new plastics, fibers, or designer oils from fields of cotton, canola, or corn.

According to proponents, the prospects for benefitting humanity are almost limitless--potentially solving some of the most critical problems of world agriculture, world ecology, and world health. To critics of genetic engineering, especially those in Europe, it is a suspect new technology that threatens all three.

Defining the Technology
Although there are many variations on a theme, there are two main methods for genetic engineering in plants. The first and older of the technologies uses a bacterial species (Agrobacterium tumafaciens) to carry the gene of interest into the host plant. Agrobacterium, a microorganism that causes plant disease and has been known since the turn of the century, possesses its own genetic engineering system. In nature, the bacteria send their own genes into the infected host and insert them into plant chromosomes. Scientists take advantage of this means of transforming plants by infecting them with laboratory-developed Agrobacterium mutants whose disease-causing genes have been replaced with specifically chosen DNA. In effect, the bacterium then acts as a microengineer, doing all the work.

The second, more modern, means of genetic engineering uses what is known as a "gene gun." It was developed, in part, to allow for transformation of cereal crops, the vast majority of which cannot be infected with Agrobacterium. In using the gene gun, selected DNA coated onto microparticles is fired into living plant cells, either cell cultures or embryos, using an explosive charge. The cells are punctured by the microbullets, the DNA enters the nucleus, and then inserts into the host chromosomes.

In both cases, the cells (either those infected by Agrobacterium or shot by the "biolistic" gun) are regenerated into whole plants, which then carry the new gene, or genes, of interest. These plants are tested, often cloned, and ultimately provide the seed for a new generation of genetically modified (GM)

Identifying and isolating the genes of interest, however, are the hard parts and the source of a modern commercial race among major chemical companies interested in agricultural biotechnology, a race almost identical to that going on in the better-known Human Genome Project. Corporate giants such as Monsanto, DuPont, Dow, and Novartis are staking claims on this genetic future. They are establishing huge research projects, relying on combinatorial chemistry, bioinformatics, and a host of cutting-edge technologies in efforts to take the lead. Their first-generation food products are already on the farm and in the market place.

Novartis recently established a research facility, the Novartis Agricultural Discovery Institute (NADI), a $600 million dollar investment, to take advantage of the new technologies, especially transgenics and genomic science. NADI is directed by Steve Briggs, who received his Ph.D. from Michigan State University in plant pathology and was a longtime researcher at both Pioneer Hi-Bred (Des Moines, IA) and Cold Spring Harbor Laboratory (Cold Spring Harbor, NY, one of the premier molecular biology research facilities in the United States). According to Briggs, in the realm of agricultural biotechnology, "Everyone wants to develop new targets or new chemistries."

New targets represent different sites of action for agricultural chemicals, for example, enzymes or receptors that can bind to new herbicides or pesticides. New targets are important, because weeds and pests mutate and become resistant over time by developing resistant target sites. This necessitates a constant influx of new targets to keep ahead of farm pests.

"New chemistries" refers to different chemical products that have the same target sites, with perhaps slightly different effectiveness in dosage or activity (consider the numerous aspirin substitutes as an example--all of which have the same target site, but differ slightly in their effectiveness, more so in their chemical structure). The development of new chemistries allows a company to climb on a particular biochemical bandwagon without fear that its product will be cited for patent or trade infringement.

Although much of this research is dedicated toward putting plants in the field, where the production or testing of specific chemical products is the desired end, laboratory or factory fermentation systems using plant or bacterial cells can sometimes yield optimal results.

Herbicides and Pesticides
In 1998, according to Robert Horsch, vice president and manager at Monsanto, more than 65 million acres of genetically engineered crops were expected to be grown around the world, mostly in the United States (Pesticide & Toxic Chemical News, May 14, 1998). The vast majority of these GM crops were engineered to be herbicide-resistant. Fully 30% of the United States soybean acreage consisted of "Roundup Ready" soybeans, engineered to be resistant to Monsanto's systemic herbicide glyphosate, first developed in 1974. "Roundup Ready" corn, canola, and cotton are routinely planted, and a wide variety of other "Roundup Ready" crops are being developed. Other companies are producing their own varieties of glyphosate-resistant crops, as well as crops resistant to a variety of other herbicides, including sulfonylurea, glufosinate, and bromoxynil. The majority of these resistance genes are from bacteria; they code for enzymes capable of breaking down the particular herbicide into nontoxic components before the treated plant is damaged.

After herbicide resistance, resistance to insects, especially using the insect-resistant Bt toxin gene, is the next largest application of GM crops. Bt toxin is a protein produced by the bacteria Bacillus thuringiensis. The compound is uniformly nontoxic to all but a few species of insects (happily, some of the most destructive). The toxin is often used in organic farming as a "natural" pesticide, in which case dead bacteria are sprayed on the crops to provide protection.

Despite the fact that Bt-toxin engineered plants are considered by most as safer to consumers than synthetic pesticides and generally provide excellent protection, widespread fear of this technology exists in the world community. For the most part, it is fear of genetic engineering per se; but there are more coherent fears among the organic farming community that excessive use of Bt-toxin producing plants (as with excessive use of any pesticide) will lead to insects developing resistance to the toxin in the field. Currently, studies are under way to develop means of managing the use of Bt-toxin engineered crops to prevent the development of pest resistance. A newly reported study by Cornell University researchers showed that Bt-containing corn pollen was lethal to monarch butterfly larvae in test feedings, increasing the controversy over this technology.

Disease Resistance
A unique form of genetic engineering for protecting plants against virus diseases uses the principle of "set a thief to catch a thief." Plant viruses (like animal viruses) consist of nucleic acids surrounded by a protective protein (or protein plus lipid) coat. In order to infect a cell, the nucleic acid must "uncoat" (break free of this protein shell) and act as a template for the synthesis of more virus nucleic acids. After much new virus DNA or RNA is produced, the virus signals the production of massive amounts of coat protein to encapsulate the newly produced viral nucleic acid. Thus, new particles form, and the next generation of virus is ready to infect more cells. To engineer resistance, scientists trick the system by incorporating the gene for the specific virus coat protein into the DNA of the host plant. When the identical invading virus infects and uncoats within the cell, it is confronted by pre-existing coat protein that immediately attaches and partially re-coats the nucleic acid, preventing it from synthesizing viral progeny. Since one virus's coat protein does not protect against unrelated viruses, often two or more different coat protein genes are engineered into crop plants such as squash or potato to protect against a battery of possible threats. More recently, transgenic plants have been produced that are resistant to a wide variety of bacterial and fungal diseases. These forms of resistance follow a number of chemical strategies, including the use of genes for bacterial toxin tolerance, antimicrobial peptides, and other defense-related proteins that tend to act as fungicidal compounds.

Nutriceuticals and Pharmaceuticals
Genetically engineering foods with a palette of antioxidants and anticancer compounds, as well as increasing vitamin and other nutritional supplements, are part of the "nutriceutical" movement: using food as medicine. There are numerous players in this plant genetic engineering sweepstakes, but the major competitors are Monsanto, Novartis, and most recently DuPont, with its affiliation with and impending purchase of Pioneer Hi-Bred. It is no accident that these main players are the biggest of the chemical companies that have dedicated themselves to expansion into the life sciences. The fusion of food and pharmaceuticals and the transdisciplinary aspects of biotechnology as a whole make such a move perhaps the most logical strategy for the huge life sciences conglomerates. According to Steve Briggs of NADI, an ideal potential product, combining the entire life sciences apparatus including the pharmaceutical, agricultural, and food marketing divisions of a company such as Novartis, would be "a new breakfast cereal that helps to prevent cancer."

As part of this push for "medicinal plants," in the metaphorical garden of Dr. Moreau, human genes have been fused to plant chromosomes to yield large quantities of experimental biopharmaceuticals. Tobacco and potatoes have been produced that yield human serum albumin. Oilseed rape and Arabidopsis have been developed that yield the human neurotransmitter Leu-enkephalin as a storage protein in seeds. Also being developed are "plantibodies"--human antibodies produced in plant tissues. Plants have been engineered to produce vaccines against infectious diseases such as cholera and rabies, and against autoimmune diseases such as diabetes. Recently, in an NIH funded study conducted by Stanford University and Biosource Technologies, anticancer antibodies (from mice) were successfully produced in tobacco plants using a genetically engineered virus. Eighty percent of mice that received the plant-derived vaccine survived non-Hodgkins lymphoma, while all control mice died three weeks after becoming diseased. Biosource plans to adapt the approach to humans and hopes to begin clinical trials within a year.

Novartis, Monsanto, DuPont, and a host of other companies and world organizations (such as the World Health Organization) are heavily funding research in the field of plant vaccines. Developing "edible vaccines" for mass vaccinations in developing nations is only one of the many prospects cited for using GM plants to benefit human health.

Chemical "Plants"
Ultimately, if there is a unifying motif plotting out the hedgerows in the garden of Dr. Moreau, it is the transformation of crop plants to chemical "plants." Biology becomes chemistry as scientists make specific gene alterations to transform botanicals into production facilities for designer foods, pesticides, antimicrobial agents, herbicide protectants, chemical feedstocks, human genes, and pharmaceuticals. Opponents of GM foods include the United Kingdom's Prince Charles, who was recently quoted as calling genetic engineering "playing God." Others see it as simply the perfect means of "naturalizing" industrial agriculture and the only logical way of feeding and medicating an overpopulated world.