Genetic modification of crops: From food to pharmaceuticals

Humankind has cultivated the Earth to feed its population for thousands of years. A document dating back to Sumer around 2000 BC contains one of the first records of agricultural cultivation, and in the 19th century, systematic crossbreeding became a means of generating new plants, fruits, and vegetables. The early 20th century saw humans genetically manipulating and then selectively cultivating their agricultural produce. Over the past 20 years, genetic modification techniques have become more sophisticated, expanding the capabilities of the agricultural toolkit and providing a potential avenue toward the defeat of world hunger.

Evolution of AgBiotech
The capabilities of agricultural biotechnology have continued to evolve over the past 20 years. Initially, companies focused on agronomic traits that were beneficial for farmers, such as insect and pesticide resistance (for a review of the techniques, see TCAW, June 1999, p 28). Eventually, scientists started producing fruits and vegetables capable of withstanding extreme conditions, such as droughts or heavy rains. Famous examples of this type of genetically modified (GM) produce are the herbicide-resistant Roundup Ready Soybean, which can be grown in the presence of Monsanto’s herbicide Roundup, and the Bt-toxin engineered plants, resistant to the commonly problematic bacteria Bacillus thuringiensis. Unfortunately, neither plant has been optimized. The stems of Monsanto’s soybean plants split open in very hot weather, reducing yields by as much as 40%. This damage has not been observed in unmodified soybeans under similar conditions. And Bt-toxin transgenic corn met much criticism by the general public when a report revealed that, when force-fed to monarch larvae, milkweed covered with pollen from the transgenic plant killed off large numbers of the larvae. Even though recent studies have disproved the deleterious effects of Bt-toxin corn on larvae (1), the reputation of GM produce has been slow to recover.

In addition to providing protection against fungal pathogens and viruses, as noted in April’s report of transgenic wheat with antifungal properties (2), gene modification can also be used to engineer salt tolerance into plants, such as Arabidopsis thaliana, which are normally salt-sensitive (3). In addition, transgenic tobacco plants that use phosphorus more efficiently than the conventional plant require less fertilization and eliminate the need to overfertilize the land. Under normal agricultural conditions, up to 80% of applied fertilizer is lost because of its immobility and unavailability for plant uptake (4).

Higher-Quality Produce. Among the most visible accomplishments in the industry over the past couple of years have probably been those in the area of producing traits desired by processors, distributors, and consumers. These traits include improved shelf life, nutrient content (e.g., addition of macronutrients and micronutrients, and removal of antinutrient toxins), taste, processibility, reproduction, appearance, and architectureof agricultural produce. The application of agricultural biotechnology can produce novel crop products, such as a canola plant that produces more oil or a potato that produces more starch.

Burdens of the Food Shortage The food security situation is very scary: 800 million people, of which 200 million are children, are malnourished. It’s not only the supply but also the nutritional content of the food that is important. Supplements, due to their cost and inefficient means of distribution, have not really worked. According to the World Health Organization, the most common nutritional deficiencies are in iodine, iron, and vitamin A. Vitamin A deficiency causes more than 1 million childhood deaths every year and blindness among 50,000–100,000 children. The most widespread nutrient deficiency, iron-deficiency anemia, affects an estimated 2 billion people, and 40–50% of children under the age of five are iron deficient. Ironically, more than 60% of the world’s poor live in the agrarian regions of South Asia and Sub-Saharan Africa, where the food supply could potentially meet local needs. With the world population currently at 6 billion and expected to increase by 30% over the next 30 years, the future does not look bright. Of this population increase, 90% will occur where the poorest already live: urban areas and developing countries. Today, there are 1 billion people who live on less than $1 per day and 2–3 billion who live on less than $2 per day. These statistics necessitate global food security with appropriate prices for everybody.

Two new crops have been developed to reduce the incidence of vitamin A deficiencies and related diseases that affect 800 million people worldwide, including vision loss, the inability to absorb proteins, and the loss of immune system functions (see sidebar, “Burdens of the Food Shortage”). In December 1999, Monsanto generated a rapeseed plant that produces -carotene-enriched oil (5). Researchers for the Institute for Plant Sciences of the Swiss Federal Institute of Technology have also developed GM rice that contains sufficient levels of -carotene to meet total vitamin A requirements. Transferring this technology to countries with nutrient-poor diets—because they do not have access to fresh fruits and vegetables and cannot afford supplements, which are expensive and difficult to distribute—could save and improve the lives of millions of people.

Protein Drugs. Using plants as drug factories has been the most recent development in agricultural biotechnology and is driven by the need for therapeutic proteins. Administered to treat cancer, inflammation, and infection, therapeutic proteins are expensive to produce, isolate, and deliver. Moreover, patients with chronic diseases normally require regular doses of these types of therapeutics, necessitating a drug that is cheap and easy to deliver. Agricultural biotechnology answers the needs of the pharmaceutical industry by producing drugs that are safe, efficacious, commercially viable, and scalable with low production costs.

Research at Integrated Protein Technologies (IPT), a unit of Monsanto, focuses on the expression and purification of therapeutic protein drugs from corn seed, rather than the leaves or stalks. IPT collaborates with pharmaceutical companies to produce purified therapeutic proteins, which so far have met acceptable drug substance specifications and are stable over several generations of plant growth, even under less than optimal conditions.

This transgenic corn was created by tissue culture of plant cells. As explained by William S. White of IPT, the IPT scientists force the gene construct—consisting of the gene encoding for the therapeutic protein—into plant cells using an electrical discharge. From the plated cells, or tissue culture, they grow a plantlet, from which the transgenic plant is grown. IPT determines which plants produce the greatest yields of the therapeutic protein and carries those forward by inbreeding. When the scientists compared therapeutic protein produced in corn seed with the same protein produced by Chinese hamster ovary (CHO) cells—a standard cell-line used to produce recombinant human proteins—they found no differences in the protein characterization studies. And the purified proteins also gave similar results in clinical lot specifications, including safety studies and human pharmacokinetics (e.g., clearance and dose-response curves).

However, the commercial advantage of using transgenic corn over laboratory CHO cells is huge: The capacity of corn fields will supply the market, the costs are low, and the purification process is made simpler by avoiding the viral clearance step, because plant viruses do not infect humans and animals. The entire system saves pharmaceutical companies enormous amounts of money, because corn is cheaper to grow than CHO cells.

Edible Vaccines. One of the biggest advantages of agricultural biotechnology is the ability to deliver a new product in an old product with established uses, means of production, and distribution channels. In this way, it bypasses the need to determine a means for delivering the therapeutic—one of the most costly steps in the drug development pathway. Using plants for the production and delivery steps of drugs culminates in the least-expensive source of protein and the infrastucture already exists to sell the product. Most oral vaccines are cost-prohibitive because the U.S. Food and Drug Administration requires stringent purification of the antigen or antibody. Through GM products, vaccines can be delivered in an edible form, and therapeutic proteins can be orally administered or topically applied, avoiding high-production, high-capital costs, and animal or human pathogens.

Last July, Prodigene (College Station, TX) received patents for edible vaccines against both hepatitis B, which infects millions of people worldwide every year, and transmissible gastroenteritis virus (TGEV), a highly infectious disease in swine that is often deadly in young pigs. Transgenic corn producing the antigenic protein for TGEV was fed to mice during the preclinical studies. The vaccine produced a large immune response, and antibodies against the TGEV antigen could be isolated, suggesting that the vaccine survives the gut. Similar results were observed with pigs. Injecting the pathogen for TGEV into pigs vaccinated with the transgenic corn gave a morbidity index reduced by 50% and yielded better results than the commercial drug used to cure the disease. These trials proved to be an innovative method to prevent human and animal disease at a time when the use of antibiotics, due to growing resistance, appears to be a losing battle.

Another advantage of this technology is the production of multiple vaccines in one plant. There are several diseases, such as small pox, polio, and hepatitis, for which a vaccine exists. However, each disease has its own specific vaccine. Producing these vaccines in one transgenic plant would confer vaccination against several different diseases when consumed.

The Second Green Revolution
The original “green revolution” called for increases in agricultural production through the use of high-yield grains, pesticides, and improved farm management in the developing world. This movement was organized three decades ago by the Consultative Group on International Agricultural Research (CGIAR)—presently an informal association of 58 public and private sector member organizations supporting 16 international agricultural research centers—and financed by the public sector. Now there’s a second revolution occurring, only this time it is financed by the private sector. Institutions such as CGIAR and the Agricultural Biotechnology Support Project (ABSP) mediate the transfer of technology from the developed world by connecting its commercial sector to the developing world. Critics of GM foods argue that developing countries, which need GM foods the most, are not benefiting from the technology. While it is true that the technology has been slow to reach developing countries, these U.S. organizations have been established to increase the capacity and develop a policy for the use, management, and commercialization of agricultural biotechnology in developing countries and transition economies.

The ABSP is a consortium of both the private and public sectors and includes Michigan State University, Cornell University, Scripps Research Institute (CA), ICI Seed (now Garst Seed Co. of Slater, IA), Monsanto (St. Louis, MO), Pioneer Hi-Breed International (IA), and DNA Plant Technology (CA). The project (www.iia.msu.edu/absp) addresses the issues of product development, policy development, intellectual property rights, and biosafety to assist developing countries in accessing and using biotechnology in an environmentally and legally responsible manner. By accessing the private sector technologies and expertise, the ABSP educates scientists of developing countries on the techniques they need to carry out their own agricultural biotechnological advances.

With the help of ABSP, Egypt, Indonesia, and Kenya adopted and implemented biosafety regulations and developed and field tested transgenic produce in their respective countries. Ciba-Geigy (now Novartis, Basel, Switzerland) made the Bt-toxin gene available to the International Rice Research Institute to develop GM rice with yields 35% greater than unmodified rice. Tested in China, Korea, and Chile, the GM rice extracts as much as 30% more carbon dioxide from the atmosphere than the control rice, presenting a new means of slowing global warming (6).

Many critics believe that GM foods will stamp out biological diversity and, for example, that corn from Iowa will become the only corn grown all over the world. However, the greatest threat to biodiversity is not monoculture cultivation, but the loss of wildlife habitats due to low-yield agriculture. Increased productivity of cultivated land through GM crops will reduce the necessity of destroying habitats to feed human populations and the reliance on hunting or fishing for food.

Now CGIAR is working toward global food security by increasing agricultural productivity, protecting the environment, and saving biodiversity. Numerous projects and organizations such as CGIAR attempt to increase the productivity of diverse tropical systems by cultivation without hurting the environment. The objectives of the Convention on Biological Diversity (www.biodiv.org) include conserving biodiversity, sustaining the growth and existence of agricultural commodities, and implementing the equitable sharing of benefits from genetic modifications. It also addresses the management of genetic resources, species, and ecosystems in order to maintain biodiversity. The International Plant Protection Convention treaty by the Food and Agriculture Organization of the United Nations outlines and requires biosafety protocols that protect resources for food and agriculture (7).

Calestous Juma, special adviser to the Center for International Diversity and visiting professor at Harvard University from Kenya, has been following the agricultural biotechnology industry for 20 years. He says that Monsanto has educated scientists in Mexico and Kenya about the use of biotechnology when their crops were threatened by native parasites. For example, Monsanto worked with the Kenya Agriculture Research Institute and ABSP to develop a sweet potato resistant to the feathery mottle virus, which can reduce sweet potato production by 20–80% and could not be controlled by traditional breeding methods (8). He adds that GM foods are crucial to sustaining the growth of the world’s human population as well as the survival of people of the African countries.

The Growing Need
The need exists to provide food for the world’s growing population without destroying the environment—producing differently, not less. Food aid and famine relief will not fix the problem over the long term. Attaining food security requires developing the production and cultivation of food in developing nations and other poverty-stricken areas of the world, thus building food self-reliance in those countries. Sustainable development and sustainable food security require the support of the public and private sectors. The world cannot afford to miss the second green revolution.

Thomas Odhiambo, founder and former president of the African Academy of Sciences, argues that Africa, with its extensive collection of plants with known medicinal properties and biodiverse produce, could cash in on its genetic resources through commercialization and agricultural biotechnology (8). However, this possibility will not be realized without the aid of the developed world. Crop production in Africa is the lowest in the world. When compared to the global average of 5.7 tons per acre for the sweet potato and 1.6 tons per acre for maize, Africa only produces 2.4 tons per acre of sweet potato—a staple product—and 0.7 tons per acre of maize. And there is no foreseeable improvement of these yields given the increased introduction of new plant viruses (9). Despite claims that Africa will not benefit from biotechnology and will only become exploited by global corporations, the small-scale farmers in Africa have benefited by using hybrid seeds, and the local farmers, in general, have benefited from using tissue-culture technologies for banana, sugar cane, cassava, and other crops (8).

Just as planting seeds and tilling soil benefited our ancestors, advancements in agricultural biotechnology provide humankind with the ability to feed its young and survive on Earth.

The Continuing Controversy While genetically modified (GM) foods may be a bounty for the undernourished, many oppose the widespread use of GM products. Many believe that GM foods will destroy the environment, threaten biodiversity, and injure humans upon consumption. Others view it primarily as a way for multinational corporations to make money, dominate the agricultural market, and take advantage of poor countries. Some make their arguments on the basis of moral and ethical reasoning, such as the claim that genetically modifying foods damages the “natural order”. The greatest disdain for GM crops comes from Europe—not surprising, given the worries over mad cow disease. Yet, on this side of the Atlantic, vandalism at the University of California and other research sites forced the California state assembly to pass a bill that fines anybody who destroys research crops. It calls for civil penalties of twice the value of the plants, including testing, research, and development costs (10). An interesting statistic from a recent European poll shows that while stories are released every day about the topic, the public continues to feel increasingly insecure and ignorant about GM foods (11, 12). As a result of this growing concern, the European Commission has set up the Biosciences High Level Group to establish a strong relationship between life scientists and European decision makers and to find ways of reconciling the interests of the public, industry, and researchers (12). In addition to keeping the public informed of technological advances, scientists need to continue researching the safety issues involved in growing GM crops.

References

1. Niiler, E. Nat. Biotechnol. 1999, 17, 1154.
2. Clausen, M. Nat. Biotechnol. 2000, 18, 446–449.
3. Apse, M.P. Science 1999, 285, 1256–1258.
4. López-Bucio, J. Nat. Biotechnol. 2000, 18, 450–453.
5. Shewmaker, C. K. The Plant Journal 1999, 20 (4), 401–412.
6. Coghlan, A. New Scientist, April 1, 2000, 19.
7. FAO and the Biosafety Protocol to the Convention on Biological Diversity. Posted July 23, 1998. http://www.fao.org/waicent/faoinfo/sustdev/rtdirect/rtre0034.htm
8. Wambugu, F. Nature 1999, 400, 15–16.
9. How biotechnology could be Africa’s route to riches. Presented at the World Conference on Science, http://helix.nature.com/wcs/a26a.html, Nature, April 29, 1999.
10. Lehrmann, S. Nature 2000, 404, 799.
11. Schiermeier, Q. Nature 2000, 405, 107.
12. McCabe, H. Nature 2000, 405, 106.

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Jennifer B. Miller is an assistant editor with Today’s Chemist at Work. Comments and questions for the author can be addressed to the Editorial Office by e-mail at tcaw@acs.org, by fax at 202-776-8166 or by post at 1155 16th Street, NW; Washington, DC 20036.

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