Genetic Engineering and Biotechnology
Genetic Engineering and Biotechnology
Genetic Engineering and Biotechnology
Around the world scientists are working to develop new varieties of crops that can resist pests, use less water, and generally thrive in less than optimal growing conditions. Hand in hand, with scientific research, countries must adopt policies that will allow their farmers to take advantage of new products being developed through research. Government policies should encourage the safe use of new technology, not cause farmers and consumers to fear it.
—Ann M. Veneman, U.S. Secretary of Agriculture, October 2002
The dawn of the new millennium saw explosive advances in biotechnology. Technological breakthroughs offered scientists and physicians unprecedented opportunities to develop previously inconceivable solutions to pressing problems in agriculture, environmental science, and medicine. Simultaneously, researchers, politicians, ethicists, theologians, and the public were challenged to assess, analyze, and determine the feasibility of using new biotechnology in view of the opportunities, possibilities, risks, benefits, and diverse viewpoints about the safe, effective, and ethical applications of genetic research.
This chapter describes several examples of existing and proposed applications of genetic research and biotechnology, including uses that address such pressing problems as environmental pollution and world hunger as well as the role of genetic engineering in developing lifesaving medical therapeutics. It also considers industry and consumer viewpoints as well as recommendations scientists, policy makers, and ethicists have made regarding the wise, judicious, and equitable use of these technologies.
AGRICULTURAL APPLICATIONS OF GENETIC ENGINEERING
Genetically modified (GM) or transgenic crops (sometimes also called genetically engineered [GE] crops) contain one or more genes that have been artificially inserted instead of received through pollination (fertilization by the transfer of pollen from an anther to a stigma of a plant). The inserted gene sequence, called the transgene, may be introduced to produce different results—either to overexpress or silence (direct a gene not to synthesize a specific protein) an existing plant gene, and it may come from another unrelated plant or from a completely different species. Transgenics is the science of inserting a foreign gene into an organism's genome. The ultimate product of this technology is a transgenic organism.
For example, the transgenic corn that produces its own insecticide contains a gene from a bacterium, and Macintosh apples with a gene from a moth that encodes an antimicrobial protein are resistant to fire blight, a bacterial infection. Although all crops have been genetically modified from their original wild state by domestication, selection, and controlled breeding over long periods of time, the terms transgenic crops and GM crops usually refer to plants with transgenes (inserted gene sequences).
Genes are introduced into a crop plant to make it as useful and productive as possible by acting to protect the plant, improve the harvest, or enable the plant to perform a new function or acquire a new trait. Specific objectives of genetically modifying a plant include increasing its yield, improving its quality, or enhancing its resistance to pests or disease and its tolerance for heat, cold, or drought. Some of the GM traits that have been introduced into food crops are enhanced flavor, slowed ripening, reduced reliance on fertilizer, self-generating insecticide, and added nutrients. Examples of transgenic food crops include frost-resistant strawberries and tomatoes; slow-ripening bananas, melons, and pineapples; and insect-resistant corn.
Transgenic technology enables plant breeders to bring together in one plant useful genes from a wide range of living sources, not just from within the crop species or from closely related plants. It provides reliable means for identifying and isolating genes that control specific characteristics in one kind of organism and enables researchers to move copies of these genes into another organism that will then develop the chosen characteristics. This technology gives plant breeders the ability to generate more useful and productive crop varieties containing new combinations of genes, and it significantly expands the range of trait manipulation and enhancements well beyond the limitations of traditional cross-pollination and selection techniques.
Although genetic modification of plants generates the same types of changes produced by conventional agricultural techniques, because it precisely alters a single gene, the results are often more rapid and more complete. Traditional breeding techniques may require an entire generation or more to introduce or remove a single gene, and using conventional methods for breeding a polygenic trait into crops with multiyear generations could take several decades.
Creating Transgenic Crops
The first step in creating a transgenic plant is locating genes with the traits that growers, marketers, and consumers consider important. These are usually genes that increase productivity and yield and improve resistance to environmental stresses such as frost, heat, salt, and insects. Identifying the gene associated with a specific trait is necessary but not sufficient; researchers must determine how the gene is regulated, its other influences on the plant, and its interactions with other genes to express or silence various traits. Researchers must then isolate and clone the gene to have sufficient quantities to modify. Establishing the genomic sequence, called plant genomics, and the functions of genes of the most important crops is a priority of public- and private-sector plant genomic research projects.
Currently, most genes introduced into plants come from bacteria; however, increasing understanding of plant genomics is anticipated to permit greater use of plant-derived genes to genetically engineer crops. In 2000 the first entire plant genome Arabidopsis thaliana was sequenced, which provided researchers with new insight into the genes that control specific traits in many other agricultural plants. There are several approaches to introducing genes into plant cells: vector- or carrier-mediated transformation, particle-mediated transformation, and direct deoxyribonucleic acid (DNA) insertion.
Vector-mediated transformation involves infecting plant cells with a virus or bacterium that during the process of infection inserts foreign DNA into the plant cell. The most convenient is through the soil bacterium Agrobacterium tumefaciens, which infects tomatoes, potatoes, cotton, and soybeans. This bacterium attacks cells by inserting its own DNA. When genes are added to the bacterium, they are transferred to the plant cell along with the other DNA.
Particle-mediated transformation involves gene transfer using a special particle tool known as a gene gun, which shoots tiny metal particles that contain DNA into the cell.
To perform direct DNA insertion or electroporation, cells are immersed in the DNA and electrically shocked to stimulate DNA uptake. The cell wall then opens for less than a second, allowing DNA to seep into the cell. (See Figure 9.1.) Following gene insertion, the cell incorporates the foreign DNA into its own chromosomes and undergoes normal cell division. The new cells ultimately form the organs and tissues of the "regenerated" plant. To ensure the systematic sequence of these steps, other genes may be added along with the gene associated with the desired trait. These helper genes are called promoters. They encourage growth of cells that have integrated the inserted DNA, provide resistance to stresses (such as toxins present in the medium used to grow the cells), and may help regulate the functions of the gene linked to the desired trait.
To be certain that the new genes are in the organism, marker genes are sometimes inserted along with the gene for the desired trait. One common marker gene confers resistance to the antibiotic kanamycin. When this gene is used as a marker, investigators are able to confirm that the transfer was successful when the organism resists the antibiotic. The ultimate success of gene insertion is measured by whether the inserted gene functions properly by expressing, amplifying, or silencing the desired trait.
Are GM Crops Helpful or Harmful?
In Genes Are Gems: Reporting Agri-Biotechnology (December 2006, http://www.icrisat.org/Publications/ Genes_Gems.htm), the International Crops Research Institute for the Semi-Arid Tropics (ICRISAT), an international nonprofit and nonpartisan organization for science-based agricultural development, notes that genetic modification of crops has proven to be the most rapidly adopted technology in the world. Figure 9.2 shows the widespread adoption of GM crops by U.S. farmers since their introduction in 1996. ICRISAT contends that transgenic crops benefit developing countries by enabling greater use of crop area, increasing the variety of crops that may be grown, affording better protection of crops from disease and pests, and improving harvest yields to deliver more food and nutrition to people in need. ICRISAT also cites environmental benefits of transgenic organisms. These include a 30% to 40% reduction in the use of herbicides and as much as an 80% reduction in the use of insecticides, as well as a reduction in environmental pollution and harmful emissions resulting from the production of chemical pesticides.
ICRISAT also commends the use of transgenic organisms, specifically transgenic microbes (microorganisms) for purposes of bioremediation (environmental cleanup). Researchers have harnessed genes that code for proteins that naturally degrade toxic wastes such as chlorinated pesticides, naphthalene, toluene, and some hydrocarbons. Efforts are under way to combine genes from several microbes to create a single, multipurpose supermicrobe that is capable of effectively combating several contaminants.
Opposition to GM crops takes several forms. Bioeth-icists who contend that freedom of choice is a central tenet of ethical science oppose what they deem to be interference with other forms of life. Environmentalists argue that transgenic technology poses the risk of altering delicately balanced ecosystems—biological communities and their environments—and causing unintended harm to other organisms. They are concerned that transgenic crops will replace traditional crop varieties, especially in developing countries, causing loss of biological diversity.
In "Turning Genetically Engineered Trees into Toxic Avengers" (New York Times, August 3, 2004), Hillary Resner reports on one controversial example: the relatively recent use of GE forest trees to change the trees' reproductive cycles, growth rates, and chemical composition so they can resist disease and absorb toxins such as mercury from soil and convert it into a less toxic form that is safe for release into the air. The aptly named "toxic-avenger trees" remove heavy metals from contaminated soils in places where other approaches to environmental cleanup are costly and labor intensive. Environmentalists are concerned, however, about the use of GE trees because they are not convinced that relocating heavy metals from the soil to the air is worth the risk of the altered genes migrating via the tree pollen to natural populations, potentially damaging existing ecosystems.
Pests may develop resistance to transgenics in much the same way certain bacteria have become resistant to the antibiotics that once effectively eradicated them. Critics also decry the infiltration of transgenic crops beyond their intended areas and fear inadvertent gene transfer to species not targeted for transgenics. Rex Dalton, in "Transgenic Corn Found Growing in Mexico" (Nature, September 27, 2001), notes that transgenic corn has been found in a remote mountain region of Mexico, and K. S. Jayaraman, in "Illicit GM Cotton Sparks Corporate Fury" (Nature, October 11, 2001), reports that transgenic cotton has been discovered in India. One way unintended gene exchange between plants may occur is through pollen. Recommendations for preventing unintended gene exchange include creation of transgenic plants that do not produce pollen or of pollen that does not contain introduced genes and establishment of buffer zones around fields of transgenic crops.
According to Graham Brookes and Peter Barfoot, in GM Crops: The First Ten Years—Global Socio-economic and Environmental Impacts (2006, http://www.isaaa.org/Resources/Publications/briefs/36/download/isaaa-brief-36-2006.pdf), transgenic crops are big business. Brookes and Barfoot estimate that worldwide, the net economic benefit to biotech crop farmers in 2005 was $5.6 billion, $6.15 billion in 2006, and was projected to approach $7 billion in 2007. Opponents fear consequences such as economic concentration—the potential for companies that grow transgenic crops to drive out smaller farmers and create monopolies. In 2006 the techniques to genetically modify seeds, as well as the seeds themselves, were held by a few multinational corporations. Related issues are patent infringement and intellectual property rights for transgenic crops and absence of regulatory oversight. Patents may increase the price of seeds and effectively exclude small farmers from growing their crops.
Health risks also concern those who object to widespread acceptance of transgenic crops. They call for the labeling of GM food to alert consumers that they are purchasing foods that contain GM organisms. As of 2006 more than half of all processed foods sold in the United States contained GM organisms, and there was no requirement that these foods be identified as transgenic or GM. Opponents cite safety issues such as possible allergies to transgenic foods and products because some trans-genes may pose health risks when consumed. For example, a plan to insert a Brazil nut protein gene into soybeans was halted when early tests indicated that people allergic to nuts suffered reactions when they consumed the modified soy products. Critics also fear that there will be unforeseen and potentially harmful long-term adverse health consequences resulting from the consumption of foods containing foreign genes.
One of the most controversial developments in agricultural bioengineering is called terminator technology, which is designed to genetically switch off a plant's ability to germinate a second time. Traditionally, farmers save seeds for the next harvest; however, the use of terminator technology effectively prevents this practice, forcing them to purchase a fresh supply of seeds each year.
The advocates of terminator technology are generally corporations and the organizations that represent them. They contend that the practice protects corporations from corrupt farmers. Controlling seed germination helps prevent growers from pirating the corporations' licensed or patented technology. If crops remained fertile, there is a chance that farmers could use any saved transgenic seed from a previous season. This would result in reduced profits for the companies that own the patents.
Opponents of terminator technology believe it threatens the livelihood of farmers in developing countries such as India, where many poorer farmers have been unable to compete and some have been forced out of business. Opponents considered it a victory when Monsanto, a major investor in this technology, decided not to market terminator technology. In Terminator Technology—Five Years Later (May-June 2003, http://www.cbdcprogram.org/final/issues/termcom79eng.pdf), the ETC Group, an organization that focuses on conservation and sustainable advancement of cultural and ecological diversity and human rights, notes that besides Monsanto, terminator patents are held by Delta and Pine Land, the U.S. Department of Agriculture, Syngenta, DuPont, and BASF, as well as the universities Purdue, Iowa State, and Cornell. According to the Pesticide Action Network North America, in "Corporate Greed t Destructive Technology = Increased Risk of World Hunger: Terminator Seed Moratorium at Risk" (January 10, 2006, http://www.panna.org/resources/panups/panup20060110.dv.html), Syngenta owns or has applied for eleven terminator patents—more than any other company—but the company has stated publicly that it will not commercialize the trait.
Still, even without terminator technology, under patent laws in Canada, the United States, and many other industrialized nations, it is illegal for farmers to reuse patented seed or to grow Monsanto's GM seed without signing a licensing agreement. This has the same effect on poor farmers as terminator technology; it renders them unable to compete. Jeffrey L. Fox reports in "Canadian Farmer Found Guilty of Monsanto Canola Patent Infringement" (Nature Biotechnology, May 2001) that a Canadian farmer was found guilty of growing patented seeds, even though he did it inadvertently. Pollen from the patented canola seeds at a nearby farm had pollinated his plants, and he was ordered to pay Monsanto for licensing and profit from the seeds.
In Monsanto vs. U.S. Farmers (January 13, 2005, http://www.centerforfoodsafety.org/pubs/CFSMOnsantovs FarmerReport1.13.05.pdf), the Center for Food Safety (CFS), a nonprofit public interest and environmental advocacy organization, reviewed Monsanto's legal actions against U.S. farmers. The report finds that Monsanto engaged in investigations of farmers, out-of-court settlements, and litigation against farmers allegedly in breach of contract or engaged in patent infringement. The report documents 90 Monsanto lawsuits in 25 states that involve 147 farmers and 39 small businesses or farm companies. Monsanto has an annual budget of $10 million and seventy-five employees exclusively devoted to investigating and taking action against farmers.
According to the CFS, by 2005 the largest judgment in favor of Monsanto was more than $3 million, and the total recorded judgments granted to Monsanto was more than $15 million. Farmers paid a mean of $412,259 for cases with recorded judgments. Some farmers were even forced to pay Monsanto's costs while they were under investigation.
In the CFS press release "Monsanto Assault on U.S. Farmers Detailed in New Report" (January 13, 2005, http://www.centerforfoodsafety.org:80/press_release1.13.05.cfm), Andrew Kimbrell, the executive director of the CFS, asserts that "these lawsuits and settlements are nothing less than corporate extortion of American farmers. Monsanto is polluting American farms with its genetically engineered crops, not properly informing farmers about these altered seeds, and then profiting from its own irresponsibility and negligence by suing innocent farmers. We are committed to stopping this corporate persecution of our farmers in its tracks."
On September 29, 2006, the Public Patent Foundation (http://www.pubpat.org/monsantofiled.htm), a not-for-profit legal services organization that represents the public's interests against the harms caused by the patent system, filed requests with the U.S. Patent and Trademark Office to revoke four patents owned by Monsanto "that the agricultural giant is using to harass, intimidate, sue—and in some cases literally bankrupt—American farmers."
In 2004 the biotechnology industry introduced what it calls exorcist technology to some GE crops. This new technology introduces chemical inducers that shed their foreign DNA before they are harvested. The industry sees this technology as an effective way to counter anti-GE critics because the harvested crops will not contain foreign DNA. However, detractors assert that the intent of exorcist technology is to shift the responsibility from the biotechnology industry to farmers and society. If gene flow poses a problem, farmers will have to use chemical inducers to remove the offensive transgenes.
U.S. BIOTECHNOLOGY REGULATORY SYSTEM
The U.S. government operates a rigorous, coordinated regulatory process for determining the safety of agricultural products of modern biotechnology. The process ensures that all biotechnology products that are commercially grown, processed, sold, and consumed are as safe as their conventional counterparts. In A Description of the U.S. Food Safety System (March 3, 2000, http://www.fsis.usda.gov/OA/codex/system.htm), the U.S. Department of Agriculture (USDA) notes that the government regulatory system is "transparent, predictable, open to public comment, and based on sound science." Within the USDA the agencies responsible for regulation are the Animal and Plant Health Inspection Service (APHIS) and the Food and Drug Administration (FDA). The Environmental Protection Agency (EPA)—which is not a part of the USDA—also plays a role in regulating biotechnology. Policies, processes, and regulations are continuously reviewed, evaluated, and, when necessary, revised to meet the challenges of this evolving technology.
APHIS oversees U.S. agriculture, protecting against pests and diseases. It is the lead agency regulating the safe field-testing of biotechnology-derived new plant varieties and certain microorganisms. As such, APHIS grants approval and licenses for veterinary biological substances including animal vaccines that may be the products of biotechnology.
The EPA approves new herbicidal and pesticidal substances. It issues permits for testing herbicides and biotechnology-derived plants containing new pesticides. When the EPA makes a determination about whether to register a new pesticide, it considers human safety, environmental impact, its effectiveness on the target pest, and any consequences for other, nontarget species. The EPA establishes and enforces the guidelines that ensure safe use of GE products classified as pesticides.
The FDA ensures that foods derived from new bio-engineered plant varieties are safe and nutritious—they must meet or exceed the same high standards of safety applied to any food product. The FDA is also responsible for issuing and enforcing regulations to ensure that all food and feed labels, including those related to biotechnology, are truthful and do not mislead consumers. Table 9.1 lists genes, gene fragments, and GM products (with their intended effects) that were submitted to the FDA from 2002 to mid-2005.
Institute of Medicine Report
In July 2004 the Institute of Medicine (IOM) of the National Academy of Sciences, an organization created by the U.S. Congress in 1863 to advise the government about scientific and technical matters, published The Safety of Genetically Engineered Foods: Approaches to Assessing Unintended Health Effects (http://www.nap.edu/books/0309092094/html/). The USDA, the FDA, and the EPA commissioned the National Academy of Sciences to assess the potential for adverse health effects from GE foods compared with foods altered in other ways, and to provide guidance on how to identify and evaluate the likelihood of those effects. Even though adverse health effects from genetic engineering have not been detected in the human population, the technique is relatively new and concerns about its safety remain.
The IOM report urged federal agencies to assess the safety of genetically altered foods on a case-by-case basis to determine whether unintended changes in their composition have the potential to adversely affect human health and called for greater scrutiny of foods containing new compounds or unusual amounts of naturally occurring substances.
The report presented a framework to guide federal agencies in selecting the course and intensity of safety assessment. A new GM food whose composition is similar to a commonly used conventional version may warrant little or no additional safety evaluation. If, however, an unknown substance has been detected in a food, more detailed analyses should be conducted to determine whether an allergen or toxin may be present. Similarly, foods with nutrient levels that fall outside the normal range should be assessed for their potential impact on consumers' diets and health.
The IOM was also charged with examining the safety of foods from cloned animals. The report recommended that the safety evaluation of these foods should focus on the product itself rather than on the process used to create it, and advised that the evaluations compare foods from cloned animals with comparable food products from noncloned animals. Although there is no evidence that foods from cloned animals pose an increased risk to consumers, the report cautioned that cloned animals engineered to produce pharmaceuticals should not be permitted to enter the food chain.
Criticisms of the U.S. Regulatory Approach
Opponents of GM foods do not believe there are sufficient government regulations in place to control U.S. production and distribution of these foods. They argue that there has not been enough research or long-term experience with these foods, and as a result the health consequences of growing and eating such foods as well as the environmental impact are not yet known. Proponents claim the benefits of transgenic foods—improved flavor, increased nutritional value, longer shelf life, and greater yields—surpass any potential risks. They also discount the health risks, observing that nearly half the soybean crop and a quarter of all corn grown in the United States consists of transgenic varieties, meaning that Americans have been consuming transgenic food products for years and, as of early 2007, there have been no reports of adverse health effects as a result.
Since the late 1990s there have been protests staged to oppose the widespread use and consumption of GM foods as well as attacks on facilities conducting research on transgenic crops and companies marketing GM products. Protesters have dubbed the transgenic crops "Frank-enfoods," likening them to Frankenstein's monster, a man-made freak created through science. Greenpeace, an organization that opposes the creation of GM foods, and other activists staged a historic protest at the World Trade Organization (WTO) meeting in Seattle on November 30, 1999. Greenpeace also hung an anti-GM banner on Kellogg's Cereal City museum in Michigan in 2000. It hopes that such actions will move U.S. lawmakers to require labeling of transgenic foods. Greenpeace is inspired by the example of European consumers, who demanded and have been granted product labeling that enables them to choose whether to purchase and consume GM foods. During 2006 Greenpeace organized protests in cornfields in Spain, the Philippines, and Mexico to protect native corn crops from contamination from genetically engineered strains. The organization also requested an inquiry into the death of cattle in India that had grazed on GM crops ("Greenpeace Opposes GM Crops," Tribune News Service, http://www.tribuneindia.com/2006/20060614/nation.htm#15). Greenpeace is calling for a worldwide ban on the release of any transgenic crop or seed and for governments to halt both commercial and experimental growing of genetically engineered crops.
On August 10, 2006, a federal court issued in Center for Food Safety et al. v. Johanns et al. the first ruling ever on biopharming, the controversial practice of genetically
|Bioengineered foods approved by the U.S. Food and Drug Administration, 2002–05|
|[By year and file number (BNF number)]|
|Food||Gene, gene product, or gene fragment||Source||Intended effect||Designation||FDA letter||FDA memo|
|Submissions completed in 2005|
|BNF No. 98, submitted May 27, 2004 by Monsanto Company, for use in human food and animal feed|
|Cotton||5-enolpyruvylshikimate-3-phosphate synthase (EPSPS)||Agrobacterium sp. strain CP4||Tolerance to the herbicide glyphosate||MON-88913-8||7-Mar-05||7-Mar-05|
|BNF No. 97, submitted March 30, 2004 by Monsanto Company, for use in human food and animal feed|
|Corn||Cry3Bb1; 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS)||Bacillus thuringiensis subsp. kumamotoensis; Agrobacterium sp. strain CP4||Resistance to corn rootworm; Tolerance to the herbicide glyphosate||MON 88017||12-Jan-05||5-Jan-05|
|BNF No. 94, submitted October 27, 2003 by Syngenta Seeds, Inc., for use in human food and animal feed|
|Cotton||VIP3A protein||B. thuringiensis, strain AB88||Resistance to lepidopteran insects||Transformation event COT102||8-Jul-05||7-Jul-05|
|BNF No. 87, submitted August 10, 2004 by Monsanto Company, for use in human food and animal feed|
|Corn||Dihydrodipicolinate synthase (cDHDPS)||Corynebacterium glutamicum||Increase lysine level for use in animal feed||REN∅∅∅38-3 or maize event LY038||5-Oct-05||30-Sep-05|
|Submissions completed in 2004|
|BNF No. 93, submitted June 30, 2003 by Mycogen Seeds c/o Dow AgroSciences LLC, for use in human food and animal feed|
|Corn||Cry1F; phosphinothricin acetyltransferase (PAT)||Bacillus thuringiensis subsp. aizawai; Streptomyces hygroscopicus||Resistance to certain lepidopteran insects; Tolerance to the herbicide glufosinate-ammonium||Event TC6275||30-Jun-04||28-Jun-04|
|BNF No. 92, submitted March 18, 2003 by Mycogen Seeds c/o Dow AgroSciences LLC, for use in human food and animal feed|
|Cotton||Cry1Ac; phosphinothricin acetyltransferase (PAT)||Bacillus thuringiensis subsp. kurstaki; Streptomyces viridochromogenes||Resistance to certain lepidopteran insects; Tolerance to the herbicide glufosinate-ammonium||Event 3006-210-23||3-Aug-04||28-Jul-04|
|BNF No. 90, submitted April 16, 2003 by Monsanto Company and KWS SAAT AG, for use in human food and animal feed|
|Sugar beet||5-Enolpyruvylshikimate-3-phosphate synthase (EPSPS)||Agrobacterium sp. strain CP4||Tolerance to the herbicide glyphosate (N-phosphonomethyl glycine)||Event H7-1||17-Aug-04||7-Aug-04|
|BNF No. 85, submitted March 17, 2003 by Mycogen Seeds c/o Dow AgroSciences LLC, for use in human food and animal feed|
|Cotton||Cry1F; phosphinothricin acetyltransferase (PAT)||Bacillus thuringiensis subsp. aizawai; Streptomyces viridochromogenes||Resistance to lepidopteran insects; Tolerance to the herbicide glufosinate-ammonium||Event 281-24-236||10-May-04||5-May-04|
|Bioengineered foods approved by the U.S. Food and Drug Administration, 2002–05 [continued]|
|[By year and file number (BNF number)]|
|Food||Gene, gene product, or gene fragment||Source||Intended effect||Designation||FDA letter||FDA memo|
|Source: Adapted from "Completed Submissions Organized by Year and File Number (BNF No.)," in List of Completed Consultations on Bioengineered Foods, U.S. Food and Drug Administration, Center for Food Safety and Applied Nutrition, Office of Food Additive Safety, 2005, http://www.cfsan.fda.gov/∼lrd/biocon.html#list (accessed November 7, 2006)|
|BNF No. 84, submitted October 6, 2003 by Monsanto Company and Forage Genetics, for use in human food and animal feed|
|Alfalfa||5-enolpyruvylshikimate-3-phosphate synthase (EPSPS)||Agrobacterium sp. strain CP4||Tolerance to the herbicide glyphosate||Event J101 and event J163||10-Dec-04||8-Dec-04|
|BNF No. 81, submitted December 11, 2003 by Mycogen Seeds c/o Dow AgroSciences LLC, for use in human food and animal feed|
|Corn||Cry34Ab1, Cry35Ab1, phosphinothricin acetyltransferase (PAT)||Bacillus thuringiensis strain PS149B1; Streptomyces viridochromogenes||Resistance to coleopteran insects; Tolerance to the herbicide glufosinate-ammonium||DAS-59122-7||4-Oct-04||28-Sep-04|
|BNF No. 80, submitted June 28, 2002 by Monsanto Company, for use in human food and animal feed|
|Wheat||5-enolpyruvylshikimate-3-phosphate synthase (EPSPS)||Agrobacterium sp. strain CP4||Tolerance to the herbicide glyphosate (N-phosphonomethyl-glycine)||MON 71800||22-Jul-04||22-Jul-04|
|Submissions completed in 2003|
|BNF No. 86, submitted August 30, 2002 by Bayer CropScience USA LP, for use in human food and animal feed|
|Cotton||phosphinothricin-N-acetyltransferase (PAT)||Streptomyces hygroscopicus||Tolerance to the herbicide glufosinate-ammonium||LLCotton25||2-Apr-03||5-Jun-03|
|BNF No. 79, submitted September 13, 2002 by Monsanto and The Scotts Company, for use in animal feed|
|Creeping bentgrass||5-Enolpyruvylshikimate-3-phosphate synthase (EPSPS)||Agrobacterium sp. strain CP4||Tolerance to the herbicide glyphosate||Event ASR368||23-Sep-03||11-Sep-03|
|Submissions completed in 2002|
|BNF No. 77, submitted April 30, 2001 by Monsanto Company, for use in human food and animal feed|
|Oilseed rape (canola)||5-Enolpyruvylshikimate-3-phosphate synthase (EPSPS); Glyphosate oxidoreductase (GOX)||Agrobacterium sp. strain CP4, ochrobactrum anthropi strain LBAA||Tolerance to the herbicide glyphosate||GT200||5-Sep-02||4-Sep-02|
|BNF No. 74, submitted June 29, 2000 by Monsanto Company, for use in human food and animal feed|
|Cotton||Cry2ab; Cry1ac||Bacillus thuringiensis subsp. kumamotoensis||Resistance to lepidopteran insects||15985||18-Jul-02||16-Jul-02|
altering food crops to produce experimental drugs and industrial compounds. The court ruled that the U.S. Department of Agriculture violated the Endangered Species Act when it permitted the cultivation of drug-producing, GE crops in Hawaii. That same month the CFS reported in the press release "Unapproved, Genetically Engineered Rice Found in Food Supply" (August 18, 2006, http://www.centerforfoodsafety.org/GE_Rice_8.18.06.cfm) that the USDA announced that an unapproved, GE rice was found contaminating commercial long-grain rice supplies. The presence of rice, which was genetically altered to survive application of the powerful herbicide glufosinate, in the food supply is illegal because it has not undergone USDA review for potential environmental impacts nor did the FDA review it for possible harm to human health.
On September 14, 2006, the CFS filed a petition with the USDA that sought to prevent after-the-fact approval of an illegal GE rice found in the world's food supply the previous month (http://www.centerforfoodsafety.org/PR9_14_06.cfm). On October 12, 2006, the CFS and reproductive rights, animal welfare, and consumer protection organizations filed a petition with the FDA calling for a moratorium on the introduction of food products from cloned animals (http://www.center forfoodsafety.org/cloning_petitionPR10.12.06.cfm). The petition also asked the FDA to establish mandatory rules for premarket food safety and environmental review of cloned foods.
U.S. Consumers' Opinions Vary
In 2005 the Gallup Organization found that only 9% of Americans were following the news about biotechnology "very closely." (See Figure 9.3.) A full 25% of Americans admitted that they were not following news about genetic engineering and genetic modification of food "at all," and an additional 35% said they did not follow such news "too closely." When queried about their support of or opposition to the use of biotechnology in agriculture and food production, equal proportions of respondents (45%) said they supported and opposed its use. (See Figure 9.4.)
In 2005 just one-third of Americans (33%) believed that foods produced using biotechnology pose a serious health hazard to consumers. (See Figure 9.5.) Fifty-four percent of respondents said they did not think GM foods pose a serious health hazard. There was less skepticism about GM foods and more support for them in the United States than in Canada or Great Britain.
AN INTERNATIONAL FOOD FIGHT
Cartagena Protocol on Biosafety
In January 2000, after participating in the negotiation of the International BioSafety Protocol, a treaty developed by the United Nations Convention on Biological Diversity in which all signatories concurred that GM crops are significantly different from traditional crops, the United States refused to join other countries in signing. Known as the Cartagena Protocol on Biosafety, the treaty aims to ensure the safe transfer, handling, and use of living modified organisms—such as GE plants, animals, and microbes—across international borders. The protocol is also intended to prevent adverse effects on the conservation and sustainable use of biodiversity without unnecessarily disrupting world food trade. By participating in the treaty negotiations, the U.S. government formally acknowledged that GM crops are not, as many government agencies had previously maintained, "substantially equivalent" to traditional crops.
The Cartagena Protocol provides countries the opportunity to obtain information before new bioengineered organisms are imported. It acknowledges each country's right to regulate bioengineered organisms, subject to existing international obligations. It also aims to improve the capacity of developing countries to protect biodiversity. The protocol does not, however, cover processed food products or address the safety of GM food for consumption. Instead, the protocol is intended to protect the environment from the potential effects of introducing bioengineered products (referred to in the treaty as living modified organisms).
In September 2003 the Cartagena Protocol on Biosafety entered into force, empowering the more than one hundred countries that ratified the protocol to bar imports of live GMOs that they believe carry environmental or health risks. If the government of the importing country has concerns about safety, it can ask the exporting country to provide a risk assessment. The protocol also established a central online database of information on risks.
Although the protocol was acknowledged as an important first step in the protection of biodiversity, environmental advocacy groups including Greenpeace cautioned that there are still important unresolved issues for the international community, such as the amount of information required on shipments of GM crops. More important, Stephen Leahy reports in "Science: Bioterror Fears Dim Biotech Potential" (February 28, 2006, http://ipsnews.net/news.asp?idnews=32325) that the United States, Argentina, and Canada—the countries that produce about 90% of GE crops in the world—have not ratified the protocol.
Europe Bans Biotech Foods and Halts U.S. Trade
Although U.S. supermarket shelves remain stocked with GM foods, European consumers and farmers have nearly driven GE foods and crops out of the European Union (EU) market, the largest in the world. Europeans were so wary of GM foods that, beginning in 1998, the EU's European Commission and member states unofficially began a suspension on imports of biotech foods. At the onset of the ban, European Commission officials advised the United States they would resume the approval process once companies submitting applications agreed to abide by newly proposed revisions to the approval procedures before they become law. Although applicant companies agreed to comply voluntarily with the new procedures, the European Commission approval process did not resume as promised.
In June 1999 EU members called for an official moratorium on new approvals of agricultural biotech products. The EU Environmental Council contended that administration of new approvals should be linked to new labeling rules for biotech foods. Ministers from Denmark, France, Greece, Italy, and Luxembourg vowed to suspend approvals until new rules were established. A year later the EU environmental ministers moved to continue the moratorium at least until the European Commission prepared proposals for labeling and for tracing minute amounts of biotech products in foods such as vegetable and corn oils. The commission assured the United States that it would develop its proposal by the end of 2000 and promptly resume the approval process.
The traceability and labeling requirements were not presented until July 2001, when the European Commission promised to lift the moratorium within weeks. Frustrated by many delays and effects of these sanctions, the USDA determined that the EU moratorium on agricultural biotech products violated international law. The USDA argued in the fact sheet "Agricultural Biotechnology: WTO Case on Biotechnology" (September 2006, http://www.fas.usda.gov/itp/wto/eubiotech/factsheets/2006-09-28-biotech-wtocase.pdf) that:
- The EU "has pursued policies that undermine the development and use of agricultural biotechnology."
- In the late 1990s six member states (Austria, France, Germany, Greece, Italy, and Luxembourg) violated European law when they "banned imports of corn and rapeseed approved by the European Union," and the European Commission did not challenge the bans.
- In 1998 member states began to block EU regulatory approval for new agricultural biotech products. The moratorium prohibited most U.S. corn exports from entering Europe and violated EU law.
- The ban also breached WTO rules, which do not require automatic approval of biotech foods. The WTO requires that measures regulating imports be based on "scientific principles and evidence" and that countries operate regulatory approval procedures without "undue delay."
The United States asked the EU to apply a scientific, rules-based review and approval process to agricultural biotech product applications. The United States contended that it was not attempting to force European consumers to accept biotech foods or products. Instead, it denounced Europe's actions, which it considered whimsical rather than based on scientific, health, or environmental evidence, as depriving consumers of choice.
In 2004 Europe's moratorium on GM foods came to an end when the European Commission agreed to import worm-resistant GM corn known as Bt-11 developed by the Swiss firm Syngenta. In 2006 the World Trade Organization condemned the long approval process for GE products entering the European market as unscientific and determined that the process amounted to a trade embargo against agriculture producers in the United States, Canada, and Argentina. EU officials declined to appeal the ruling, but European consumers continued to view GE products with suspicion, and in early 2007 more than one million signatures had been gathered by Greenpeace in a petition drive calling for further investigation of biotech products entering Europe.
GE Foods in International Markets
Consumer rejection of GM foods has also been an issue to varying degrees in Japan, South Korea, Australia, New Zealand, India, and other nations. According to Roberto Verzola, in The Genetic Engineering Debate (July 2001, http://www.biotech-info.net/verzola_GE_debate.pdf), in May 2000 the Tokyo Grain Exchange soy futures market began to offer wholesale traders a choice of GE or conventional soybeans. On the first day of trading, 914,000 tons of conventional soybeans were purchased, compared with only 364,000 tons of GE soybeans. Beginning in 2001 Japan's Ministry of Health required all agricultural producers to screen imported GM foods for potential food allergies and other health hazards and strengthened mandatory labeling rules on GM food ingredients. However, according to the Foreign Agricultural Service of the USDA, in spite of the testing and labeling guidelines U.S. agricultural products retained a strong market in Japan as of 2006. Annual exports to that country included 16 million metric tons of corn and 4.5 million metric tons of soybeans, much of it genetically engineered (http://www.fas.usda.gov/info/fasworldwide/2006/04-2006/JapanBiotech.pdf).
Consumer rejection of biotech products persists in Australia. In "Australia Struggles to Win Support for GMO Crops" (Reuters, March 9, 2005), Michael Byrnes notes that opposition to GM crops forced the country's poultry producers to stop feeding GM soy feed to the 450 million birds they sell each year. The Australian government has been actively trying to convince Australian consumers to welcome GM crops, and the country's farmers fear that they will suffer economic consequences if they cannot compete with farmers using GM organisms.
BIOTECHNOLOGY CORPORATIONS RESPOND TO CHALLENGES ABOUT GM FOODS
Corporations involved in genetic engineering research and production of GE crops and other products are alternately viewed as industry leaders providing valuable products and services or villains perpetrating economic, environmental, and health hazards on unsuspecting consumers throughout the world. Mounting consumer opposition to GM foods, especially outside the United States, prompted many of the giants in the agricultural biotech industry to scale back or even entirely halt production of some GM products.
For example, in 2000 Monsanto closed its NatureMark plant in Maine, a transgenic laboratory that produced Bt potatoes. Bt potatoes are gene-spliced with the soil bacterium Bacillus thuringiensis to repel the Colorado potato beetle. In November 1999 McCain's and Lamb-Weston, the two largest potato processors in North America, announced that they would no longer accept gene-altered potatoes; and the United States' leading potato purchasers, including McDonald's, Burger King, Frito-Lay, and Procter & Gamble, eliminated Bt potatoes from their french fries and potato chips. The Bt potatoes joined the growing list of GM foods abandoned by Monsanto. In 1996 Monsanto-Calgene Flavr Savr tomatoes were withdrawn from the market after they failed to meet expectations in terms of sales figures. Other major U.S. food corporations (including Gerber, Heinz, Mead-Johnson, and Frito-Lay) and several supermarket chains (such as Whole Foods, Wild Oats, and Genuardi's) announced plans to entirely forgo GM foods and products.
In May 2003 the World Agricultural Forum held the conference "A New Age in Agriculture: Working Together to Create the Future and Disable the Barriers" in St. Louis. Presenters from the biotech firms Nestlé, Cargill, and Monsanto offered their intent to pursue free trade as well as their plans for using GM crops to help address world hunger.
To counter consumer opposition to GM foods and products, in 2000 the Council for Biotechnology Information aired television advertisements and launched a Web site to inform consumers of the potential benefits of GM foods. The media campaign emphasized that GM foods have been tested by U.S. government agencies and found to be safe; that biotechnology increases the nutritional content of foods, improves food quality, and can help feed the world's hungry; and that GM crops reduce the use, and environmental consequences of, toxic pesticides. In 2003 the council publicized in "Higher Corn Yields Are Making Ethanol More Energy Efficient" (http://www.whybiotech.com/index.asp?id=2213) the conclusions of the USDA study The Energy Balance of Corn Ethanol: An Update (July 2002, http://www.transportation.anl.gov/pdfs/AF/265.pdf). The study found that ethanol production is becoming increasingly energy efficient because corn yields are rising, less energy is required to grow it, and ethanol conversion technologies are becoming more efficient. These findings resulted from the use of GM corn crops. The council also offered as evidence the results of the National Center for Food and Agricultural Policy report Plant Biotechnology: Current and Potential Impact for Improving Pest Management in U.S. Agriculture—An Analysis of 40 Case Studies (June 2002, http://www.heartland.org/pdf/15786.pdf). The report found that "8 biotech cultivars adopted by U.S. growers increased crop yields by 4 billion pounds, saved growers $1.2 billion by lowering production costs and reduced pesticide use by 46 million pounds. These cultivars include insect resistant corn and cotton, herbicide tolerant canola, corn, cotton and soybean, and virus resistant papaya and squash. The adopted cultivars provided a net value of $1.5 billion."
In 2005 and 2006 the Council for Biotechnology Information continued to advance its premise that GM foods are safe by enlisting the support of other organizations including the American College of Nutrition, American Medical Association, International Society of Toxicology, and World Health Organization to attest to the safety of foods developed using biotechnology. The council asserts in "Food and Environmental Safety: Experts Say Biotech Food and Crops Are Safe" (2006, http://www.whybiotech.com/index.asp?id=2985) that more than 3,300 scientists, including twenty Nobel Prize winners, have signed a declaration in support of biotechnology and its safety. In "Protein-Rich Potato Could Help Combat Malnutrition in India" (2005, http://www.whybiotech.com/index.asp?id=4323), the council extols the virtues of genetically enhanced protein-rich potatoes, which could help to combat malnutrition in India.
PROMISE AND PROGRESS OF GENOMIC MEDICINE
Progress in understanding the genetic basis of disease has arrived at a rapid-fire pace. Genetic and genomic information gained from the Human Genome Project promises to revolutionize prevention and treatment of disease in the twenty-first century. Physicians will be able to accurately predict patients' risks of acquiring specific diseases and advise them of actions they may take to reduce their risks, prevent disease, and protect their health. There are equally promising therapeutic applications of genetic research including custom-tailored treatment that relies on knowledge of the patient's genetic profile and development of highly specific and effective medications to combat diseases.
According to Dave Carpenter in "Biotech: Practical Genomics" (Hospitals and Health Networks, May 2003), the genomics revolution has already arrived in some U.S. hospitals. Carpenter finds more than just the traditional genetic screening of newborns. He describes cardiovascular patients screened via sophisticated genetic analysis technology that employs computer software to determine patients' risk of complications, such as deep-vein thrombosis (blood clots in the leg veins).
The use of genetic analysis technology illustrates what industry observers call the shift from reactive patient care to predictive, preventive, and personalized care. Treatment can begin earlier and medication will be custom tailored for each patient. Physicians, administrators, and consumers expect that such genetic applications will prevent costly and potentially adverse surgical complications.
Molecular Farming Harvests New Drugs
Molecular farming or biopharming runs the gamut from tobacco plants harboring drugs to treat acquired immune deficiency syndrome (AIDS) to plants intended to yield fruit-based hepatitis vaccines. An example of a plant with the potential to produce a GM pharmaceutical is corn grown by the researcher Andy Hiatt at Epicyte Pharmaceutical in San Diego. According to Margot Roosevelt, in "Cures on the Cob" (Time, May 19, 2003), a human gene that codes for an antibody to genital herpes—a sexually transmitted disease that affects about sixty million Americans—is being grown in the corn plants. Epicyte is also developing plant-grown spermicides and antibodies to combat respiratory viruses, treat Alzheimer's disease, and counter Ebola, should the virus be used as a weapon in an act of bioterrorism.
Opponents call molecular farming "Pharmageddon," and environmentalists fear that the artificially combined genes will have unintended, untoward consequences for the environment. Consumer advocates, wary about the proliferation of GM foods, dread the possibility that plant-grown drugs and industrial chemicals will end up in food crops. To prevent such a scenario, the FDA issued new regulations to safeguard the food supply during the last quarter of 2003.
Preclinical Disease Detection
At the close of the twentieth century technological advances offered opportunities to identify diseases at stages before they were visible, in terms of biochemical or symptomatic expression. Called preclinical detection, this ability to predict and as a result intervene to prevent or avert serious disease involves an understanding of three levels of disease detection involving genomes, transcriptomes (the transcribed messenger RNA complement), and proteomes (the full range of translated proteins).
In "An Initial Map of Insertion and Deletion (INDEL) Variation in the Human Genome" (Genome Research, September 2006), Ryan E. Mills et al. describe a new kind of computer-based analysis to look for a type of genetic variation called an insertion and deletion (INDEL) polymorphism and the development of an initial map of human INDEL variation that contains 415,436 unique INDEL polymorphisms. In an INDEL variation, building blocks are added or deleted, not just switched on a one-for-one basis, and an insertion or deletion can involve thousands of blocks. Mills and his collaborators assert that INDELs represent about 25% of all genetic variations and believe that their work represents the dawn of a new era of predictive health.
Genes Explain Disease, Drug Resistance, and Treatment Failures and Successes
Research suggests that some people possess genes that enable the immune system to act unusually quickly. In "HLA and NK Cell Inhibitory Receptor Genes in Resolving Hepatitis C Virus Infection" (Science, August 6, 2004), Salim I. Khakoo et al. note this may explain how an estimated 20% of infected patients fend off or completely cure themselves of hepatitis C—a virus that causes serious and often fatal liver disease—without any medical treatment. The researchers posit that a specific gene combination allows the body to quickly let loose its frontline defense: natural killer cells. Natural killer cells are continually ready to counter an invading virus. Inhibitory receptors restrain natural killer cells between infections, to ensure they do not attack healthy tissue. Khakoo and his associates identified a particular gene combination that controls one inhibitory receptor, and the molecule attached to it was twice as common in recovered patients as in patients who remained infected with hepatitis C. To find the genes involved in this immune response, the researchers analyzed the DNA of 1,037 hepatitis C patients, 352 of whom spontaneously recovered. Khakoo et al. conclude that "[i]n the long term, whether we can use this information to modulate the body's immune system to improve therapeutics or vaccine design—that is the ultimate goal."
Amy Holleman et al., in "Gene-Expression Patterns in Drug-Resistant Acute Lymphoblastic Leukemia Cells and Response to Treatment" (New England Journal of Medicine, August 5, 2004), identify a set of genes linked to either resistance or sensitivity to the anticancer drugs commonly used to treat acute lymphoblastic leukemia. The researchers tested leukemia cells from 173 children newly diagnosed with leukemia for sensitivity to four chemotherapy drugs used in leukemia treatment. They found a particular group of genes that when present in leukemia cells determined their sensitivity or resistance to the drugs. The study also showed that these genes predicted treatment success or relapse in the 173 children as well as another group of 98 children with leukemia who were treated with the same drugs. Holleman and her coauthors assert that the presence or absence of these genes may explain why nearly 20% of children with leukemia do not respond to drug treatment.
In "EGFR Mutation and Resistance of Non-Small-Cell Lung Cancer to Gefitinib" (New England Journal of Medicine, February 24, 2005), Susumu Kobayashi et al. report that gene mutations explain why some lung cancer tumors become resistant to treatment with new cancer drugs meant to disrupt a molecular target that helps tumors grow. They find that mutations in the epidermal growth factor receptor gene are associated with favorable responses to treatment. They also find that the tumor stops responding to the cancer drugs if or when a secondary mutation in the same gene develops—three of six patients in the study who had this secondary mutation experienced a recurrence of their tumors. Kobayashi and his collaborators hypothesize that the anticancer drugs may give cancer cells that have the second mutation a growth advantage.
Marc Buyse et al., in "Validation and Clinical Utility of a 70—Gene Prognostic Signature for Women with Node-Negative Breast Cancer" (Journal of the National Cancer Institute, September 6, 2006), report that a new 70—gene assay will be able to more accurately predict the prognosis for women with breast cancer that has not yet spread to the lymph nodes. The technique accurately assesses whether the subjects—women fifty-five years or younger with node-negative breast cancer whose tumors were smaller than five centimeters in diameter—were low risk (a ten-year metastasis-free survival probability of greater than 90%) or high risk (a five-year probability of metastasis-free survival greater than 90%). This type of gene profiling will not only improve the accuracy of prognoses but also may help to predict which patients will benefit most from therapy.
Gene therapy aims to correct defective or faulty genes with one of several techniques. Most gene therapy involves the insertion of functioning genes into the genome to replace nonfunctioning genes. Other techniques entail swapping an abnormal gene for a normal one in a process known as homologous recombination, restoring an abnormal gene to normal function through selective reverse mutation, or changing the regulation of the gene—influencing the extent to which a gene is "turned on" or "turned off." Danny Penman Subtle notes in "Gene Therapy Tackles Blood Disorder" (October 11, 2002, http://www.newscientist.com/article.ns?id=dn2915) that gene repair of faulty messenger ribonucleic acid (mRNA) is being used by researchers at the University of North Carolina to treat blood disorders such as thalas-semia and hemophilia as well as cystic fibrosis and some cancers. According to Bob Holmes, in "Gene Therapy May Switch Off Huntington's" (March 2003, http:// www.newscientist.com/article.ns?id=dn3493), University of Iowa investigators report preliminary success with a related technique, known as RNA interference or gene silencing, to turn off production of an abnormal protein involved in Huntington's disease.
Early work in gene therapy focused on replacing a gene that was defective in a specific well-defined genetic disease such as cystic fibrosis. Recent research reveals that gene therapy technology may be more helpful in treating several nongenetic diseases for which there are no available effective treatments. Gene therapy clinical trials are currently under way for pancreatic cancer and sarcoma (a malignant tumor arising from nonepithelial connective tissues); end-stage (advanced) coronary artery disease, in which factors that improve blood supply to the heart may be lifesaving; and macular degeneration, for which loss of sight might be prevented.
To treat each of these disorders, the appropriate therapeutic genes are inserted by using in vivo (in a living organism, rather than the laboratory) gene therapy with adenoviral vectors. (Adenoviruses have double-stranded DNA genomes and cause respiratory, intestinal, and eye infections in humans.) A vector is a carrier molecule used to deliver the therapeutic gene to the target cells. The most frequently used vectors are viruses that have been genetically altered to contain normal human DNA. Researchers exploit viruses' natural abilities to encapsulate and deliver their genes to human cells. An unanticipated benefit of this type of gene therapy is that highly specific immunity could be induced by injecting into skeletal muscle DNA manipulated to carry a gene encoding a specific antigen. Because this form of therapy does not lead to integration of the donor gene into the host DNA, it eliminates potential problems resulting from disruption of the host's DNA, a phenomenon that was observed by investigators using ex vivo (outside a living organism, usually in the laboratory) gene therapy. Figure 9.6 shows how ex vivo cells are used to create a gene therapy product.
Figure 9.7 shows the steps involved in gene therapy using a retrovirus as the vector. In this process the vector discharges its DNA into the affected cells, which then begin to produce the missing or absent protein and are restored to their normal state. In this example the patient's own bone marrow cells are used as the vector to deliver severe combined immune deficiency-repaired genes to restore the function of the immune system.
Besides virus-mediated gene delivery, there are non-viral techniques for gene delivery. Direct introduction of therapeutic DNA into target cells requires large amounts of DNA and can be used only with certain tissues. Genes can also be delivered via an artificial lipid sphere, called a liposome, with a liquid core. This liposome, which contains the DNA, passes the DNA through the target cell's membrane. DNA can also enter target cells when it is chemically bound to a molecule that in turn binds to special cell receptors. Once united with these receptors, the therapeutic DNA is engulfed by the cell membrane and enters the target cell. Sylvia Pagán Westphal reports in "DNA Nanoballs Boost Gene Therapy" (May 12, 2002, http://www.newscientist.com/article.ns?id=dn2257) that researchers at Case Western Reserve University and Copernicus Therapeutics have created tiny liposomes able to transport therapeutic DNA through the pores of the nuclear membrane. Furthermore, Anil Ananthaswamy notes in "Undercover Genes Slip into the Brain" (March 20, 2003, http://www.newscientist.com/article.ns?id=dn3520) that researchers at the University of California at Los Angeles have successfully inserted genes into the brain using a liposome. This is a significant accomplishment because, previously, viral vectors were too large to cross the blood-brain barrier. The ability to transfer genes into the brain bodes well for patients suffering from neurological disorders such as Parkinson's disease.
In 1999 the death of the American teenager Jesse Gelsinger after he participated in a clinical gene therapy trial for ornithine transcarbamylase deficiency shocked and saddened the scientific community and diminished enthusiasm for technology that promises that healthy genes can replace faulty ones. Since then other adverse outcomes have tempered some initial success stories. In "Scientists Use Gene Therapy to Cure Immune Deficient Child" (British Medical Journal, July 6, 2002), Judy Siegel-Itzkovich notes that in 2002 an international team of scientists reported curing a child with severe combined immunodeficiency using gene therapy. The child spent the first seven months of her life inside a plastic bubble to protect her from all disease-causing agents because she totally lacked an immune system. After suppressing her defective bone marrow cells, the researchers introduced, using a GE virus, a healthy copy of the gene she was missing (for adenosine deaminase) into her purified bone marrow stem cells. The baby recovered quickly; within a few weeks she was no longer in isolation and went home healthy. Researchers credited the gene alteration treatment with the cure.
Two other children with similar conditions who received comparable gene therapy subsequently developed conditions resembling leukemia. As a result, in January 2003 the FDA temporarily stopped all gene therapy trials using retroviral vectors in blood stem cells. The FDA reconvened its Biological Response Modifiers Advisory Committee in February 2003 to determine whether to permit retroviral gene therapy trials for treatment of life-threatening diseases to proceed with additional safeguards. The committee indefinitely suspended such trials, and as of early 2007 they had not resumed in the United States.
In 2004 the Biological Response Modifiers Advisory Committee was renamed the Cellular, Tissue, and Gene Therapies Advisory Committee to describe more accurately the areas for which the committee is responsible. The FDA described the function of the renamed committee as evaluating "data relating to the safety, effectiveness, and appropriate use of human cells, human tissues, gene transfer therapies and xenotransplantation products" (September 24, 2004, http://www.fda.gov/cber/advisory/ctgt/ctgtchart.htm). Xenotransplantation is any procedure that involves transplantation, implantation, or infusion into a human recipient of live cells, tissues, or organs from a nonhuman animal source; or human body fluids, cells, tissues, or organs that have had any contact with live nonhuman animal cells, tissues, or organs. It has been used experimentally to treat certain diseases such as liver failure and diabetes, where there are insufficient human donor organs and tissues to meet demand.
The FDA and the National Institutes of Health (NIH) jointly oversee regulation of human gene therapy in the United States. The FDA focuses on ensuring that manufacturers produce quality, safe gene therapy products and that these products are adequately studied in human subjects. The NIH evaluates the quality of the science involved in human gene therapy research and funds the laboratory scientists involved in development and refinement of gene transfer technology and clinical studies.
RECENT ADVANCES IN GENE THERAPY
Andrew Pollack reports in "Method to Turn Off Bad Genes Is Set for Tests on Human Eyes" (New York Times, Septembe 14, 2004) that the FDA granted Acuity Pharmaceuticals permission in September 2004 to conduct the first human test of RNA interference (called RNAi) on patients suffering from macular degeneration—a deterioration of the retina that is the leading cause of blindness in older adults. The disease was chosen because the RNA can be directly injected into the eye, overcoming problems associated with delivering the RNA to the affected cells. Although RNAi has demonstrated efficacy in the laboratory, it is not yet known whether it will work in people. Other techniques once considered promising ways to turn off genes have not produced effective drugs. Other companies are investigating the use of RNAi to treat Huntington's and Parkinson's diseases, hepatitis C, and human immunodeficiency virus (HIV; the virus that causes acquired immunodeficiency syndrome). Pollack notes that Natasha J. Caplen, a gene therapy expert with the National Cancer Institute, said the FDA had not yet determined how it would regulate RNAi drugs. Until such regulations are in place, companies will be unable to begin clinical trials.
H. Bobby Gaspar et al., in "Gene Therapy of X-Linked Severe Combined Immunodeficiency by Use of a Pseudotyped Gammaretroviral Vector" (The Lancet, December 18, 2004), report a successful gene therapy that corrects the cause of X-linked severe combine immunodeficiency (SCID-X1) and restores immunity. Bone-marrow stem cells were infused with human gamma-c cloned into an ape gamma-retroviral vector and then returned to the young patients, who ranged in age from four to thirty-three months. Gaspar and the other researchers conclude that "gene therapy for SCID-X1 is a highly effective strategy for restoration of functional cellular and humoral immunity."
According to Alice Dembner, in "Research to Unleash Gene Therapy on Arthritis" (Boston Globe, August 14, 2006), in 2006 scientists began testing gene therapies for osteoarthritis, a joint disease that afflicts more than twenty-one million Americans. One therapy involves injecting a gene into a diseased joint that will continuously pump medicine directly where it is needed. Another involves the use of GM cells that will pump proteins into the joint to stimulate growth of damaged cartilage.
In November 2006 researchers at the University of Pennsylvania's Abramson Family Cancer Research Institute reported promising results of a preliminary trial of a potential new gene therapy for HIV. In "Gene Transfer in Humans Using a Conditionally Replicating Lentiviral Vector" (Proceedings of the National Academy of Sciences, November 7, 2006), Bruce L. Levine et al. note that they removed immune cells from the patients and introduced a virus called a lentivirus into the cells. This change prevents HIV from reproducing and, in the laboratory, demonstrated the ability to fight HIV in cells that have not been treated. This first human study was conducted on patients with HIV infections that have been treatment resistant, and it showed that the treatment was safe and effective.
Genetically Enhanced Athletes
In "Gene Therapy May Be Up to Speed for Cheats at 2008 Olympics" (Nature, December 6, 2001), David Adams reports that gene therapy may enable athletes to genetically modify themselves to boost their performances. Athletes might target performance-enhancing genes such as those encoding growth factors capable of building muscle strength or widening blood vessels, or a hormone called erythropoietin that increases the number of oxygen-carrying red blood cells. Furthermore, the researchers Adams interviewed said such modifications might be impossible to detect and that artificial genes "can and most likely will be abused by healthy athletes as a means of doping." The International Olympic Committee has established an advisory group to monitor progress in gene therapy and to prevent a GM athlete from competing in the 2008 Olympic Games in Beijing.
MORE APPLICATIONS OF GENETIC RESEARCH
Most applications of genetic biotechnology are scientific, agricultural, and medical. However, geneticists are also engaged in product research and development of related technology and in legal determinations. Involvement with legal matters and the criminal justice system often takes the form of DNA profiling, also known as DNA fingerprinting. Because every organism has its own unique DNA, genetic testing can definitively determine whether individuals are related to one another and whether DNA evidence at a crime scene belongs to a suspect. It can also accurately identify a specific strain of a bacterium.
One example of researchers' use of genetic profiling to identify disease-causing bacteria was reported by Rex Dalton in "Genetic Sleuths Rush to Identify Anthrax Strains in Mail Attacks" (Nature, October 18, 2001). Dalton describes how the anthrax attacks in the eastern United States during the first weeks of October 2001 spurred researchers to work quickly to identify the strains of bacteria involved. The researchers hoped to help identify the origin of the anthrax spores and presumably trace them to their source. Paul Keim, a geneticist at Northern Arizona University in Flagstaff, led the research that used amplified fragment length polymorphism DNA analysis and another test called multilocus variable-number tandem repeat analysis (used with microorganisms to examine the Bacillus anthraces ).
Dalton notes that it took Keim's research team about twelve hours to analyze a single sample. Even though several samples were ultimately determined to have been derived from the virulent Ames strain, it was not a simple task to trace the Ames strain to a single source because it has been passed around the world by researchers. It had been commonly used in laboratory research to develop vaccines and tests after its original isolate was removed from a dead animal in the 1950s near Ames, Iowa.
The seventeenth edition of the Merck Manual of Diagnosis and Therapy (2003) describes forensic genetics as using molecular genetic techniques to identify an individual's genetic makeup. Forensic genetics relies on the measurement of many different genetic markers, each of which normally varies from individual to individual, and may be used to determine whether two people are genetically related. For example, because half of a person's genetic markers come from the father and half from the mother, analyses of these DNA markers enable laboratory technologists to establish that one person is the offspring of another. Analysis of DNA derived from blood samples can determine whether the supposed parents of a particular child are actually the biological parents. DNA markers may also be used to identify a specimen and establish its origin—that is, definitively determine the individual from whom it came. Biopsies, pathologic specimens, and blood and semen samples can all be used to measure DNA markers.
Forensic investigations often involve analyses of evidence left at a crime scene such as trace amounts of blood, a single hair, or skin cells. Using the polymerase chain reaction (PCR), DNA from a single cell can be amplified to provide a sample quantity that is large enough to determine the source of the DNA. In PCR the double strand of DNA is denatured into single strands, which are placed in a medium with the chemicals needed for DNA replication. The single strands both become double strands, yielding twice the amount of the initial DNA sample. The double strands are once again denatured to form single strands, and the process is repeated until there is a sufficient quantity of DNA for analysis. Analysis is usually performed using gel electrophoresis, in which DNA is loaded onto a gel and an electrical current is passed through the DNA. Investigators are then able to observe larger molecules migrating more slowly than smaller ones. Examining variable-number tandem repeats (VNTRs) is a procedure that identifies the length of tandem repeats in an individual's DNA. VNTR is an especially useful technique in forensic genetics, because when it is performed in careful lab conditions the probability of two individuals having the exact same VNTR results is less than one in a million.
DNA evidence is preferred by forensic specialists because, even though fingerprints can often be erased or eliminated and hair color and appearance may be altered, DNA is immutable. It can be used to identify individuals with extremely high probability and is more stable than other biological samples such as proteins or blood groups. Forensic genetics can be a powerful tool and has been used successfully to eliminate suspects and clear their names. Though not as useful in proving guilt, it provides solid and often convincing evidence when many alleles match.
The first admission of DNA evidence in criminal court occurred in Florida v. Tommy Lee Andrews (1987), when the state of Florida used it as part of the prosecution case to convict a suspect of a series of sexual assaults. In 1989 the Federal Bureau of Investigation (FBI) began accepting work from state forensic laboratories, and in 1996 the National Research Council published The Evaluation of Forensic DNA Evidence, which cited the FBI statistic that approximately one-third of primary suspects in rape cases are excluded by using DNA evidence.
The International Society for Forensic Genetics promotes scientific knowledge in the field of genetic markers analyzed for forensic purposes. Many Americans first became aware of the use and importance of DNA evidence during the sensational and widely publicized 1994 trial of O. J. Simpson for the murder of Nicole Brown Simpson and Ron Goldman. Nicole Simpson's blood was found in O. J. Simpson's vehicle and house, but the defense discredited the DNA results by claiming the police had conducted a sloppy investigation that caused the samples to be contaminated and, alternatively, that the blood was planted in an attempt to frame Simpson.
A nanometer—the width of ten hydrogen atoms laid side by side—is among the smallest units of measure. It is one-billionth of a meter, one-millionth the size of a pinhead, or one-thousandth the length of a typical bacterium. Figure 9.8 shows the incredibly tiny scale of nanometers. According to an NIH definition (June 12, 2000, http://www.becon.nih.gov/nstc_def_nano.htm), nanotechnology
involves research and technology development at the atomic, molecular, or macromolecular levels in the dimension range of approximately 1-100 nanometers to provide fundamental understanding of phenomena and materials at the nanoscale and to create and use structures, devices, and systems that have novel properties and functions because of their small and/or intermediate size. The novel and differentiating properties and functions are developed at a critical length scale of matter typically under l00 nm. Nanotechnology research and development includes control at the nano-scale and integration of nanoscale structures into larger material components, systems, and architectures. Within these larger scale assemblies, the control and construction of their structures and components remains at the nanometer scale.
Nanotechnology is sometimes called molecular manufacturing because it draws from many disciplines (including physics, engineering, molecular biology, and chemistry) and considers the design and manufacture of extremely small electronic circuits and mechanical devices built at the molecular level of matter. K. Eric Drexler, the chief technical adviser of Nanorex, a company developing software for the design and simulation of molecular machine systems, coined the term nanotechnology in the 1980s to describe atomically precise molecular manufacturing systems and their products. He states in his book Engines of Creation (1986) that it is an emerging technology with the potential to fulfill many scientific, engineering, and medical objectives.
Researchers anticipate a myriad of practical applications of nanotechnology such as home food-growing machines that could produce virtually unlimited food supplies and chip-sized diagnostic devices that would revolutionize the detection and management of illness. Investigators envision computer-controlled molecular tools much smaller than a human cell and constructed with the accuracy and precision of drug molecules. Such tools would enable medicine to intervene in a sophisticated and controlled way at the cellular and molecular level—removing obstructions in the circulatory system, destroying cancer cells, or assuming the function of organelles such as the mitochondria. Other potential uses of nanotechnology in medicine include the early detection and treatment of disease via exquisitely precise sensors for use in the laboratory, clinic, and in the human body, plus new formulations and delivery systems for pharmaceutical drugs. In "Nanocontainers Deliver Drugs Directly to Cells" (Scientific American, April 28, 2003), Sarah Graham describes how researchers at McGill University in Montreal have developed tiny drug delivery vehicles that are able to pass through the cell wall of a rat and even penetrate some cell parts such as the mitochondria and Golgi apparatus. Such highly refined and specific drug delivery systems may enable physicians to administer smaller doses of toxic medications more safely. In the not-too-distant future, nanorobots may act as programmable antibodies. As disease-causing bacteria and viruses mutate to elude medical treatments, the nanorobots could be reprogrammed to selectively seek out and destroy them, and others might be programmed to identify and eliminate cancer cells, leaving normal cells unharmed.
The technology may also be used to develop immediately compatible, rejection-resistant implants made of high-performance materials that respond as the body's needs change. Nanotechnology will lead to new biomedical therapies as well as prosthetic devices and medical implants. Some of these will help attract and assemble raw materials in bodily fluids to regenerate bone, skin, or other missing or damaged tissues. Nanotubes that act like tiny straws could conceivably circulate in a personés bloodstream and deliver medicines slowly over time or to highly specific locations in the body.
NEW DEVELOPMENTS IN NANOMEDICINE
Rick Weiss describes in "Nanomedicine's Promise Is Anything but Tiny" (Washington Post, January 30, 2005) some recent applications of nanotechnology to medicine, including:
- Quantum dot diagnostics—tiny bits of silicon just a few atoms in diameter—are being used to track the movement of substances in cells and to identify diseases in blood or other tissue.
- Tiny amounts of amino acids adhering to nanofibers that help nerve cells to heal and grow are delivered, suspended in a liquid gel called a nanogel.
- Photo-thermal nanoshells—gold-coated spheres just 130 nanometers in diameter absorb near infrared light and can be inserted deep into the body to the site of a tumor and heated to 122 degrees Fahrenheit, frying the tumor but not the surrounding tissue.
Another diagnostic application of nanomedicine is detailed by Dimitra G. Georganopoulou et al. in "Nano-particle-Based Detection in Cerebral Spinal Fluid of a Soluble Pathogenic Biomarker for Alzheimer's Disease" (Proceedings of the National Academy of Science, February 15, 2005). The Northwestern University researchers report how nanoscience enables ultrasensitive detection of a biomarker for Alzheimer's disease, a neurode-generative dementia that afflicts an estimated four million people in the United States. Until recently, Alzheimer's disease could only be conclusively diagnosed after death, when brain tissue could be examined for the plaques and neurofibrillary tangles that are the hallmarks of the disease.
Specific peptides—amyloid beta-derived diffusible ligands (ADDLs)—are believed to be the causative agent in memory loss associated with Alzheimer's disease. The researchers developed a bio-barcode assay, which is 100,000 times to 1 million times more sensitive than other available tests in the detection of ADDLs in the brain linked to Alzheimer's disease. Georganopoulou et al. hope that detecting ADDLs and other protein markers at significantly lower concentrations than conventional tests will lead to earlier diagnosis and intervention as well as development of new therapies for Alzheimer's and other diseases.
The editorial "Nanomedicine: A Matter of Rhetoric?" (Nature Materials, April 1, 2006) states that in 2006 an estimated 130 nanotech-based drugs and delivery systems were being developed worldwide. According to the Nanomedicine Roadmap Initiative (January 27, 2006, http://nihroadmap.nih.gov/nanomedicine/nanoinfomtg/pdf/NanoInfoMtg012706_Schloss.pdf), the NIH has established a national network of eight nanomedicine development centers, staffed by multidisciplinary biomedical scientific teams including biologists, physicians, mathematicians, engineers, and computer scientists. These centers aim to:
- Characterize quantitatively (through measurement) the physical and chemical properties of molecules and nanomachinery in cells
- Gain an understanding of the engineering principles used in living cells to build molecules, molecular complexes, organelles, cells, and tissues
- Use this knowledge of properties and design principles to develop new technologies, and engineer devices and hybrid structures for repairing tissues and for preventing and curing disease