Genetic Engineering

GENETIC ENGINEERING

GENETIC ENGINEERING is the deliberate manipulation of an organism's genetic makeup to achieve a planned and desired result. Proponents of genetic engineering consider it an extension of the selective breeding practiced for thousands of years in the domestication of agricultural products and animals. The genesis of modern biotechnology, most scholars agree, came in the early 1970s with the advent of recombinant DNA (rDNA). Since biotechnology often refers to the use of organisms in agriculture, industry, or medicine, its origins can be traced back to the use of yeast for baking bread and the fermentation of alcohol. The impact of contemporary genetic engineering and biotechnology affects nearly every area of human activity. The introduction of rDNA engineering has revolutionized our relationship to the organic world and to ourselves, demanding a reconsideration of our values, our notion of progress, and the morality of scientific research.

The History of Genetic Engineering

Genetic engineering owes its existence to the developments in molecular genetics, virology, and cytology that culminated in the determination of the structure of DNA by James Watson and Francis Crick in 1953. Building on research involving bacteriophages (a bacterial virus), Joshua Lederberg, a geneticist at the University of Wisconsin, found that bacteria can transfer genetic information through plasmids, small mobile pieces of DNA that exist independent of the chromosomes. In the 1950s, Lederberg pioneered the earliest techniques in genetic engineering, shuffling genetic material between bacterial cells. After the identification of restriction enzymes capable of "cutting" DNA in specific locations in 1968, scientists were able to insert foreign DNA directly into bacterial cells. The discovery that the foreign DNA would naturally bond with the host DNA, made it possible to splice together genes from multiple organisms, the technique used in recombinant DNA engineering. Although highly complicated, rDNA engineering can be simply explained: genetic material from the donor source is isolated and "cut" using a restriction enzyme and then recombined or "pasted" into the genetic material of the receiver. By 1971, advanced transplantation techniques had been developed and rDNA techniques using the restriction enzyme EcoRi were operable the following year, leading to the first experiments in genetic engineering.

In 1973, Stanford biochemist Stanley Cohen under-took one of the first rDNA experiments, inserting a piece of bacterial DNA into Escherichia coli (E. coli ), a bacterium found in the human intestine. However, the research soon became controversial, particularly when American molecular biologist Paul Berg designed an experiment to insert DNA from simian virus #40 (sv40)—a known cancer-causing agent—into E. coli. As word of the daring procedure spread, the public was captivated and fearful, afraid that a genetically engineered virus, inured to antibiotics and carried in a common bacterium, could escape and cause an epidemic. Hoping to diffuse fears of a potential biohazard and maintain control of their research, over one hundred and fifty molecular biologists and related specialists met at the Asilomar Conference Center in Monterey, California, in late February 1975. The conference represented an extraordinary moment in the history of science, as the research community, recognizing its social responsibility, officially adopted a moratorium until appropriately safe procedures and guidelines could be developed. The conference ultimately resulted in the "National Institutes of Health Guidelines for Research Involving rDNA Molecules" and an ongoing National Institute of Health rDNA Advisory Committee (RAC)founded in 1974.

Yet the guidelines only increased public concern over genetic engineering. Critics charged that attempts to splice genes together from different organisms were akin to "playing God" and could result in dangerous and immoral hybrids. Adopting the literary example of "Dr. Frankenstein's monster" as an appropriate symbol of misguided science, opponents of rDNA engineering converged on research laboratories and public meetings. An attempt to build a recombinant laboratory at Harvard University set off such a firestorm that local politicians created a review board to assess potential risks, eventually requiring more stringent controls than those set by the NIH. By 1977, protests of rDNA facilities had spread to other campuses—the University of California San Diego, the University of Wisconsin, the University of Michigan, and the University of Indiana—while the state legislatures of New York, New Jersey, and California held public hearings. However, it was the resolution of an old court case and the introduction of a new form of rDNA engineering that ultimately created the greatest controversy.

In a monumental decision handed down on 16 June 1980, the United States Supreme Court held in Diamond v. Chakrabarty that man-made life forms were subject to patent laws and protection. The decision resolved a longstanding issue on patents and organic material, as the case dated to 1972, when Ananda Chakrabarty, a researcher at General Electric, applied for a patent on a form of Pseudomonas bacteria bred (but not genetically engineered)to digest oil slicks. By a narrow five to four margin the court construed the Patent Act, originally drafted by Thomas Jefferson, so as to include all products of human invention, relying on a 1952 Senate report that recognized as patentable "anything under the sun that is made by man." More than any other single event, the ruling galvanized many mainstream religious communities and environmental groups, eventually resulting in a letter of protest to President Carter and an indepth review by the President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research (1980–1983). The commission's report, issued in 1982 and entitled Splicing Life: The Social and Ethical Issues of Genetic Engineering with Human Beings, emphasized the importance of rDNA engineering to biomedical progress and American industries, arguing that it was best that the research be conducted under the auspices of government regulation and control. However, while the study resolved anxiety over rDNA engineering and patenting, proponents of genetic engineering still had to address concerns over the development of "germ-line" engineering, a controversial procedure that allowed scientists to literally create new strains of organisms.

Germ-line engineering differs from rDNA engineering in that the donor genes are inserted into a "germ," or reproductive cell, thereby permanently altering the genetic makeup of the organism's descendants. For example, in 1982, Ralph Brinster of the University of Pennsylvania Veterinary School inserted the gene that produces rat growth hormone into mouse embryos. The resulting strain of mice, dubbed "super mice" by the press, expressed the gene and thus grew into a substantially larger and more powerful new breed of mouse. Critics of germ-line engineering quickly denounced the technique as immoral and argued it was a form of "anthropomorphic Lamarckism." Jean-Baptiste de Lamarck, a nineteenth-century French naturalist, had proposed that traits acquired during an organism's lifetime were passed on to its progeny—an idea refuted by Darwinian evolutionary theory. Yet, in germ-line engineering, traits acquired during the organism's lifetime are passed on, but only those traits deemed necessary or desirous by man. Environmental groups also denounced germ-line engineering because of "biosafety" concerns, fearing that genetically engineered species, which would possess a distinct advantage over nonengineered species, could upset the globe's finely tuned ecological systems. However, because most politicians, scientists, and manufacturers believed the potential benefits from rDNA and germ-line engineering outweighed its potential dangers, the protests were overshadowed by the development of a biotechnology industry based on genetic engineering.

Contemporary Applications of Genetic Engineering

The decision to allow patents on genetically engineered organisms, combined with the commission's sanction of rDNA engineering, and a national commitment to biomedical progress, led to tremendous growth in the biotechnology industry. In 1975, only five biotech companies participated in the Asilomar conference, by 1980 the number of similar companies had increased to one hundred. Today there are over 1,300 companies involved in genetic engineering, many of which are located in the United States, a clear indication of the rapid growth of the American biotechnology sector and the applicability of the powerful new techniques. Indeed, genetic engineering influences nearly every area of human activity, including agriculture and aquaculture, industry and environmental remediation, and the development of medicines and therapies.

Although agriculture has been one of the most successful industries in utilizing genetic engineering, the techniques have also made an impact in other areas of food production. In 1990, Chymosin, an enzyme necessary for cheese production, became the first genetically engineered food product to go to market. A few years later, in 1994, the Monsanto Company created a bovine growth hormone designed to stimulate milk production, a hormone now estimated to be given to 30 percent of dairy cows. The same year, the "Flavr-Savr" tomato developed by Calgene passed the Food and Drug Administration standards for genetically engineered foods and also went to market. Like many transgenic foods, the "Flavr-Savr" was designed to have increased shelf life and resist spoilage, although disputes regarding labeling and advertisements combined with high production costs caused the company to discontinue the product in the late 1990s. Nonetheless, genetic engineering is integrated into agriculture production; researchers estimate that as of 2001, nearly one-third of the corn and one half of the soybeans grown in the United States were transgenic. A study conducted in 2000 by the Grocery Manufacturers of America reported that the majority of processed foods sold in America contained transgenic ingredients. To help develop aquaculture, researchers at Johns Hopkins University have taken a gene from flounder and inserted it into both trout and bass in the hopes of making the fish more resistant to cold climates, thus increasing commercial and sport fishing.

Genetic engineering also has substantial applications in many other industries from plastics and energy to the new field of bioremediation. In 1993, Chris Sommerville, director of plant biology at the Carnegie Institute in Washington, D. C., successfully inserted plastic-making genes into a plant; the Monsanto Company hopes to market a cotton/polyester plant early in the twenty-first century. Scientists at numerous biotech companies are currently working on strains of E. coli bacteria capable of transforming agricultural refuse into ethanol, an efficient and clean source of energy. Genetic engineering is also aiding environmental clean-up through the emerging field of bioremediation—the use of organisms to reduce waste. Bacteria were employed to help with the Exxon Valdez oil spill in 1989, while scientists at the Institute for Genomic Research are among those hoping to engineer microbes that can detoxify waste, including radioactive materials. However, the fastest growing, and one of the most controversial, fields of biotechnology is applied human genetics, which includes transgenic medicines, xenotransplantation, and human gene therapy.

In 1982, Eli Lilly and Company began marketing bacterial-produced insulin, the first transgenic commercial product and an excellent marker of the industry's progress. Today, the vast majority of insulin used by Americans diabetics is genetically engineered and over 300 transgenic proteins and medicines are currently in production, many of which are made by animals. Indeed, animal "pharming" has been central to biomedical research and development since the introduction of genetic engineering; in 1988, Harvard University patented the "oncomouse," strains of mice missing or carrying specific genes and used in cancer research. In 1996, Genzyme Transgenics created a goat capable of producing anti-thrombin, an experimental anticancer drug; the following year PPL Therapeutics engineered a calf whose milk contains proteins necessary for nursing babies, including those born prematurely. Human hemoglobin, a protein essential for oxygen transportation in the bloodstream, can now be harvested from genetically engineered pigs. Transgenic pigs are also used in xenotransplantation, the transference of organs or parts from nonhuman species to humans. Nextran, a leading biotech company, hopes to use genetically engineered pig livers as temporary external reservoirs for patients suffering from acute liver failure. In the future, researchers hope that these transgenic medicines and proteins will help supplement human gene therapy, one of the boldest and most ethically and medically problematic areas of genetic engineering.

The history of human gene therapy is one of great promise and success mixed with controversy and stringent regulation. In the early 1980s, Martin Cline, a medical researcher at the University of California in Los Angeles, performed rDNA procedures in Italy and Israel on patients afflicted with hereditary blood disorders. Cline's unauthorized experimentation, although legal because the countries lacked genetic regulations, ultimately cost him funding and a department chairmanship. In response, the RAC established the Human Gene Therapy Subcommittee in 1984 to issue protocols and review applications. Years later, in 1990, researchers at the National Institute of Health (NIH)attempted the first approved human gene therapy for Ashanti DeSilva, a young girl forced to live inside a "bubble" because of severe combined immune deficiency, or ADA. As in most cases of human gene therapy, the researchers removed cells from the patient, genetically engineered the desired changes, and then replaced the cells. However, for ADA, as for most diseases, gene therapy offers only treatment, not a cure, as the procedure must be repeated periodically. Nonetheless, the success of Ashanti's procedure stimulated human gene therapy research; in 1992, Bernadine Healy, then director of the NIH, approved a "compassionate use exemption" to increase access to promising gene therapy trials for critically ill patients. Within a year, procedures had been approved for familial hypercholesterolemia, cystic fibrosis, and Gaucher's disease, and trials for cancer, AIDS, Parkinson's, Alzheimers, arthritis, and heart disease were being conducted. Unfortunately, the 1999 death from liver disease of Jesse Gelsinger, an eighteen-year-old student taking part in a University of Pennsylvania gene therapy trial, led to questions regarding the safety of established protocols, as the fatality resulted from a common immune reaction to the adenovirus vector (see Genetics) that the researchers could have easily anticipated.

Although genetic engineering remains in its infancy, the rapid development of the science and its related techniques has generated considerable disagreement in the attempt to address its moral and legal implications. The birth of the sheep "Dolly" in 1997, the first cloned adult mammal, led to debates over the sanctity of life and the individual, while the advent of human gene therapy has revived fears of eugenics programs and genetically engineered "designer" children. The marketing of transgenic foods stimulated the growth of an "organic" agricultural industry and created ongoing international disputes over patent rights, truth-in-labeling claims, and restrictions on genetically engineered imports. Some critics fear that xenotransplantation will promote the transference of animal diseases to humans, while others decry the use of animals simply for the benefit of mankind. The development of stem cell research, promising because the embryonic cells can be manipulated to become nearly any type of cell in the body, has led to protests by many pro-life organizations over the use of embryonic or fetal tissue; in August 2001, President Bush declared that only a limited number of cell lines were acceptable for federal research funding. Whether involved in human gene therapy, xenotransplantation, industry, or agriculture, genetic engineering and biotechnology will no doubt continue providing astounding advancements alongside heated controversy and debate well into the future.

BIBLIOGRAPHY

Bud, Robert. The Uses of Life: A History of Biotechnology. New York: Cambridge University Press, 1993.

Fiechter, A., ed. History of Modern Biotechnology. 2 vols. Berlin: Springer Verlag, 2000.

Rifkin, Jeremy. The Biotech Century: Harnessing the Gene and Remaking the World. New York: Putnam, 1998.

Shannon, Thomas A., ed. Genetic Engineering: A Documentary History. Westport, Conn. : Greenwood Press, 1999.

Von Wartburg, Walter P., and Julian Liew. Gene Technology and Social Acceptance. Lanham, Md. : University Press of America, 1999.

J. G. Whitesides

See also Microbiology ; Molecular Biology .