Medicine as an art demands constant evaluation, weighing new treatments against old practices, benefits against risks, successesagainst failures. On occasion, the evidence leads to different conclusions. Nowhere is this more evident than in the management of the cancer patient. OPINIONS will present the views of specialists on a wide spectrum of controversial subjects. It is hoped that the frank expression of ideas will provide a framework within which our readers may form their own opinions. Publication does not constitute endorsement by the Amercian Cancer Society.

JOHN J. HOLLAND, Ph.D. Professorof Biology University of California La Jolla, California RECOMBINANT DNA: HYPOTHETICAL FEARS VS. POTENTIAL BENEFITS Research in recombinant DNA is per haps the fastest-growing field in biology today and one of the most controversial topics in the history of science. Nobel Prize winners are to be found among both its proponents and opponents; gov ernmental regulatory bodies often voice conflicting opinions in regard to over seeing the work; the scientific commu nity is in the midst of a debate of pro found consequence, the like of which has not been seen since the controversy over the development of atomic power. Those involved hold out visions of as tonishing medical advances combined with crucial insights into the basic func tioning of life. Critics spin scenarios of unprecedented ecological catastrophe, of genetic engineering that will create biological horrors and of tragic tamper ing with evolutionary forces ill-under stood. Where does the truth lie? The technique of recombinant DNA involves the use of newly-discovered re striction enzymes to combine genes VOL.27, NO 3 MAY/JUNE1977

from the DNA of one organism with those of another. Gene-splitting can be done between species as disparate as mammals and plants and may result in combinations never before seen in na ture. It is this point that many find unset tling. Clearly, there are hazards in any new technology and I would not want to downplay these dangers. However, I do believe that much of the criticism has gotten out of hand and even borders on hysteria. As an objective observer, not now involved in recombinant DNA re search, I am in agreement with other sci entists, such as Stanley M. Cohen, Pro fessor of Medicine at Stanford Univer sisy School of Medicine, who strongly believe that we must distinguish fear of the unknown from fear that has some basis in fact.' This is at the heart of the controversy surrounding recombinant DNA. Research is now being conducted by 86 universities in the United States, at least nine private companies, as well as several nations around the world. These investigators are working with a new technique and are trying to control it in a rational manner. They are not, as many critics allege, acting irresponsibly. In fact, good scientists performing recom binant DNA research in this country find themselves relatively handicapped as 167

compared to their counterparts in other countries. In an attempt to deal with various po tentially hazardous conditions, which have been brought to attention by advo cates and critics of the work, the Na tional Institutes of Health has issued its “¿Guidelinesfor Research Involving Re combinant DNA Molecules.―2 An ex amination of these guidelines may serve to alleviate fear of the unknown, as well as to show what precautions have been taken to eliminate fear of the known dangers. While the NIH has given its approval for the resumption of research in this field, it has most assuredly not given a green-light for any and all experiments in genetic engineering. The guidelines specifically prohibit certain types of ex periments, many of which cause grave concern among critics. For example, the cloning of recombinant DNAs derived from higher-risk pathogenic organisms (Classes III, IV and V) or from onco genic viruses classified by the NC! as moderate-risk, or from cells known to be infected with such agents, is strictly for bidden. Also prohibited is the deliberate formation of recombinant DNAs con taining genes for the biosynthesis of po tent toxins, such as diptheria, or recom binant DNAs from plant pathogens that would be likely to increase in virulence and host range. The release of any orga nism containing recombinant DNA into the environment, the transfer of a drug resistant trait to an organism not known to acquire it naturally, and large-scale experiments with recombinant DNAs known to produce harmful products all these are not to be carried out. Also of concern to many is the use of E. coli as the host-vector system. The guidelines take into account that there are potential dangers in using an organ ism so closely connected with man but the NIH has judged that the wealth of knowledge about this bacterium, com bined with stringent safety precautions, 168

makes it the most reliable bacterium for the experiments. A special strain of E. coli has been developed specifically for use in recombinant DNA research. The bacterium has been altered so that it can exist only under particular laboratory conditions and is not likely to survive outside the laboratory (e.g., it cannot survive in sunlight). This biologically disabled bacterium is suitable for the work, while meeting doubts as to its safety. In addition, the guidelines en courage serious efforts toward the devel opment of alternate host-vector systems, such as Bacillus subtilis. The standards for the containment of possibly hazardous materials, or those known to be deleterious to health, begin with strict adherence to good microbio logical practices and are supplemented by four levels of additional restrictions to ensure optimum protection for those inside and outside the confines of the laboratory. The levels of containment run from P1 (minimal level) for experi ments with microorganisms of no or minimal biohazard to P4 (high level) for microorganisms of great hazard or those that might cause serious epidemics. The highest level demands uncompromis ing, rigid precautions before any work can be undertaken. For example, labora tories designed for work at the P4 level must be either in a separate facility or physicially isolated from the rest of the building by monolithic walls, with all ducts, conduits, etc., sealed to prevent the escape of any microorganism. Access to the facility is under strict con trol. There must be air locks through which supplies can be safely brought into the laboratory. Negative air pres sures and directional air flow must be maintained by a separate ventilation sys tem. Exhaust air is to be decontaminated before it is released into the atmosphere. In fact, the regulations are so severe that Dr. David Baltimore, a member of the original committee that recom mended a temporary halt in recombinant

CA—A CANCER JOURNAL FOR CLINICIANS

DNA research until the hazards were better understood and means of preven tion were developed, has now been quoted in Science as saying that because of the restrictions upon work with tumor viruses “¿it is only barely possible to go forward.―3 Since it seems to be virtually impossi ble to contain research in this field—cer tainly if not done in the United States, it will be done elsewhere—we may rightfully wonder what potential bene fits can be expected from responsible ap plication of this tool. In my opinion, the technique is likely to provide great in sight into cell functioning and the nature of that complex series of diseases of the cell, cancer. While there will be no over night cures for cancer, it is quite possible that recombinant DNA research will provide answers to a number of ques tions basic to an understanding of the mechanisms of cancer. Such questions include: Do chemical carcinogens di rectly change genes? If so, what genes are changed in the cancer cell? What aspects of cellular metabolism are in volved in growth control? In addition to gains in vital theoretical knowledge, new avenues to cancer pre vention and therapy may be opened as@ well. New kinds of purified protein vac cines may be produced against many viruses, including those suspected in cancer etiology; important human hor

VOL. 27, NO. 3 MAY/JUNE 1977

mones not now available and even new therapeutic agents might be produced by using precisely defined bacteri3. These few examples serve to indicate the vast horizons that lay before the combination of human imagination and sound scientific work. No one wishes to see such serious matters, with such grave consequences, undertaken lightly and we should make certain that the ap plications of this research are carefully considered beforehand to ensure that they are beneficial. But the technique of recombinant DNA research, applied with strictest adherence to the current safety measures, provides tremendous potential benefits to mankind at minimal risk to health and safety. This work does not seem to involve any Faustian bargain but rather is a result of man's yearning for—knowledge, of his desire to explore ever deeper into the mysteries of life, both within himself and in his environ ment. References I. Cohen, S.N.: Recombinant DNA: Fact and Fic tion. Science 195:654-657, 1977. 2. National Institutes of Health Guidelines for Re search Involving Recombinant DNA Molecules. Washington, D.C.: U.S. Department of Health, Education and Welfare, Public Health Service, Fed. Regist. 41 (No. 131), 1976. 3. Wade, N.: Recombinant DNA: Guidelines De bated at Public Hearings. Science 191:834-836, 1976.

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Recombinant DNA: hypothetical fears vs. potential benefits.

Medicine as an art demands constant evaluation, weighing new treatments against old practices, benefits against risks, successesagainst failures. On o...
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