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210 THE LIFE SCIENCES edge and understanding in sound management programs can man expect to conserve the natural resources that are his great heritage. INDUSTRIAL TECHNOLOGY Biological science finds application in many aspects of the economy. There is no precise biology-related equivalent of the chemical or electronics in- dustries, which bear one-to-one relationships with specific areas of science. As we have seen, agriculture, medicine, protection of the public health, and conservation of renewable resources all directly apply increments in bio- logical understanding. Here we shall indicate briefly a few additional in- dustries whose capabilities, scale, and quality rest on applied biology. Pharmaceuticals Reference has repeatedly been made to the role of the pharmaceutical industry; suffice it to note, then, the magnitude of this industrial endeavor. In 1967 the industry had gross sales of about $4.2 billion. Of this, 10.5 percent was allocated to its own research and development programs- about one fifth of the nation's entire biomedical research enterprise in which just under 20,000 scientists and supporting personnel were employed. Table 5 summarizes the categories of drugs sold in 1967. The magnitude of the research task is shown by the number of animals required (Table 61. By now, the general pattern of pharmaceutical research is somewhat standardized. Research directors, aware of the Ileeds of human and veteri- nary medicine, monitor the output of worldwide fundamental biomedical research for clues to potential new drugs. Chemists then either purify some TABLE 5 1967 U.S. Drug Shipments in Major Categories (In $ Millions TOTAL HUMAN AND VETERINARY DRUGS Drugs for treatment of cancer, endocrine and metabolic diseases Hormones Corticoids Oral Contraceptives Other Other 4,143.0 439.6 413.5 141.7 103.5 168.3 26.1

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BIOLOGY IN THE SERVICE OF MAN 211 TABLE 5 continued Drugs acting on the central nervous system and sense organs Internal Non-Narcotic Analgesics Internal Narcotic Analgesics Tranquilizers Antidepressants Central Nervous System Stimulants Barbiturate Hypnotics Nonbarbiturate Hypnotics General and Local Anesthetics Other Drugs acting on the cardiovascular system Drugs acting on the respiratory system Drugs acting on digestive or genito-urinary system Antacids Antidiarrheal Drugs Laxatives Antiulcer Drugs Motion-Sickness Remedies Urinary Antibacterials and Antiseptics Diuretics Other Dermatological preparations Hemorrhoidal Drugs Other Dermatological Drugs Nutrients Vitamins Hematinics Other Drugs affecting parasitic and infective disease Antibiotics Sulfonamides Antifungal agents Antibacterials and antiseptics Other Pharmaceutical preparations for veterinary use Pharmaceutical preparations not specified by kind 1,130.1 448.4 40.3 321.4 45.0 80.5 25.4 35.4 47.4 86.3 204.0 366.6 552.4 137.3 41.4 79.0 73.5 24.6 28.7 94.8 73.1 236.9 27.6 209.3 168.5 204.1 58.5 145.6 698.8 468.3 32.5 28.7 133.1 36.2 140.4 1.6 t' Data from U.S. Department of Commerce, Bureau of the Census, Current Industrial Reports, "Pharmaceutical Preparations, Except Biologicals-1967," December 4, 1968.

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212 THE LIFE SCIENCES TABLE 6 Animal Usage in the Pharmaceutical Industry in 1965 a Mice Rats Hamsters Guinea Pigs Rabbits Dogs Monkeys Cats 23,200,000 9,900,000 900,000 350,000 250,000 93,000 60,000 33,000 a Data from a survey made by the Institute of Laboratory Animal Resources, Division of Biology and Agriculture, National Research Council. naturally occurring material or synthesize a desired chemical entity and a series of variations on this theme. The potential drug is then put through a "screen," an increasingly large and diverse battery of biochemical and physiological tests. If the material still appears to have the desired activity, it is tested in animal models of the human disorder, where such exist, and then screened for short-term and long-term toxicity in a variety of animal species. If all appears to be in order, permission is requested of the Food and Drug Administration to test the drug in man. After a tolerable dosage level is established in a few subjects, a much wider group of patients is treated with the drug for its specific use, while also being observed for any signs of toxicity. When a sufficient series has been tested, if the drug has proved efficacious for its intended purpose and if undesirable side reactions are minimal, permission is sought for free marketing. Finally, the Food and Drug Administration must balance hazard against benefit as it comes to a decision. No foreign compound is totally devoid of untoward effects. Indeed, were aspirin invented tomorrow, the Food and Drug Administra- tion would have a difficult time in deciding whether to issue a license. If the benefits warrant and the hazards are tolerable- particularly if the drug offers decided advantages over existing drugs or is truly lifesaving the Food and Drug Administration will issue the desired license, about 5 to 10 years and $5 million to $10 million after the start of the project. The overall results are evident in the facts that no more than 10 percent of drug sales represent entities available before 1940, that mortality from all infectious diseases fell from 88,000 deaths in 1941 to 17,000 in 1961, that tuberculosis sanitariums are closed, tranquilizers have emptied thou- sands of sanitarium beds, and few of us any longer are asked to bear extreme pain, thanks to nonaddicting, powerful analgesics.

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BIOLOGY IN THE SERVICE OF MAN 213 Food Once harvested or slaughtered, the products of agricultural practice must be "brought to the table." This is accomplished by the many components of the food industry, employing 14 percent of the working population in an endeavor aggregating $90 billion in 1966. Through the combined efforts of applied biologists, chemists, and engineers, the housewife may now choose among 8,000 items in the supermarket. This team has solved the problems of raw storage; out-of-season processing; long-term storage; min- imization of contamination by agricultural chemicals, bacteria, yeast, and molds; maintenance of moisture and nutritional content. It has upgraded the nutritional value of various native foods; monitored all stages of the preparative and marketing process; established the optimal conditions for transport and storage; devised such preservative mechanisms as ethylene oxide, sulfur dioxide, and nitrogen gas atmospheres, as well as procedures such as vacuum-, spray-, drum-, and freeze-drying, while monitoring such processes as fermentation of sauerkraut, cheese, or buttermilk and sterile filtration of beer, wine, and fruit juices. It has devised the wide variety of food additives now available and has developed specialized foods for dia- betics, phenylketonurics, and galactosemics, as well as for those with heart or kidney disease or gastrointestinal limitations. Pesticides As noted earlier, the properties of DDT and 2,4-D inaugurated a new era in management of our living resources and gave rise to a new industry. Each touched off a wave of research that continues to the present, seeking newer compounds that are species-specific, safe, and degradable. For the moment, the use of such compounds is indispensable; until superior means and materials are found, these compounds are essential to the success of our agriculture, while assisting in maintenance of our woodlands and pro- tection of our health. It is the scale of this use, rather than their intrinsic toxicity, that has properly generated public concern over the effects of these chemicals on the public health. In 1966, total production of all pesticides in the United States was 1,012,598,000 pounds. The rapid increase in use occurred because new pesticides have been developed that control hitherto uncontrolled pests, and broader use of pesticides in large-scale agriculture has increased crop yields significantly. Current trends in crop production involving large acreages, greater use of fertilizers, and intensive mechanized cultivation and harvesting offer par- ticularly favorable opportunities for insect pests and would result in large crop losses to these pests unless control measures were applied.

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THE LIFE SCIENCES The increased number of new pesticides in part resects a second gen- eration of pesticides with more appropriate persistence for economic con- trol of specific pests, more complete control of the pest, less hazard for the applicator, or less hazardous residues on the crop. An additional impetus to the development of new pesticides comes from the fact that many insect pests have developed resistance to the older pesticides. The development of pest resistance does not necessarily entail the development of more dan- gerous pesticides; the new agent need only be chemically different to over- come resistance. The continuing search for new, more nearly ideal pesti- cides requires the joint effort of research teams composed of organic chemists, biochemists, pharmacologists, physiologists, entomologists, and botanists. The effort is managed much like the development of new drugs, each chemical entity being tested in a "screen" of a variety of insects. About 73 percent of the total insecticide usage is in agriculture, and about 25 percent is used in urban areas by homeowners, industry, the military, and municipal authorities. The remaining 2 percent is applied to forest lands, grassland pasture, and on salt and fresh water for mosquito control. Over 50 percent of the insecticide used in agriculture is applied to cotton acreage alone. When insect-control measures are not used in agriculture, insect pests take 10 to 50 percent of the crop, depending on local conditions. Losses of this magnitude are not readily tolerated in the United States in the face of a rapidly increasing population and a concomitant decrease in agricul- tural acreage. In this sense, the use of insecticides might be deemed essen- tial at this time for the production and protection of an adequate food supply and an adequate supply of staple fiber. While alternative methods of pest control are under investigation and development, they are not yet ready to displace completely the chemical pesticides, and it appears that a pesticide industry will be required for some years to come. Pesticides have been tremendously effective, but individual pesticides, like sulfa drugs and antibiotics, tend to lose their effectiveness as species resistance to them develops. Hence, there will be a continuing search for new pesticides as long as pesticides are considered to be required for the economy or the public health. This search will require the continuing par- ticipation of able biologists. As with drugs, new pesticides, optimally, should be selectively toxic for specific pests, rather than broadly toxic against a wide variety of pests with serious side-effects on nonpest species. Broad- spectrum pesticides affect an essential enzyme or system common to a wide variety of pests. A selective pesticide, on the other hand, either should affect an essential enzyme or system peculiar to a particular pest or should be applied in such a way that only the particular pest gains access to it.

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BIOLOGY IN THE SERVICE OF MAN 215 An interesting example of a selective pesticide is the rodenticide norbor- mide, which is highly toxic for rats, particularly for the Norway rat. By contrast, the acute oral toxicity of norbormide for other species is much lower, the lethal dose for a great variety of birds and mammals, per kilo- gram of body weight, being more than 100 times greater. The mechanism of the selective toxic action of norbormide for rats is not yet elucidated. Achievement of target specificity requires a sophisticated knowledge of the anatomical, physiological, or biochemical peculiarities of the target pest as compared with other pests or vulnerable nonpests; a pesticide may then be developed that takes advantage of these peculiarities. This is obviously not easy to accomplish, and norbormide may prove to be unique for many years. An alternative is the introduction of a systemic pesticide into the host or preferred food of the target pest. Other pests or nonpests would not contact the pesticide unless they shared the same host or food supply. As an example, a suitable pesticide may be applied to the soil and imbibed by the root system of a plant on which the pest feeds. The pest feeding on the plant then receives a toxic dose. The application of attractants or re- pellents (for nontarget species) would increase the selectivity of the sys- temic pesticide. The use of systemic pesticides on plants used for food by humans or domestic animals poses an obvious residue problem. There has been a strong public reaction against the continued use of pesticides on the grounds that such use poses a potential threat to the public health as well as being a hazard to wildlife. Careful investigations have so far failed to establish the magnitude of the threat to the public health; i.e., there are as yet few if any clear-cut instances of humans who have suffered injury clearly related to exposure to pesticides that have been used in the prescribed manner. Report No. 1379 of the 89th Congress (July 21, 1966 ~ * concluded: The testimony balanced the great benefits of disease control and food production against the risks of acute poisoning to applicators, occasional accidental food con- tamination, and disruption of fish and wildlife.... The fact that no significant hazard has bee'' detected to date does not constitute adequate proof that hazards will not be encountered in tile future. No final answer is possible now, but we must proceed to get tlze answer. (Italics ours) Failure to establish such hazard does not mean that it does not exist. There are no living animals, including those in the Antarctic, that do not * U.S. Congress. Senate. Committee on Government Operations. Interagency Environmental Hazards Coordination, Pesticides and Public Policy (Senate Report 1379). Report of the Subcommittee on Reorganization and International Organiza- tions (pursuant to S.R. 27, 88th Cong., as amended and extended by S.R. 288), 89th Cong., 2d sees., Washington, D.C., U.S. Government Printing Once, 1966.

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216 THE LIFE SCIENCES bear a body burden of some DDT. Large fish kills and severe effects on bird populations have been demonstrated. The large-scale use of these agents has been practiced for less than two decades, and use has increased annually until this year ( 1969 ~ . Whereas the anticholinesterase compounds, which have high acute toxicity (and hence are highly hazardous to the applicator), are readily and rapidly degraded in nature, the halogenated hydrocarbons are not. With time, their concentration in the soil and in drainage basins, lakes, ponds, and even the oceans must continue to increase, thereby assuring their buildup in plant and animal tissues. Over a sufficient time period, this is potentially disastrous. And should such a period pass without relief, the situation could not be reversed in less than a century. Because of the large economic benefit to the farmer, it is pointless to adjure him to be sparing; unless restrained by law, he will make his judgment in purely personal economic terms. But mankind badly needs the incremental food made possible by use of effective pesticides, and the enormous benefit to public health of greatly reducing the population of insects that are disease vectors is a self-evident boon to humanity. Thus it is imperative that alternative approaches to pest control be developed with all possible dis- patch, while we learn to use available pesticides only where they are clearly necessary and desirable and to apply them in the minimal amounts adequate to the purpose. A recent development in insect-pest control has been the possible use of juvenile hormone. This hormone, normally produced by insects and essential for their progress through the larval stages, must be absent from the insect eggs if the eggs are to undergo normal maturation. If juvenile hormone is applied to the eggs, it can either prevent hatching or result in the birth of immature and sterile offspring. There is evidence to suggest that juvenile hormone is much the same in different species of insects, and analogs have been prepared that are effective in killing many species of insects, both beneficial and destructive. There would, therefore, be great danger of upsetting the ecological balance if juvenile hormone were applied on a large scale. What is needed, then, is development of chemical modifications of juvenile hormone that would act like juvenile hormone for specific pests but not for other insects. For example, a preparation from balsam fir, which appears to be such an analog, has been identified and is effective against a family of bugs that attack the cotton plant, but not against other species. If it proves possible to synthesize similar analogs specific for other pests, a new type of pesticide may emerge. If this happens, it will be extremely important to explore possible side-effects on other insect species and on warm-blooded animals before introduction of yet a new hazard into the biosphere.

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BIOLOGY IN THE SERVICE OF MAN We cannot rest with existing pesticides, both because of evolving pest resistance to specific compounds and because of the serious long-term threat posed by the halogenated hydrocarbons. While the search for new, reasonably safe pesticides continues, it is imperative that other avenues be explored. It is apparent that this exploration will be effective only if there is, simultaneously, ever-increasing understanding of the metabolism, physiology, and behavior of the unwanted organisms and of their roles in the precious ecosystems in which they and we dwell. Fermentation Industry Wine and leavened bread date back to antiquity, but the fermentation industry is a product of modern biological science. In sum, the disparate fermentation industry constitutes a major national resource. Each of the major companies in that industry retains a staff of microbiologists, bio- chemists, chemists, and engineers. Together, they are responsible for the continuing monitoring control of the fermentations with which they are concerned. The microbiologists constantly search, by the conventional techniques of bacterial genetics, for new strains of micro-organisms that will more efficiently or more rapidly conduct the fermentation in question. Rarely do these groups, as such, discover new fermentations yielding new products of value. Most have been encountered earlier in the course of systematic microbiology, and the industrial research team develops the procedures whereby a laboratory observation is scaled up to the requisite industrial magnitude. An important exception has been the systematic hunt for new antibiotics by the drug companies. Bakers', food, and fodder yeasts were produced in excess of 180,000 tons in 1967. Alcohol fermentation amounting to 685 million gallons in 1945 has largely been replaced by a process starting with petroleum- cracking fractions, as has the fermentative production of acetone and butanol. But 5 billion pounds of raw grains were used to produce 110 million barrels of beer and ale, while 235 million gallons of wine and 185 million gallons of distilled spirits were also produced by fermentation. Other fermentation procedures produce lactic acid, vinegar, dextrans for drilling muds and as a plasma substitute, verbose, and glutamic acid. Bacteria are grown as legume inoculants and as bioinsecticides. Molds and streptomyces are grown as a source of at least 30 distinct antibiotics in general use, as well as of citric acid and a variety of other organic acids. One mold is now used to make giberellin, which stimulates seed germination, improves growth of young trees, increases the flowering of plants, "sets" tomato fruit clusters, and breaks the dormancy of potatoes.

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218 THE LIFE SCIENCES Allied to these processes is the use of molds, streptomyces, and bacteria in synthetic chemistry to accomplish specific reactions not readily feasible by chemical means. At least 25 such procedures are in current use in steroid synthesis in pharmaceutical laboratories. Related, also, is a relatively new industry, the manufacture of enzymes on a substantial scale. At least 20 enzymes are now articles of commerce. Thus, amylases from pancreas. barley malt, or fungi are used to de-size textiles, start brewing fermentation, precook baby foods, or cold-swell laundry starch. Papain from papaya, bromelin from pineapple, and subtilisin from B. subtilis are used as meat tenderizers, to stabilize chill-proof beer, and most recently as adjuncts to laundry detergents. Still other enzymes are used in candy manufacture, in clinical diagnostic procedures, to clarify wine and beer, to tan leather, and for debridement of wounds. The list of enzymes and their uses is growing, limited only by imagination. No estimate of the magnitude of these diverse biological industries is available, but clearly in sum they represent several billion dollars of the gross national product. In every instance, biological understanding under- lay the original industrial concept, guided the necessary research and de- velopment, gave direction to the industrial installation, and is required for continuing monitoring of the process. instrumentation The scale and sophistication of modern biological research and its appli- cations have necessitated birth of a new industry the manufacture of biological instruments. The need for and use of most instruments usually arises in a research laboratory. But, thereafter, if it is to be more generally available, conveniently packaged, simple and reliable in performance, and readily serviced, its production must be taken over by a commercial manu- facturer. Competition among manufacturers is the stimulus that has pro- vided a stream of increasingly useful, sensitive, and reliable instruments, annual sales of which now approximate $1 billion. Appreciation of the diversity of such instruments may be gained from the data concerning use and need presented in Chapters 3 and 4. When established, such instruments are modified to monitor and con- trol industrial biological processes and for diagnostic and therapeutic use in hospital practice. An excellent example is the development of an auto- mated apparatus that can accept an unmeasured small volume of blood, perform about 15 different analytical procedures thereon, calculate the results in conventional units, and record them on the patient's record. These data are decidedly more reliable than are individual determinations per

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BIOLOGY IN THE SERVICE OF MAN formed manually by technicians, and the cost is comparable to that of a single such manual procedure. In consequence, the physician's armamen- tarium is markedly expanded, at no additional cost to the patient or to society. From this brief summary it will be evident that the skills and understanding of the modern biologist find their way into a remarkable variety of human endeavors, rendering life more secure, healthier, longer, more comfortable, and more pleasant, while giving employment to millions.