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C H A P T E R T W O BIO LO G Y IN TH E SE RVICE OF MAN Progress in biological understanding has proceeded at a spectacular rate for two decades. The deepening insights into the nature of man and his diverse living kin could well be reward enough for the large investment of effort and funds. Such understanding is more than a highlight of our culture; it is a primary tool of our working civilization. In the pages that follow we shall seek to illustrate and document that statement. Only a small sampling can be offered here, but it should become evident that the life sciences have dramatically altered our life style, contributing to our security, our health, our comfort, and our enjoyment. BIOLOGICAL RESEARCH AND MEDICAL PRACTICE The impressive and rapidly growing, though fragmentary? conceptual struc- ture of biology has greatly increased understanding of disease mechanisms; presumably, as the conceptual framework becomes more general and more coherent, comprehension of disease will grow correspondingly' thereby enlarging opportunity for the alleviation and prevention of many disorders. 142

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BIOLOGY IN THE SERVICE OF MAN In considerable measure, the history of biology is the history of attempts to cope with disease. Many disorders have fruitfully been viewed as "nature's experiments" and, as such, have proved to be cardinal clues in elucidation of major fundamental phenomena. Thus, vitamin-deficiency diseases e.g., pellagra, beriberi, sprue, and scurvy were the clues to the very existence of vitamins and, hence, to the coenzymes of metabolism; investigations of diabetes and glycogen-storage diseases revealed the hor- monal control of carbohydrate metabolism and, indeed, the pathways of that metabolism; the prevalence of pernicious anemia revealed the existence of vitamin Be., and of the unique biochemical reactions it makes possible; the requirement for agents to manage infectious diseases stimulated the discovery of antibiotics, and these, in turn, proved to be powerful tools in the elucidation of the mechanism of operation of the genetic apparatus and the synthesis of bacterial cell walls; the dramatic changes in the volume, pH, and salt concentrations of blood plasma in such disorders as infantile diarrhea, pernicious vomiting, diabetic coma, and Addison's disease have been both the primary stimuli and the major "experiments" in revealing the complex homeostatic mechanisms that control the volume, acidity, and electrolyte composition of the body fluids of both the intracellular and extracellular compartments; the variety of cardiac disorders has revealed the fine mechanisms and neural control of the cardiovascular system; and the existence of sickle cell anemia and other instances of altered hemo- globin structure were the first demonstration that a "point" mutation results in a specific amino acid replacement in a protein, as well as the demonstra- tion that the genetic code in man must be identical with that in the bacterial species in which it was first determined. In each instance, the knowledge so gained, abetted by insights from other areas of biology, has resulted in expansion and improvement of the therapeutic armamentarium to the great benefit of those afflicted with the very disorders that served as clues. This mutual feedback has characterized much biomedical practice. Advances in practice have come only when the intellectual stage was set and suitable methods were in hand. Painstaking analyses of the electrolyte composition of the blood in health and disease, over a period of 40 years, contributed much to current understanding. But the analytical methods required were tedious slow, and unreliable in the hands of any but highly qualified experts. In the last decade, these were replaced by a variety of thoroughly reliable, semiautomated procedures allowing the benefits of this understanding to be brought to virtually all those requiring it. The precise control thus afforded, symbolized in the bottles of intravenous in- fusions so common in modern hospital practice, has dramatically reduced mortality in a variety of illnesses and has been a major contribution to the success of current heroic surgical procedures. Hence, one no longer en

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144 THE LIFE SCIENCES counters the once painfully exact irony, "The operation was successful but the patient died." The new analytical methods and their use in guiding parenteral fluid therapy are the fruit of thousands of painstaking investiga- tions. This chapter cannot hope to provide a comprehensive summary of such contributions but will, rather, describe a few recent noteworthy illus- trations. The National Health The dramatically altered national health picture since the turn of the cen- tury broadly illustrates the changes man has wrought through his science and suggests those yet to be accomplished. Fifty years ago the major medical problems afflicting individuals in the United States were similar to those now facing developing nations. In 1900, both influenza and pneumonia killed more persons than any other disease. Tuberculosis came next. The combined death rate (deaths per 100,000 of population) from these diseases was greater than that from heart disease today, a malady that killed more than 712~000 persons in 1965, when cancer took the lives of an additional 300,000 individuals. In the early 1900's, the death rate from tuberculosis exceeded that from either of these causes, while diphtheria, now almost unknown, was the tenth leading cause of death. For three decades, pellagra deficiency of the vitamin nicotinic acid-was the leading cause of death in eight southeastern states, whereas cases of this disease have rarely been reported since 1945, and mortality is zero. Diagnosis, Disease, and Drugs SULFONAMIDES AND ANTIMETABOLITES Quite evidently, many people who would have succumbed to infectious disease in an earlier day now survive to die, at a later age, of degenerative disease or cancer. The advent of antibiotics deserves major credit for cur- rent ability to cope with infections. Moreover, antibiotics have played a major role in the development of drugs and approaches to the treatment of other diseases, including cancer, by illuminating the broad principle of drug design, which is fundamental to much current research. From understanding of the mechanism by which sulfonamides inhibit the growth of bacteria came the concept of antimetabolites and new insights into the essential relationship between molecular form and physiological function. Simply stated, an antimetabolite inhibits the activity of an enzyme

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BIOLOGY IN THE SERVICE OF MAN that cells need for growth or other normal activity because it closely re- sembles the natural substrate of that enzyme. However, the antimetabolite cannot be affected by the enzyme and remains attached to its surface; in consequence, the enzyme cannot perform its normal function. The discovery of specific bacterial inhibition has a long history. In 1904, Paul Ehrlich, a German scientist, postulated that infectious diseases could be treated if chemicals could be found with a greater affinity and toxicity for parasite organisms than for host cells. Using dyes against trypanosomes and arseni- cals against spirochetes, he demonstrated the validity of his hypothesis and provided the earliest useful treatment for syphilis. In 1935, a dye called Prontosil was shown to be effective in treating streptococcal infections in patients, though it had no effect on bacteria in a test tube. The demonstra- tion that individuals treated with Prontosil excrete sulfanilamide, a degrada- tion product of the dye in the body, was soon followed by observation that this compound inhibits both infection in patients and the growth of organ- isms in laboratory test media. A vigorous program of chemical modification of the basic structure led to a new class of drugs, the sulfonamides. Even now, these are the drugs of choice in the treatment of gastrointestinal and urinary-tract infections. Early empirical success with sulfanilamide rendered it imperative that the mechanism of its effect be understood, so as to permit design of even more effective congeners. A lengthy series of observations, conducted in a multitude of laboratories at home and abroad, yielded the following con- clusions: Sulfonamides inhibit bacterial growth by preventing the organisms from synthesizing folio acid, a vitamin for man, lack of which results in sprue. Normal synthesis of folic acid by bacteria and plants commences with the incorporation of p-aminobenzoic acid. In molecular structure, p-amino- benzoic acid and the sulfonamides are distinctly similar. NH2 COOH p-aminobenzoic acid NH2 SO2NH2 sulfanilamide When a sulfonamide attaches itself to the enzyme responsible for the normal reaction with p-aminobenzoic acid, synthesis is blocked, and, for lack of folio acid, the bacterium cannot survive. Because man is unable to

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146 THE LIFE SCIENCES synthesize his own folio acid, the sulfonamides do his metabolism no harm, selectively attacking bacteria while leaving human cells undamaged. It was these observations that gave rise to the concept of antimetabolite drugs. Many have since been usefully synthesized, but no better example of the concept is yet available. ANTIBIOTICS Penicillin was discovered in 1929 when a British bacteriologist observed the inhibitory properties of the fungus Penic~ll~um notatum' which secretes penicillin into surrounding media. This substance, destined to become the most widely used antibiotic, was, however, originally discounted as im- practical because of its seeming chemical instability. But by 1940 other British scientists showed that it was reasonably stable when partially purified and dried. Their material, only 50 percent pure, proved to be nontoxic to man and very active against susceptible micro-organisms, including staphylo- cocci. Although effective, penicillin was tedious to purify, and problems of mass production seemed insurmountable when the calamity of war prompted members of the British group to look across the Atlantic for help. The mass outbreak of typhus during World War ~ and the loss of count- less wounded to secondary bacterial infection, followed in quick succession by the influenza pandemic of 1917-1918 gave urgency to the search for an effective antibacterial agent as we entered World War II. It took the crisis of the Second World War, which harnessed the potential of the American drug industry, until then running a distant second to Europe as a source of new drugs, plus the resources of the Department of Agriculture, to create the antibiotic age. The results were nothing less than spectacular. Success was based upon already developed techniques for large-scale cultivation of micro-organisms, the isolation of Penicill~um strains that secreted large quantities of penicillin, and the development of suitable growth media. By September 1943, there was enough of this drug to supply all the Allied forces. This phenomenal accomplishment not only markedly reduced mor- tality among the wounded but also launched a new and fruitful search for other antibiotics. After elucidation of the chemical structure of penicillin, in due course natural penicillin was replaced by semisynthetic penicillins, which are com- paratively simple to manufacture and which retain the essential molecular configuration of the parent molecule, which is so eRective against Gram . . . positive organisms. The attempts to prepare semisynthetic penicillins bore an additional fruit. The earliest such attempts, which seemed entirely rational, failed. When the explanation was found, it proved to be an important extension

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BIOLOGY IN THE SERVICE OF MAN . of the antimetabolite principle. Sulfanilamide and p-aminobenzoic acid are essentially planar molecules; thus the analogy suggested by the two- dimensional formulae above is indeed valid. But the unsuccessful semi- synthetic penicillins, which appeared to be reasonable analogs of natural penicillin as these structures are conventionally represented on paper- differed significantly when three-dimensional models, based on x-ray evi- dence, were constructed. Since then, chemists engaged in the synthesis of new drugs have been acutely aware of the fact that, to be effective, the drug must attach properly to the surface of the enzyme or membrane to be affected, and this must be a property of its three-dimensional conformation. Extensive screening of soil samples, largely by drug manufacturers, then led to the discovery of an ever-increasing family of antibiotic agents, among them streptomycin, chloromycetin, aureomycin, and terramycin. Although there is as yet no universally effective agent, one or another of these drugs can mitigate virtually all known infections. Antibiotics have drastically altered the patterns of medical practice. Prior to 1940, thousands of hospital beds were occupied by patients with infec- tious diseases. Today, in the main, these patients receive a prescription for antibiotics and return home. The morbidity associated with postoperative infections has dropped sharply. And the damaging, once frequent, chain of events that began with a "strep throat" and went on to scarlet fever, . . . rheumatic lever, and serious heart disease has been broken. The search for new and better antibiotics continues in an effort that counts on both ration- ally exploited chance and accumulated skills and understanding. New anti- biotics are still discovered by screening methods in which activity is sought in extracts of thousands of yeasts and fungi and soil samples of unknown microflora from around the globe. Modified, improved semisynthetic com- pounds then follow as drug designers attempt to deal with the two most critical problems posed by these drugs. As predicted by scientists familiar with the physiology and genetics of bacteria, as use of antibiotics spread throughout the population, so, un- fortunately, did bacteria that are antibiotic-resistant. The antibiotic boom fostered selective processes that bred resistant organisms. Among a normal population of bacteria there are, almost invariably, a few organisms that have spontaneously mutated, the mutation rendering them immune to the bactericidal action of a given antibiotic. As the drug suppresses the growth of sensitive members of the colony, resistant mutants flourish. In some cases, simultaneous use of two antibiotics with differing modi operandi is effective to a limited degree. But the problem is compounded by the fact that resistance, like an infectious disease, is catching. Both by sexual mating and by transduction, a process in which a virus carries a bacterial gene from one cell to another, bacteria can spread their resistance among related

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148 THE LIFE SCIENCES strains, and some organisms have been isolated that are resistant to several antibiotics at once. Recent work describing transduction may open the way to "outwitting" this threatening phenomenon, as should continuing improve- ment of semisynthetic antibiotics that are of greater potency and specificity than natural antibiotics but that are insensitive to the enzymes that destroy the latter. The spectacular success of these antibiotics gave sharp stimulus to inquiry into their mode of action, an inquiry that continues with increasing intensity. In a few instances, partial answers are already available. Thus, penicillin selectively inhibits one specific enzymatic step in the complex process wnerecy tne ceil walls of Ram-positive bacteria are fabricated. Each such wall is a single "bag-shaped" macromolecule built of 10 different kinds of subunits. As the cell grows, or divides, linkages must be broken and addi- tional subunits inserted. Interruption of this process leaves the cell without a casing and, hence, renders it susceptible to damage by diverse physical or chemical changes in its environment. since mammalian ~ ~mninv an ^~ ~u ~ a:_ ~ ~C ~ ~ ~ 1 1 quell ~db111g, LIl~y dE~ UIla~eCtea By penicillin. Actinomycin D, which has found only limited use as an antibiotic, operates by interference with the mechanism by which RNA is made on the surface of DNA. Because it affects mammalian cells in the same way, it has found little clinical use as an antibiotic. Streptomycin in some manner so affects the ribosomes of Gram-negative bacteria that they make mistakes in translating RNA into protein, and hence make useless, nonfunctional proteins. As this field progresses as the secrets of naturally occurring antibiotics are revealed- it should be possible to improve on antibiotics, permitting synthesis of chemical entities that are lethal for invading organisms yet relatively innocu- ous for man. In each case, the new drug must be so constructed as to fit, sterically, onto an enzyme or a membrane surface in such fashion that it will seriously limit normal function, presumably by extension of the anti- metabolite principle. A more sophisticated understanding of the operation of the pathways by which products are synthesized in the body has offered a new approach to drug design. Early attempts to block the synthesis of a given product, e.g., cholesterol, sought to inhibit an enzyme known to be vital to its biosyn- thesis. Research generally was directed at finding a drug that mimicked the substrate with which a specific enzyme reacted, as noted earlier. How- ever, a new avenue of pursuit was opened by the understanding that the "committed step" in most synthetic metabolic pathways (pathways that involve a series of consecutive reactions) is subject to allosteric feedback inhibition by the final product, which bears little resemblance to the sub strate of the enzyme responsible for the committed step. It is clear that ingestion of cholesterol drastically inhibits its own biosynthesis. Patently,

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BIOLOGY IN THE SERVICE OF MAN a foreign molecule that, in low concentration, could accomplish the same event might serve as a potent drug for prevention of atherosclerosis, and a series of other such possibilities is also under active investigation. But until the principle of allosteric feedback inhibition had been revealed in studies of bacterial metabolism, this approach could not have been con- ceived. There is good reason to expect a considerable increase in the sophistica- tion of drug synthesis in the near future. In addition to the factors con- sidered above, it is evident that many drugs- e.g., morphine and digitalis- work by attachment to specific loci on cell membranes or intracellular membranous structures. Partial understanding of how a drug interacts with a cell membrane at the molecular level has only evolved in recent years. As this field matures-as the structures of membranes are revealed it may well become possible to alter them usefully in specific states. Quantitative information about the biochemical events in metabolic disease is badly needed, permitting construction of mathematical models of metabolic events in a form manageable in a computer. Such information can be applied in testing new drugs for a given disorder and in determining suitable dosage regimens. For years, the interrelationships between levels of blood glucose and secretion of insulin after the administration of sugar to normal volun- teers and to diabetics have been crudely understood. More recently, a carefully constructed mathematical model describes the effect of admin- istered insulin on the uptake of glucose by the tissues, with resultant changes in blood-glucose levels and in the release of insulin from the pan- creas. Use of this model permits more nearly normal regulation of the blood-sugar levels of diabetics. The benefits to man to be derived from this advance are not yet certain, but the potential is huge. The insulin regimens available since 1920 have sufficed to maintain the lives of hun- dreds of thousands of diabetics. In time, however, they progress to a series of highly undesirable sequelae cataract, peripheral vascular disease, hyper- tension, atherosclerosis, and a disease of the lining of the minute filters of the kidneys. A generation will be required to establish whether the dosage schedules suggested by the new mathematical model, which, far more than in the past, mimics the release of pancreatic insulin by normal individuals, will also prevent the physical deterioration that is characteristic of diabetics treated with insulin for the last half century. As understanding of disease has dramatically increased, so have demands for better comprehension of what disease is on the molecular level. Simul- taneously, the development of a new drug has become a considerably more complex operation due to the effort to meet increased requirements for specific details about mode of action, specificity of action, safety, and effec- tiveness in man. From the time a scientist arrives at an idea of the phar - 149

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150 THE LIFE SCIENCES mycological potential of a new compound to the time that compound actually reaches the market a period of five to ten years a pharmaceutical house must invest between $5 million and $10 million. Yet, this is our ultimate hope for useful new drugs, and increasingly such developments must rest on sound fundamental studies. VIRAL DISEASES In contrast to the great success of antibiotic therapy for bacterial infections, only trivial progress has been achieved in coping with viral diseases. A virus consists of a relatively small amount of genetic information, as either DNA or RNA, with a protein coat. This coat is shed as the nucleic acid enters the cell, where it usurps the normal genetic apparatus, shutting off normal production of cellular RNA and proteins so as to turn out many copies of the virus itself. Patently, any drug or procedure calculated to interfere with this process must also similarly interfere with normal opera- tion of the genetic apparatus. Although this is probably tolerable for brief periods in a tissue such as muscle, it could be highly injurious to such rapidly dividing tissue as that of' the bone marrow or the intestinal tract. Clearly, drugs intended to serve these ends must possess a very high degree of specificity and, despite much work, only a few useful leads are available. One noteworthy example is the treatment of viral eye infections' e.g., the herpesvirus, with a halogenated pyrimidine compound, S-iododeoxyuridine. Although quite toxic systemically, it can be safely applied as eye drops. In the eye this compound is incorporated into the new viral nucleic acid, which then, as if mutated, directs the synthesis of inappropriate proteins, and the infection cannot sustain itself. A recent finding of considerable promise is that an antibacterial anti- biotic, rifampicin (rifantin), also has very significant antiviral potency. Its mechanism of action is highly interesting; for unknown reasons, in the presence of this compound, the coat proteins of several viruses cannot assemble on the viral nucleic acid surface. Hence, although both nucleic acid and coat proteins are made in the infected cell, the full virus cannot be assembled and fails to leave the cell in which its components were syn- thesized, and thus the infection is terminated. Since there is no analogous assemblage in the metabolism of mammalian cells, the antibiotic can be used in animals, in adequate dosage, as an antiviral daunt without c~nrfArn that it will interfere with any vital process in the host animal cells. For the present, the major defense against virus infection must remain man's own principal defense mechanism the immune system. The efficacy of this system was long evident in the list of diseases that strike but once in a lifetime, e.g., smallpox, measles, mumps. In each case the 'antigen the foreign material that is "recognized" as foreign and that both elicits formation of antibodies and combines with them is the viral protein coat.

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BIOLOGY IN THE SERVICE OF MAN Effective defense is possible either by deliberate immunization in advance, or by enhancing the immune response early in natural infection. Deliberate immunization has long been practiced, as in smallpox vaccination, while enhancement of the immune response has, until recently, consisted largely of administration of antibodies from someone who has already had the disease, as in administration of pooled ~y-globulin to prevent a suspected case of measles. Understanding of the nature and behavior of viruses, coupled with methods for culturing them, lay behind the development of the polio vaccine. As recently as 1954, this crippling disease struck 20,000 Americans an- nually. Eleven years later, only 61 cases were reported in the United States, the dramatic achievement of a mass-immunization campaign. Although the general principles of immunization had been known since Jenner intro- duced smallpox vaccine, much fundamental knowledge had to be acquired before it could be applied with impunity to the polio virus. It was first necessary to develop a cell system monkey tissues grown in culture-in which polio viruses could be grown. Initially, viruses grown in this way were chemically inactivated and then administered. The subsequent per- fection of live polio vaccines depended upon an independent line of research and the discovery of three mutant forms of the virus that could no longer cause disease but retained their immunizing effect. A development of molecular biology that may yet offer large dividends is the recently acquired knowledge of a material called "interferon." This is a protein, perhaps an enzyme, that is produced in small amount by ani- mal cells infected with a virus. In sufficient quantity it increases remark- ably the efficacy of the immune response. Until techniques become available for its large-scale production, the best hope has appeared to be stimulation of the mechanism by which one's own cells engage in interferon synthesis. The primary trigger seemed to be the viral nucleic acid. Following this clue' it was found that synthetic double-stranded RNA (a simple polymer devoid of meaningful genetic information) is at least as efficient a stimulus as viral nucleic acid. When given early in an infection-e.g., mice given sufficient virus of hoof-and-mouth disease to assure 100 percent lethality- such material has offered complete protection, not only sparing lives but preventing the disease. This may yet prove to be the basis of a truly useful clinical approach to viral infection with the happy property of being generally useful without regard to the specific virus in question in any riven patient. CANCER THERAPY Insights into the nature of DNA, its biosynthetic processes, and its role in cell growth and development have had wide application in recent cancer research. Coupled with recognition of the antimetabolite principle, these

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52 THE LIFE SCIENCES insights stand behind the development of a series of anticancer drugs that are able to check the growth of tumor cells, prolonging the lives of some patients by several years. Cancer, second only to heart disease in the mortality tables, Is not one but many diseases. Slow-growing solid tumors, such as lung cancer, are extremely difficult to treat unless the tumor is localized so that it can be removed by surgery or destroyed by irradiation. Significant progress has been made in treating by chemotherapy fast-growing tumors such as leu- kemia or other blood or lymph cancers. Cancer of both types is character- ized by abnormal, uncontrolled growth of cells. Successful therapy depends upon an understanding of the metabolism and synthetic activities of those cells and rests on the principle of attacking them when they are in a vul- nerable state. The process of cell replication occurs in four stages: two pauses or rest- ing states, a period of DNA synthesis, and one of mitosis and cell division. Dill Brent chemical agents selectively inhibit cell metabolism at different stages in this cycle and, because the cancer cells in an individual are not all synchronized that is, they are not all in the same phase at the same time- judicious use of a combination of antimetabolites is necessary to destroy the maximum number of tumor cells. =~1; - ^~;rl ;^ .~,1 1~.w ~ __ (Ella d\;1U 15 used any man as a coenzyme in the process of synthesis of DNA precursors. Therefore, it was reasoned, an antimetabolite that could disrupt this sequence would inhibit the growth of tumor cells in the DNA- synthetic phase. Of a series of structural analogs that were tested, one called methotrexate ~ amethopterin ~ is clinically useful. Its drawback is its lack of specificity; it acts against all cells in the DNA-synthetic phase, whether they are cancerous or not. The turnover of normal cells, however, is distinctly less than that of rapidly dividing cancer cells; in weighing risk versus benefit, it was concluded that the toxic effects of methotrexate are less than its benefits, particularly in the treatment of leukemia. Another agent in the arsenal of anticancer agents is actinomycin, origi- nally found as an antibiotic, which checks cell growth by limiting RNA synthesis on DNA. When used against choriocarcinoma, an all too fre- quently fatal cancer of Vouno wom~.n of rhilrlh~rinc~ ~ it ~f[=,~o ~ 50 percent cure rate (remission of symptoms for five years). In combination with methotrexate, cures are achieved in close to 80 percent of cases. The same combination effects a 70 percent cure rate in Wilm's tumor, a kidney cancer, and a 25 percent cure rate in cases of Burkitt's lymphoma, a malig- nancy of the lymph glands first identified in children in Central Africa but now known to be widespread. Patently, without knowledge of the mode of action of actinomycin as an antibiotic, there could have been no reason to consider it as a potential anticancer agent. = .. ~^ _~4 ~V~4A~= ~l ~11~LO a

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166 THE LIFE SCIENCES the pharmacology of the existing drugs is imperfectly understood. Knowl- edge of the electrical basis for the formation and conduction of impulses within the heart gained impetus when it became possible to record the transmembrane potentials of single cardiac fibers by implanting micro- electrodes within cells. By means of this technique and associated studies, it became possible to characterize the ionic basis of cardiac electrical ac- tivity, to identify the unique properties of certain specialized cells, and to observe the influence of, for example, quinidine and digitalis on these param- eters. Now, from studies of the electricity of the heart and of the ionic processes associated with it, highly detailed, though not yet complete, pic- tures have been drawn of each of the major clinical types of arrhythmia, a new beginning is under way, and suitable test systems are available for the search for specific antiarrhythmic drugs. Critical to ultimate management of these disturbances is improved under- standing of the underlying electrical activity, which is the result of the operation of the cellular "electrolyte pump." It must be more than fortui- tous that the "cardiac glycosides," particularly ouabain, which can assist a failing heart are the most effective known inhibitors of the cellular transport system, which, in cardiac muscle as in all other cells, achieves the outward movement of sodium ions and the inward movement of potassium ions using the energy of ATP. The responsible protein is associated with cell membranes; the model proposed in Chapter 1 for transport processes seems an adequate description of its function, viz., binding of 3Na+ and lATP, a conformational change that permits rotation in the membrane, hydrolysis of the ATP, discharge of the Na+, binding of K+, and rotation to the original position. Control of this basic life function, which is adapted to the special purpose of "electrical" conduction in nerve and muscle fibers, appears central to progress in a variety of cardiac disorders. Parenthetically, one may note that hyperactivity of this system in the various secretory glands is one of the manifestations, now used as a definitive diagnostic sign, of cystic fibrosis. In yet another context, it is the genetically controlled syn- thesis of this same transport protein in kidney tubules that is regulated by aldosterone, the adrenal hormone that, in excess, causes (:ushing's disease and lack of which occasions Addison's disease. The advent of cardiac surgery (and indeed, of cardiac transplantation) is one of the most dramatic episodes in the history of medicine. Clearly, these heroic procedures could not have been attempted until all the neces- sary knowledge, skills, materials, and tools were at hand. Illustrative is the instrument that has become the sine qua non of modern heart surgery-the heart-lung machine. When the heart is opened for repair of a valve or closure of a hole be

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BIOLOGY IN THE SERVICE OF MAN 167 tween the two ventricles (pumping chambers), the heart-lung machine is temporarily employed to assume the function of the heart and lungs, to pump blood, supply oxygen, and eliminate carbon dioxide. First used successfully in man in 1953, its origins can be traced through preceding centuries to the 1500's and 1600's, when double-valve, one-way pumps were designed to draw water from deep mines. These, in turn, apparently inspired William Harvey to recognize the true nature of the heart, which he likened to a water pump. In the 1800's, physiologists attempted to duplicate the work of the heart by perfusion of various animal organs such as the liver and kidney, using a pump to better understand the functions of these organs. In time, physiologists tried to add oxygen and remove carbon dioxide from the blood used in perfusions, thus experimenting with crude forerunners of the heart-lung machine. Their glass, rubber, or metal parts, however, severely damaged the delicate red blood cells, a fact of little con- sequence in short-term experiments on isolated organs but of obvious import for human application. The plastics industry solved this problem by offering virtually inert, smooth plastics with nonwetting surfaces, which minimize damage to the blood cells as they pass through the pump. Once developed, successful application of the heart-lung machine awaited solution of one other problem. When blood comes into contact with sur- faces other than normal blood vessels, it clots. Indeed, this would happen in the blood vessels themselves were they not coated with natural anti- clotting compounds. Among these is heparin, which can be obtained in quantity from beef lungs. Heparin inhibits the clotting mechanisms, per- mitting blood to course through the tubes and chambers of the machine for hours. Many refinements in recent years have made the heart-lung machine safer and more readily available. Artificial heart valves and plastic blood vessels, developed in collaboration with engineers, are available to surgeons. Even totally implantable artificial hearts have been tried in man. And long years of animal experimentation, coupled with the availability of immuno- suppressive drugs and techniques for determining tissue matching, make human heart transplantation a feasible, though still highly experimental, procedure. Yet the road ahead is long. Oxygenators causing less damage to blood than those currently available are needed if heart-lung bypass is to be applied for long periods of time. Such an instrument is essential to save patients with serious but reversible lung diseases, such as hyaline membrane disease in newborns. The use of artificial pumps either partially or completely to support the circulation of patients during a heart attack is a logical move that has already been attempted, but it is far from routine and demands considerable refinement. Significant progress toward pro

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168 THE LIFE SCIENCES auction of totally artificial hearts is thwarted by our inability to produce compact, long-lasting power sources capable of responding to the bio- chemical signals that control muscle blood flow. But there is reason to hope. Remarkable as all these accomplishments are, it must not be forgotten that a large fraction of the conditions that impose these requirements for drastic surgery are the consequence of one process, atherosclerosis, the deposition of mushy lipids on the surface and within the walls of the arteries, which then calcify, become brittle, and serve as foci for clot for- mation and infection. In the long run, it is to be hoped that understanding of this process will permit its prevention, thereby obviating the need for many current surgical and therapeutic procedures. The alternative, more than a thousand cardiac transplants per day in the United States alone, is scarcely an appealing prospect. Meanwhile, the efforts of thousands of scientists have brought surgery to this remarkable peak. If the physiologist originated the idea of a heart-lung machine, he also has greatly benefited by its sophisticated use in the hands of surgeons and engineers, for today he uses the same instrument as a tool for learning still more about the intricate mechanisms of the heart and lungs. And, even- tually, the information he gathers will further enlighten the physicians and surgeons in their battle against disease. Diuretics A serious, occasionally life-threatening, complication of heart failure, liver and kidney diseases, and hypertension is edema, the excessive accumulation of salt and water in body tissues at large. Today, diuretics, drugs that interfere with the mechanisms by which kidneys retain sodium, and hence chloride and water, control edema rather successfully in most patients. A major class of modern diuretics was made possible by observa- tions during the early history of sulfanilamide. Ironically, no one would have predicted that the background essential to the rational development of diuretics would be supplied by research quite unrelated to the function of the kidney or to the need for such agents. Early in the clinical use of sulfonamides, it was noted that such patients excreted an alkaline urine and developed a mild acidosis (acidification of blood plasma). Then, biochemists observed that sulfanilamide inhibits the enzyme carbonic anhydrase that catalyzes the simple hydration and dehy- dration of carbon dioxide, a process necessary to the escape of carbon dioxide from the blood as it travels through the lungs. When carbonic anhydrase was then found to be present in quantity in the kidney, it became apparent that this enzyme plays a role in kidney mechanisms for excretion of acid and that sulfanilamide's inhibitory effect on the kidney enzyme accounted for its effect on urinary secretion, with consequent acidosis. Accumulation of acid is the consequence of excretion of sodium ions. In

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BIOLOGY IN THE SERVICE OF MAN otherwise normal individuals, e.g., the sulfanilamide-treated patients, this effect is undesirable. But in patients whose kidneys are failing to excrete salt (sodium ions) normally, the same process could be decidedly bene- ficial. At that point, chemists had a rational test system for fashioning a drug that would be a more effective inhibitor of carbonic antydrase than sulfanilamide by modifying the structure of sulfanilamide, and designed acetazolamide (Diamox), which, in 1950, became the first useful oral diuretic. Incidentally, it also became a remarkably successful agent for treatment of glaucoma, excessive secretion of fluid into the anterior chamber of the eye, by interfering with the carbonic anhydrase of the overactive secretory cells. While Diamox was safe, it was not an ideal agent because it could not be used continuously. Five years later, by continuing modification of the basic structure, another diuretic, chlorothiazide (Diuril), was constructed and proved useful not only for treatment of water and salt retention in ambulatory, nonhospitalized patients but also in lowering their blood pres- sures. In the five-year period following its introduction, prescriptions for diuretics in the United States increased sixfold. But Diuril, too, had limi tations, particularly limited ability to cope with massive edema and excessive stimulation of urinary excretion of potassium and sodium. Pharmaceutical chemists then looked to aldosterone, the adrenal hormone that normally occasions retention of sodium and loss of potassium from the body. Several compounds that structurally resemble aldosterone, yet are sufficiently dif- ferent that they do not possess its pharmacological actions, were synthesized to displace the hormone from sites where it is normally bound in the kidney. By thus occupying the effecter sites of the natural hormone, they function as antimetabolites and prevent excessive secretion of potassium. Meanwhile, another approach resulted in a diuretic of an entirely dif- ferent class. It had long been known that mercurial compounds are diuretic, but their toxicity precludes their use. These agents were known to work by reacting with sulfhydryl groups of proteins in the lining of the kidney tubules. Accordingly, a compound was sought that also reacts with such groups but lacks the toxicity of mercurials. The result, ethacrynic acid, is so effective that it must be used with great caution. Happily, like Diuril it can be taken orally. With this armamentarium it is now possible to treat successfully virtually all forms of salt retention except for those that reflect primary disease of the kidney itself. Such cases can be managed only by dialysis with an "artificial kidney," itself the product of two decades of research, entirely dependent upon growing understanding of the role of a normal kidney. As is so often true in science, new discoveries seldom have only a single application. Investigations of sulfanilamide culminated in establishment of 169

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70 THE LIFE SCIENCES the antimetabolite principle and development of Diamox, and Diamox, in turn, became an important tool for fundamental research. First, it repre- sented the beginning of a rational scientific approach to seeking diuretics by relating chemical structures to kidney mechanisms. Second, it became extremely useful as a device enabling renal physiologists to evaluate the role of carbonic anhydrase in kidney-transport processes. It was of prime importance in elucidating the renal mechanisms of bicarbonate reabsorption and hydrogen secretion. The concepts thus developed were then amply supported by direct renal-micropuncture experiments. This development had an important influence on clinical care of patients because the new understanding of physiology enabled scientists to predict the specific elec- trolyte losses in the urine produced by various drugs. Much public concern and attention is directed to the problem of pro- viding the best of medical care to all Americans, a concern we fully share. But the nature of medical care and its relation to research should be clearly understood. The component of medical practice that makes the greatest demands on our resources measured in the time of physicians, nurses, paramedical personnel, hospital beds, and the ever more complex technol- ogy of intensive medical care is the management of those disorders for which research has, to date, made possible only palliative or physiologically corrective measures, termed by some "half-way medical technologies." When research has provided a definitive therapeutic or preventive regimen, it is invariably cheaper and simpler than the palliative treatment previously available for the same disease. This is surely true for a wide range of infectious diseases such as lobar pneumonia, poliomyelitis, tuberculosis, bacterial endocarditis, typhus, typhoid fever, and diphtheria, to name but a few. Almost all nutritional diseases e.g., pellagra, beriberi, rickets, and scurvy and a variety of other ailments such as pernicious anemia, Addi- son's disease, goiter, juvenile diabetes, Parkinsonism, and glaucoma fall within this category. Only a few years ago, it was these disorders that dominated the efforts of the health care system. Most remain serious, but they are but a minor aspect of medical practice. The diseases that now overwhelm the health care system are those for which research has not yet provided the understanding required to design truly definitive pro- cedures. It is not lack of physicians, nurses, technicians, or hospitals that limits our capability to manage such problems as most forms of cancer, coronary occlusion, myocardial infarction, stroke, acute rheumatic fever, osteoarthritis, pyelonephritis, bronchial asthma, schizophrenia, muscular dystrophy, cystic fibrosis, and multiple sclerosis; it is lack of understanding sufficient to permit development of a really therapeutic procedure. Bio- medical research, which represents only 1.5 percent of total expenditures for health, is, therefore, both the biggest health bargain one can purchase

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BIOLOGY IN THE SERVICE OF MAN and the only hope for future progress. If this opportunity is neglected or minimized for shortsighted fiscal reasons, then, by the turn of this century, our nation must double the number of physicians, nurses, technicians, hospital beds, and sanitaria and learn to live with the equivalent increment in human suffering. Grim prospect indeed! Population Control While biomedical scientists pursue greater sophistication in the under- standing and treatment of disease, this attempt must be matched by a con- certed effort to solve the crisis being brought on by the continuing increase in human population. No matter what contributions scientific investiga- tion and new technologies make in the coming decades, it is hard to imagine that they will come quickly enough or be sufficient to meet man's needs if his sheer numbers continue to mount unchecked. The problems of popu- lation control are both biological and sociological. From studies in repro- ductive biology must come new and better contraceptive procedures, which must then be put into general use. The oral contraceptives that became widely available in 1961 are con- sumed by millions of women the world over; they symbolize society's recognition of the need for birth control. They also illustrate the beneficial results of concentrated, deliberate research. Birth-control pills in current use are usually a combination of the two hormones that regulate the repro- ductive cycle a synthetic estrogen and a progestin, a synthetic version of natural progesterone. If taken as prescribed, they appear to be almost invariably effective, although reproductive biologists are not entirely certain why. That these agents strikingly alter the output of the related regulatory pituitary hormones is certain. Beyond that, explanations of their mechanism of action are tentative. They may not actually prevent ovulation each month, yet exert their contraceptive effect nonetheless. The appearance of the endometrium that lines the uterus is somewhat altered in women taking these drugs; perhaps this relates to the failure to conceive. Another possibility is that the progestin in the combination products stimulates the release of cervical secretions so viscous that they effectively entrap sperma- tozoa. Indeed, there is some evidence that progestin alone is an effective contraceptive, and various experiments with low-dose progestational com- pounds are under way. Unfortunately, it was one of this class of compounds that was recently shown to induce tumor formation in dogs; hence, the future of this program is uncertain. The availability of the current pill is the culmination of 70 years of study of the operation of the mammalian reproductive apparatus. Step by tedious step, understanding of the nature and function of the two pituitary

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THE LIFE SCIENCES hormones the estrogen of the ovary and the hormone of its corpus luteum -as well as the progesterone of the uterus was achieved. The accumu- lated information found its way into pregnancy tests, diagnoses of abnormal pregnancies, and correction of faulty development of secondary sex char- acteristics. Natural sources of estrogens and progesterones were inadequate; substitutes were synthesized that were more effective than the natural forms and that could be taken by mouth. Detailed studies revealed the precise cellular changes occasioned by each natural and synthetic hormone; slowly, the precise clockwork that governs the menstrual cycle and the stabilization and climax of pregnancy was elucidated. With such knowledge came successful diagnosis of the cause of a large fraction of all instances of sterility imbalance of the two pituitary hor- mones. Therapeutic trials failed until it was realized that only human hor- mone is effective. This is available in urine, and a modest supply now permits pregnancy for many childless wives. But the supply is limited and one must await precise establishment of the amino acid sequence of this hormone, followed by synthesis using the recently developed methods for polypeptide synthesis, to overcome this shortage. It was with this slow and difficult accumulation of understanding that the search for a contraceptive pill began, both estrogens and progestins being tested separately before it became clear that a combination might be required. Most important is the realization that, until the whole stage had been set, the final undertaking could not have been possible. There has been no better illustration of the culmination of many years of interac- tion between clinical observation and clinical and basic research. As use of the pill increased, reports of clotting disorders and breast tumors became more frequent. Even at this writing, the validity of such claims is somewhat uncertain, and the adverse effects of the pill remain to be estab- lished with certainty. Assuming the reality of such effects, there remains the societal decision of weighing hazard against benefit the death rate due to pregnancy versus that associated with the pill and the risk entailed versus the societal imperative that population growth be brought under control. Meanwhile, the search for other, less hazardous but still effective, measures must be prosecuted vigorously. The search for contraceptive drugs began with animal studies and now returns to the laboratory to create the next generation of pills. In addition to seeking an explanation of the mechanisms of current agents, investigators must explore the phenomenon of conception itself even further. A quite subtle interruption in this delicately balanced sequence of biological events may well prevent conception just as surely as the grosser effects of present agents.

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BIOLOGY IN THE SERVICE OF MAN 173 The newly established Center for Population Research at the National Institutes of Health has initiated a program focusing on four targets: 1. The reproductive physiology of the male, particularly the processes that permit the maturation of sperm cells. Only a mature sperm can pene- trate and fertilize an egg. If the biochemical events surrounding this process could be controlled, a new approach to contraception would be available. 2. The structure and function of the oviduct through which an egg travels from the ovary to the uterus. 3. The function of the corpus luteum, the yellow body, formed after ovulation, that produces progesterone for the maintenance of pregnancy. 4. The biology of the fertilized egg cell before and during implantation in the uterine wall. Prior to the introduction of oral contraceptives, reasonably satisfactory methods of mechanical or physiochemical contraception existed. Human nature limits the success of these methods; all too often they are used improperly or not at all. They are not, however, to be discarded, nor are the increasingly satisfactory intrauterine devices. If population control is to be achieved on an acceptable scale, a variety of contraceptive methods will be required. This will be possible only in the light of additional knowl- edge. If indeed a promising lead for the development of a new contraceptive drug does emerge from research, there will remain an extremely lengthy process, prescribed by the Food and Drug Administration (FDA), before it can be brought to market. Such research and development is performed in the laboratories and under the auspices of pharmaceutical companies, which spend collectively, even now, more than half of all funds devoted to research on reproductive physiology, quite apart from the high costs of prolonged toxicity testing and development. Precisely because such a drug would be taken by "normal" women over many years, the FDA procedures are conservative, demanding prolonged test trials to establish safety, side reactions, and so on. At best, there can be no way to shorten the testing trials in women and the world's population will have increased by at least one billion before widespread, unrestricted use of such a new drug could be considered, even if the structure of the compound were known, its synthesis worked out, and its general biological properties known at this writing. The great expense of the necessary prolonged procedures is a serious deterrent to the undertaking of such activity by the drug manufac- turers, who must somehow be assured that they will at least recover their investment. Meanwhile, the needs of humanity are so great that we suggest

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74 THE LIFE SCIENCES that the Secretary of Health, Education, and Welfare develop some new set of relationships wherein the government joins with the drug manu- facturers in funding such research activities, utilizing to the full the orga- nized multidisciplinary capabilities of these organizations, underwriting their costs, and pooling their competence. Confronted by the crisis of population growth, the government is justified in taking emergency measures. The Early and Latter Years of Life Half the individuals born today will die before their seventieth birthdays; yet, for all the hazards that beset man during his middle years, the gravest threat remains with the first year of life. Infant mortality (deaths in the first year of life) has been declining steadily in the last half century as a result of significant advances in infant care, but it is still higher in the United States than in several other countries 22.1 deaths per 1,000 live births in 1967. Human biological potential is conditioned, in large measure, by the events of prenatal and early postnatal life. The quality of adult life is predetermined by such phenomena as inherited defects, environmental influences, including disease, exposure to radiation or drugs, and the quality of nutrition. The first stages of man's life are the object of growing scientific attention, yet there are few areas in which clinical applications are as severely handicapped by lack of fundamental understanding. There is, as yet, no precise description in biochemical terms of the notating of sperm and egg. The fetus, in the protective environment of its mother's womb, nourished through the placenta, is particularly susceptible to environ- mental influences as its cells differentiate and become specialized tissues, and it is subject thereafter to the health of its mother. Diabetes, toxemia of pregnancy, and blood-group incompatibility can threaten its health, and even its survival. Parturition must come neither too early nor too late, and the newborn must then adjust to his world. Whereas a significant fraction of infant mortality may be eliminated by applying available under- standing, further progress will be entirely dependent on improved knowledge of the entire process from conception to the early years of life. No problem appears more urgent than definitive establishment of the consequences in later life of early nutrition. This problem first came to attention with respect to peoples of developing nations as it became evi- dent that the apathy, stunting, s~.ntihili~v to inf~.~.tion lack of ~.n~rav ~. . . . _ < ~_J _ ~_ _ __ ~_ ~=~ ~ and, perhaps, limited intelligence of certain tropical populations were re- lated to their nutritional status, since this characteristic is particularly obvious among those groups in which kwashiorkor (generalized protein deficiency) is rife. Significantly, the data also indicate that there is no

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BIOLOGY IN THE SERVICE OF MAN 175 genetic basis for this problem. Accordingly, there is urgent need to learn how protein deficiency results in these sequelae, whether there are key amino acids, what level of nutrition is required to prevent the process, etc. Early evidence strongly indicates that the brain of the protein-deficient individual may contain as many as 30 percent fewer than the normal num- ber of neurons (nerve cells). Since the process of neuron generation is completed within the first two years of life, this deficit can never be over- come. Solution of these problems could go a long way toward helping protein-deficient people to help themselves. Equally important is the need to establish the extent to which similar nutritional influences are at work in the United States. Animal studies will continue to be revealing, but safe and sensitive techniques for monitoring the physiological state of the fetus as it develops are sorely required. To know the mechanisms of genetic and environmental effects and to comprehend the role of nutrition, the influence of hormones in fetal life, and the interactions of tissues, these factors must be measured and charted. Efforts to accomplish this are under way. New methods are now being applied to measurement of maternal excretion of hormones, particularly estriol (an estrogen), and relating it to fetal development, to monitoring of fetal heart rates and correlating these with the fetal condition, and to analysis of fetal blood, even during labor itself, by obtaining microsamples that are examined by new microchemical procedures. At the opposite end of life's scale, the process of aging is even less well understood. Indeed, it has yet to be described adequately. What processes are responsible for the progressive decline in the structure and function of an adult organism? What aspects of the process are intrinsic to the organism, i.e., the consequence of its initial genetic complement, and what aspects result from environmental assaults? How would we age in the absence of intercurrent trauma or infectious disease? In both young and old organ- isms, muscles contract, nerves conduct, glands secrete, and so on. The changes occurring in tissues that distinguish youth from age are too subtle to be detected by currently available techniques. How does deterioration in structure and function become incompatible with life? Has anyone ever died of "natural causes"? One aspect of aging seems incontrovertible. With the passage of time, cells die in certain organs the brain, the muscles, the lymphatic system- and are not replaced. Is aging merely the consequence of this one-way process? If so, what clockwork fixes the norm for a mouse at one year, for man at three score and ten, for the giant sea tortoise at 500 years, and for the sequoia at several millennia? Can this clockwork be reset? One prominent theory of aging holds that it reflects a developed insta- bility of the genetic apparatus of individual cells, i.e., that aging occurs

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76 THE LIFE SCIENCES because of highly specific deviations within single cells rather than among whole cell populations. Perhaps, for example, in the course of time, subtle errors in the self-duplicating process of DNA accumulate. Perhaps the accuracy of transcription fades, though it does not fail completely. To date it has been possible only to refine these questions, not to subject them to rigorous test, for lack of a reasonably short-lived but acceptable model. Current efforts utilize mammalian cells in tissue culture and such organisms as the thousand-celled rotifer. A suitable test model should have a short life-span and well-established standardized nutritional requirements, should be maintained in freedom from infections and other external insults, and must possess genetic uniformity. An alternative hypothesis suggests that, whereas cell death and failure of replacement do indeed lie at the heart of the aging process, the reason may not be intrinsic in the cells themselves but may be secondary to changes in their environment. Certainly, with the passage of time, connective tissue becomes tougher, thicker, and less elastic. If such changes also occur on a minute scale at the level of capillaries, this could result in local nutritional failure or intoxication by the products of the cells' own metabolism. Regrettably, all such studies are in their infancy. Only when they have produced sufficient understanding will it be clear whether man may aspire to a prolonged span of enjoyable, fruitful years. This brief summary has only touched upon the approaches to biomedical research that may be anticipated in the next decade. Predictions of the future direction of clinical investigation, like those of other human affairs, are hazardous, but the record suggests that the greatest benefit will accrue from the slow accumulation of basic knowledge concerning the nature of normal and pathological physiological and chemical processes. Obviously, one cannot apply knowledge to the prevention and treatment of disease until that knowledge exists. Biomedical research has come of age. In the intensively managed, highly instrumented clinical research units of our great hospitals, clinical investi- gation has become a legitimate science. Human biology is being explored with unprecedented vigor and sophistication, and the information net of the biomedical community assures that scientific discovery in all dis- ciplines is readily applied to human disease. This endeavor, the focal activity of university medical centers, is less than two decades old. How, then, shall one measure its success? Not alone by the large and small insights into the nature of life or the pathogenesis of disease, nor by the pain alleviated or the lives saved. We are all too aware of the woeful limitations of medicine, of the anguish of suffering, tortured humanity, including those who are left behind after death. The