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452 THE LIFE SCIENCES THE OPPORTUNITIES Biology and Medicine It is in improved medical practice that advances in biological understanding make their most immediate impact on most people. As we have seen, biological and medical research are intimately intertwined; the fundamental discoveries that have found useful clinical application have been of such general character that they are best termed "biological," regardless of the institutional setting in which they are made. In our society, the benefits of such studies are to be found in innumerable individual events in medical practice from prenatal care through infancy, childhood, and adulthood to old age. The prolongation of life expectancy at birth is one of the impressive overall measures of the success of medicine. However, even in affluent societies this prolongation has been due primarily to a dramatic reduction, if not a near abolition, of infant mortality. Increases in life expectancy past the age of 45 have remained smaller, although by no means negligible. Even medically advanced countries still experience different life expectancies and infant mortalities, and it is likely that at least a major share of the differences is the result of social differentials. It is regrettable that infant mortality in the United States still exceeds that in more than a dozen other advanced nations. The largest single contribution to our infant mortality is to be found among the economically and socially disadvantaged segments of our society, although it is also unacceptably high even in middle-class families. The problem then is not lack of knowledge but to provide prenatal and early pediatric care of the quality available to the rest of the population. (See Table 70.) MOLECULAR DISEASES Future advances in the control of disease will come from better epidemi- ological knowledge, improved control of the environment, and deeper understanding of the regulation of life processes. Many of these advances will be based on applications of the fundamental information provided in recent years by molecular biology. With sufficient understanding will come a more powerful ar~amentarium for chemotherapy of endocrine disorders and cancer, treatment of autoimmune diseases, prevention of the degenera- tive disorders of the circulatory system, and therapy for metabolic dis- orders. There seems to be no reason why deposition of lipids in the great blood vessels atherosclerosis should be a necessary concomitant of

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BIOLOGY AND THE FUTURE OF MAN TABLE 7() Countries Reporting Twenty Lowest Infant-Mortality Rates per 1,000 Live Births, 1967 INFANT RANK COUNTRY MORTALITY INFANT RANK COUNTRY MORTALITY 1 Gibraltar 11.8 11 Australia 18.2 2 Sweden 12.6 12 United Kingdom 18.8 3 Japan 13.3 13 Luxemburg 20.4 4 Iceland 13.7 14 East Germany 21.2 5 Netherlands 14.7 15 United States 22.1 6 Finland 15.0 16 Canada 23.1 7 Norway 16.8 17 West Germany 23.5 8 Denmark 16.9 18 Belgium 23.7 9 France 17.1 18 Czechoslovakia 23.7 10 New Zealand 17.7 20 Ireland 24.4 21 Israel 25.3 Sources: Data from United Nations, Monthly Bulletin of Statistics (October 1968), Population and Vital Statistics Report (July 1, 1968), Demographic Yearbook (1967). human life. Research directed at rational prevention of this process by simple means should markedly reduce or delay the incidence of coronary artery disease, aneurysms of the great vessels, and stroke. Death will still come to all, but the quality of adult life should be markedly enhanced as the onset of debilitating disease is delayed into the latter years of a pro- longed life. Life should be not only longer but ever more enjoyable and free of the ravages of ill health in consequence of increasingly effective preventive and therapeutic measures. It is yet too soon to engage in speculation concerning future progress in prevention or therapy for the major psychoses. Only the success of tran- quilizers and mood-elevating drugs offers any basis for hope. Until the underlying basis for schizophrenia and the other psychoses is understood, it will not be clear whether there are fruitful chemical or surgical approaches to therapy. This should not be true of peripheral necrologic diseases. Even now, there are hopeful bits of progress in understanding the demyelinating disorders; and there has just appeared a drug that seems quite specific for relief of Parkinson's disease. Insofar as diseases have specific molecular etiology, there is hope for specific molecular therapy or prevention. INFECTIOUS DISEASES Yet another major problem, concerning which assessment remains diffi- cult, is the panorama of virus diseases. Man lives in equilibrium with large numbers of each of what appears to be an ever-increasing number of differ

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THE LIFE SCIENCES ent viruses. Our chief protection against them remains our own intrinsic biology, particularly our immune mechanisms. The strategy appropriate to assisting the defense against an established infection is unclear. A truly effective synthetic substitute for the naturally occurring "interferon" would probably be a most useful drug. Hope in this direction is afforded by the demonstration that synthetic, double-stranded RNA is an effective stimulus to interferon release and can protect mice against otherwise lethal inocu- lations of the virus that causes hoof-and-mouth disease. Most drugs that interfere with replication of viral DNA or RNA must also seriously affect our own duplicating cells, as do most chemicals that interfere with protein synthesis. However, this approach is not necessarily hopeless because synthesis of viral nucleic acids within the host cell is accomplished by enzymes synthesized by the host-cell machinery under the control of the infecting viral nucleic acid not by the original host-cell enzymes. A few antibiotics have already been found to block one or another of these virally induced processes without damage to the host cell. Increased understanding of the genetic machinery and exploration of drugs that interfere with its operation or create a temporary diversion are our greatest hope of finding a rational basis for antiviral therapy, although there is, as yet, nothing to assure success. The most promising avenues of approach to the problem of cancer derive from the fact that a variety of neoplastic lesions in experimental animals are definitely associated with the presence of specific viruses in affected tissues. Only suggestive evidence presently links most tumors of man with similar viruses, but the evidence is incontrovertible in several instances. It is thus apparent that there is more than one "cause" of cancer, but to the extent that human neoplasia may have a viral etiology, the route to successful cancer chemotherapy may prove to have much in common with the search for antiviral therapy generally. Indeed, it is conceivable that current procedures that enjoy some measure of success-e.g., radiation to solid tumors, antifolic acid compounds and cytosine arabinoside for treatment of leukemias- actually operate by their effects on viral repro- duction rather than by limiting cell division itself. In any case, it is impera- tive that studies designed to establish whether human tumors are, in effect, manifestations of infection with the equivalent of an otherwise silent "temperate lysogenic virus" should be prosecuted with utmost vigor. Morbidity and mortality from bacterial infections have been dramatically reduced by the availability of antibiotics. But this battle is never won. Resistant strains of almost every bacterial pathogen have repeatedly ap- peared. Each must be met with yet another antibiotic or combination thereof, and the search for new, more effective antibiotics, conducted largely by the pharmaceutical industry, must be unceasing. No episode in the

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BIOLOGY AND THE FUTURE OF MAN Vietnam war is more dramatic, and certainly none more gratifying, than the successful development of therapy for a virulent, highly lethal form of malaria carried by the Aedes falciparum mosquito, based on a combination of two drugs that affect two different aspects of the life cycle of the malarial plasmodium. There remain many infectious disorders, particularly in the tropics, such as schistosomiasis, for which no adequate drug is available. Appropriate agents must be sought, based on detailed understanding of the unique metabolism and life cycles of these organisms. If historical prece- dent is valid, there is good reason to be sanguine concerning the prospects in these regards, but the attack must be intensive and relentless. TRANSPLANTATION AND ARTIFICIAL ORGANS Important advances will surely come from application of technology to deficiencies in the function of whole organs. An artificial lung, external to the body, can be used to replace the physical action of the muscles neces- sary for breathing; an artificial kidney can serve as a chemical device for removing metabolic products from the blood when the original excretory organs cannot perform that function. Artificial blood vessels made of synthetic tubing can serve as substitutes for defective natural vessels, and external artificial hearts can, at least for some hours, take over the pumping function of the inborn organ. And there is every reason to believe that each of these devices can be improved markedly in the future. But it should be emphasized that, while each of these is a triumph of bioengineering and invaluable to those who require them, each also represents a failure of biological research to have found a solution to the underlying biological problem. If artificial structures are less adequate than natural ones, transplantation of organs from one person, alive or after death, to another offers another avenue to saving of life. Successful transplantation requires mitigation or abolition of the usual incompatibility of the transplanted tissue of-the donor with the immune mechanisms of the host, which otherwise results in rejec- tion of the transplant as well as undesirable systemic reactions in the host. Experiments with chickens, mice, and cultured human blood cells, as well as the heroic measures used in successful human heart and kidney trans- plants, indicate that such antagonistic effects can be minimized. Although numerous tissue types exist, only a limited number serve as antigens to elicit production of antibodies, which then react with and damage the trans- plant. Although this number is large compared with classical blood types, it is small enough to permit the development of reliable typing procedures so that donor and recipient may be matched reasonably closely. In addi- tion, a growing number of drugs is available to depress the production of

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456 THE LIFE SCIENCES antibodies. A combination of these procedures should significantly improve future management of transplant patients. It will be clear, however, that this approach, while dramatic in the extreme, is of limited value. It is inconceivable that hundreds of thousands of such operations can or should be performed annually. For coronary artery disease, prevention and early therapy of atherosclerosis must surely be the more fruitful long-term ap- proach. Moreover, a useful mechanical heart, responsive to body needs, offers more promise as a replacement for a seriously defective heart than does homotransplantation for the medium term, while avoiding the serious ethical problems occasioned by the latter procedure. Nevertheless, ever- improving ability to perform and manage transplantation should be of continuing value in some endocrine diseases, in nephritis, and in an occa- sional heart patient. These insights and techniques are capable of prolonging life beyond the normal span, but they create great new difficulties. Millions of individuals would profit from the transplantation of organs or from the use of "spare parts," but for years the supply of these and of the medical teams required for their installation will be inadequate to fill the demand. The ethical conflicts that the physician faces are crushing when he is forced to decide who is to benefit and who is to be denied vital help. Currently the occasions for such decisions are still rare since the numbers of available natural organs or substitute mechanical "organs" are so limited. In the future, yet other life-saving devices will be invented, and the problems of assigning them to specific patients while withholding them from others will increase in frequency. Even if such devices could be made available in large num- bers, the cost of keeping a small fraction of the population alive by these means may be so high a fraction of the gross national product as to com- pete seriously with other needs for the well-being of the population. THE ETHICS OF TERMINAL MEDICAL CARE Another difficulty goes even deeper. Relatively little progress has been made in prolonging the adequate functioning of the human brain. The perpetuation of the physical workings of many parts of the body has not been accompanied by a perpetuation of its normal mental aspects. The death of individual neurons in the central nervous system is an attribute of the "normal aging process," and brain damage occurs not infrequently in consequence of trauma or illness. Here lies a great challenge for basic research and the beneficial application of the insights to be hoped for. Some of the best minds among biologists, psychologists, and physical scientists have recently turned their efforts to neurophysiology and brain function. Their studies should help to understand the riddle of the physical basis of

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BIOLOGY AND THE FUTURE OF MAN the mind, while helping also to discover the basis for procedures for allevi- ating the tragic situation of keeping the body alive without the full mental attributes that characterize a normal person. One may hope for progress in prolonging the physical and mental health of the aged, but then the problem of disha~onious functioning will simply be displaced to the end period of a more extended life-span. Biology, the science of life, has to be complemented by new insights into the biology of death. The application of such insights will intensify concern with questions already demanding answers. Is society justified in keeping the aged alive when those mental functions that distinguish human beings from vegetating bodies have ceased? Where is the limit of anguish and material burden that the relatives of such aged persons and society at large can bear a problem that is increasing in frequency and severity? Research in aging involves the whole range of biological phenomena, from a study of the molecular changes of such substances as the collagen in our connective tissues and bones to the study of the most complex func- tioning of the central nervous system with its basis for consciousness, learn- ing, reasoning, memory, and other psychological attributes. It is imperative that such research be prosecuted as vigorously as possible. It should be clear, however, that there are no indications, as yet, that the aging process can be delayed or mitigated, except in a most limited way. Support of the aged cannot be considered separately from economic and demographic facts. The success enjoyed by other aspects of medicine places in society ever larger numbers of aged, nonproductive individuals. Some continue to enjoy life, but to some life is a burden. The cost and effort to provide care for this group becomes an increasingly large fraction of total goods and services. A highly advanced civilization will have to find an appropriate solution to this problem. Meanwhile, the need for support of research that will benefit the health of the newborn and of young productive people in general competes for the personnel and material resources required for research on aging. The need for dedicating large-scale support to children and adolescents may limit the effort society can devote to keeping the aged alive beyond a reasonable state. Moreover, similar considerations must also apply to the dedication of resources to the care of nonproductive individuals as compared with that of potentially productive persons. Viral diseases of childhood, congenital malformations, hereditary disease, leukemias of childhood, endocrine dyscrasias, demyelinating diseases that strike young mothers, trauma, acci- dents, etc., all appear more worthy of attention than do the afflictions of advanced age. But these are harsh decisions and should not be made in an absolute manner. Our nation has the resources and can afford attack on the entire front. Moreover, as we have already noted, research cannot

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458 THE LIFE SCIENCES be forced. Alert clinical investigators in sufficient numbers should be poised to apply new understanding flowing from basic research to allevia- tion of the human condition as opportunity affords, avoiding attempts to apply the inapplicable. GENETIC DISEASES The main illnesses of man have changed greatly in importance during the last hundred years. Infectious diseases have been combated effectively as their biological nature has become clarified. For example, malaria was recognized as being caused by mosquito-borne protozoa, tuberculosis by bacteria, and influenza by viruses. Sulfa drugs and the antibiotics were found to kill the infectious agents without damaging the host. Other dis- eases, like rickets, pellagra, and scurvy, were shown to be caused not by the presence of an abnormal agent but by the absence of normally required substances, the vitamins. Improved nutrition in the light of this knowledge has greatly reduced the incidence of such deficiency diseases in the devel- oped nations. However, kwashiorkor, the consequence of protein defi- ciency, and xerophthalmia, due to deficiency of vitamin A, afflict tens of millions of the young in the tropical and subtropical countries around the globe. Resolution of these problems does not require further understanding of human biology; it requires a vast effort to upgrade education, agricul- tural practice, and the economies of these nations. Increasingly, the diseases that plague man are "inborn errors" that, as the effects of abnormal genotypes, lead to gross congenital malformations or to subtle derangements of metabolism. Many of these inborn errors are now understood in biochemical terms. The example that we considered earlier, phenylketonuria, is a rare but serious inherited condition in which a specific enzyme, formed in the liver of normal persons, is not synthesized in the livers of affected individuals. A single gene, present in normals and absent or present in a defective mutant form in phenylketonurics, is responsible for the difference. The result of the absence of the enzyme is accumulation of the amino acid, phenylalanine, which normally is trans- formed by the enzyme into some other substance. This accumulation results in brain damage expressing itself in mental defect. The presence of this genetic defect can be discovered soon after birth by the presence of an abnormal derivative of phenylalanine in the urine or by an excess of phenylalanine in the blood. It took 20 years to unravel the biochemistry and genetics of the disease. Only then did it become possible to devise a treatment for it. Phenylalanine, a constituent of proteins, is essential in our diet. If, beginning in early infancy, a phenylketonuric individual is given a special diet very low in phenylalanine, development may proceed in

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BIOLOGY AND THE FUTURE OF MAN 459 improved fashion and the mental abilities of the child may approach nor- mality. It is hardly more than 10 years since phenylketonuria has been treated this way, and the last word has not yet been said about the real degree of success. Nevertheless, phenylketonuria is an example of the modern attack on genetic disease. Although the defective gene itself, which is responsible for the absence of the enzyme, cannot be "cured," its effect can be circum- vented in greater or less degree. In diabetes, a disease with a complex genetic basis involving more than one gene, the defect is overcome to a considerable extent by furnishing the body with insulin from the outside. In galactosemia, the ingestion of milk sugar generates a problem, evident as stunted physical and mental growth and cataracts. Avoidance of milk ~.. .. ~. c, _ . and use ot a synthetic formula containing cane sugar Is all that is required. Or, in a congenital malformation such as cleft lip and palate, plastic surgery can not only save the life of severely affected infants but also produce an esthetically acceptable appearance. Clearly, a euphonic solution has to be discovered separately for each untoward genetic effect. Only a few such solutions have been found, and further search will be an important area of biological effort. There is reason to expect that future work will extend the range of euphonies to many errors that are presently beyond repair. In turn this will engender the serious problem, considered earlier, of pro- tecting the gene pool. One special class of genetic disorder warrants specific comment. A ~I, ~_ ~ ~ A _ ~ ~ _ variety of serious disorders are the expression of a deranged chromosomal pattern, broken chromosomes, or an extra chromosome (trisomy), which can now be detected during uterine life or at birth. The survival of an infant so afflicted is an emotional and economic burden to its parents and a drain on the society, which must support and maintain it in an institution for its entire life. REGENERATION After the first few years of life, accidents are a leading cause of death. Even more frequent than fatal accidents are damaging accidents that maim or cripple. Whereas human amputees are doomed to empty sleeves or trouser legs, some lower forms the lobster or newt-can perform pro- di~ious feats of regenerations replacing entire limbs. There are few leads a . .. . ~ , . ~ ~ . .. ~ . , ~ ~ ~ ~ to Indicate the underlying oasis for superlorlly In Inls aulll~y lI1 ~ Villlt:Ly of species, as contrasted with man's inability. But it would seem that a determined effort in this regard is certainly warranted. The boon to humanity would be huge, indeed, were it to find any success.

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460 THE LIFE SCIENCES THE DELIVERY OF MEDICAL CARE We cannot leave the subject of the future of medicine without noting that a substantial fraction of American society, the urban and rural disadvan- taged, today lack access to medical care of the quality available to their more privileged fellow citizens. Many may be permanently limited by the experiences of very early life. Chronic illness, excess rates of infant and maternal mortality, and unnecessarily foreshortened life-spans are their lot. Humane considerations, loss of potential productivity, and the heavy burden upon the rest of society all argue for early amelioration of these circumstances. No agency of our society has either the knowledge or the means to do so. Hence, we urge the organization and implementation of a series of substantial field trials addressed to the design of an appropriate system of medical care for this segment of society. _. . . Early Environmental Influences Inadequate environments may lead to defects in genetically adequate persons, whereas an appropriate environment may minimize the conse- quences of genetic defectiveness. Recently, much attention has centered on the effects of early environmental influences. As commonly used, "early influences" denotes the conditioning of be- havior by all the experiences of very early life. Early experiences, however, do more than condition behavioral patterns; they also profoundly and lastingly affect many biological characteristics of the adult. Events during the prenatal and early postnatal period condition the initial growth rate, maximum adult size, efficiency in utilization of food, resistance to malnu- trition, to infection, and to other forms of stress. Early influences affect some of the most obvious characteristics of human populations. Throughout the past century, for example, there has been a constant trend toward greater size and earlier sexual maturity of children. This phenomenon was first detected in the United States, then in other western countries; it is now particularly striking in Japan and in other areas that have adopted western ways of life. Evidence for increased growth is provided by the greater heights and weights of children at each year of age, by the faster growth rates during adolescence for both boys and girls, and by earlier onset of the menses. Early nutritional influences, exaggerated by infection, can also deleteri- ously affect later growth, mental ability, and general health. This is readily documented in the underprivileged areas of the world; very high infant mortality, slow growth during childhood and adolescence, with physical and mental lethargy continuing throughout life, are among the pathological

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BIOLOGY AND THE FUTURE OF MAN manifestations commonly observed in all seriously deprived social groups. These disorders are not racially determined. For example, they are found alike among the deprived Indians of Central America and among the popu- lations of European origin who share the Indians' ways of life. In contrast, these manifestations are rare among both groups when born and raised in social and economic environments similar to those now prevailing in the prosperous communities of the United States and Europe. And there is every reason to suspect that similar influences may be at work among the urban and rural disadvantaged sector of American society, creating indi- vidual handicaps that can never be overcome. The most important effects of the environment are those experienced during very early childhood or the last trimester of fetal life. Most im- portantly, when environmental phenomena act adversely on the human organism in early life, their anatomical, physiological, and psychological effects are to a large extent irreversible; the fact that the various tissues and organs develop at different rates accounts for the existence of several critical periods in giving complete or partial irreversibility to responses that the developing organism makes to environmental forces. In the human species, the critical periods for the development of various mental capacities probably occur before 6 to 8 years of age and most critically during the first year, a phenomenon of great relevance to the determination of "intel- ligence" in different socioeconomic and ethnic groups. ERects of the environment are much more likely to be reversible when experienced after the end of differentiation and development. Virtually all effects of prenatal and early postnatal influences so far recognized in human populations occur also in other animal species. A large variety of stimuli, acting on the pregnant animal during gestation or on the young shortly after birth, affect diverse phenotypic expressions throughout adult life. Exposure to toxic agents, malnutrition, undernu- trition or overnutrition, overt or subclinical infections, emotional distur- bances of the mother or of the young, crowding, isolation, and other forms of social deprivation are some of the variables that have been used to design experimental models for the study of early influences. These influences have been studied with regard to their effects on anatomical structures, physiological characteristics, metabolic activities, behavioral patterns, and learning ability in adult life. In all cases critical periods have been recog- nized, differing as to initiation and duration, depending upon the nature of the early influence and of the effect studied. Nevertheless, the body of knowledge concerning the effects of early influences is superficial and episodic. Even the phenomena that have been most extensively studied such as imprinting, the fixation during a critical period of a young animal's life of a stimulus that invariably elicits a par 461

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462 THE LIFE SCIENCES ticular response are poorly understood, albeit highly reproducible in their details. In the absence of broad scientific generalizations, it is not possible to extrapolate from one animal species to another, let alone to man. Yet there is no doubt that very early influences are of great importance in human life, a fact recognized by the earliest psychiatrists and repeatedly documented since. Knowledge of these potentialities points to the safest and most effective way of affecting the mental as well as the physical de- velopment of man. At the same time, if improperly exploited by an authori- tarian government, they could be of enormous danger to society. Future studies of the effects of early influences should be conducted at several different levels: Epidemiological observations in man, taking advantage of the fact that different human societies exhibit a wide range of customs with regard to gestation, parturition, lactation, and physical and behavioral manage- ment during the early postnatal period. These differences in social patterns can be considered as experiments on man, performed without awareness of their consequences, demanding careful description and analysis. 2. Development and refinement of experimental models in various ani- mal species. To yield the greatest scientific rewards, these models should use laboratory animals of known genetic and experiential history, observed throughout their life-spans and, preferably, for several successive genera- tions. Such longitudinal studies will require appropriate animal quarters, extensive facilities for recording and retrieving information, and, possibly, a new type of scientific organization. 3. Detailed analysis of the mechanisms through which early influences exert their lasting effect. Controlled Sex Determination More than a half century has passed since it was learned that a man pro- duces two kinds of sperm cells in about equal numbers. In addition to 22 chromosomes that are visibly alike in all sperm, half the nuclei possess the relatively large X chromosome and half the small Y chromosome. In conception, X-bearing sperm are female-determining; Y-bearing sperm, male-determining. It may be possible to separate the two kinds of sperm by biological or purely physical methods such as differential centrifugation. Admittedly, no success has been attained yet, in spite of some promising leads. If success comes, insemination with the X or Y fraction of semen would then assure control of the sex of the offspring. Application to ani- mal breeding could be of considerable economic importance, as in the

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BIOLOGY AND THE FUTURE OF MAN production of dairy cattle. If applied to man, subtle psychological changes in the population might be expected. It is likely that no great deviation from a 1:1 sex ratio would result since most parents of more than one child seem to desire children of both sexes. The sequence of sexes in a family may, however, change considerably. Instead of the random sequence of boys and girls, the majority of firstborn might be boys and that of second- born girls. Since position in the birth order has an effect on both physical and personality traits of the developing offspring, the consequences of the firstborns being all boys and secondboms all girls might well be reflected in behavioral shifts of the population. If widely available, this could also serve as an adjunct to programs of population control by assuring offspring of the desired sexes to all families. An alternative method for deliberate choice of the sex of offspring is technically feasible even now, albeit less attractive. Relatively simple surgical procedures permit determination of the sex of the young fetus. A family that desires to limit its size should be permitted the option of such inspection and, having one boy, for example, abort the next fetus if it is not a girl. Patently, this technical feasibility raises the same ethical and legal questions as does abortion of a genetically defective conceptus or of an unwanted child, but with less justification. Differential Fertility From time to time serious questions are raised about the long-range bio- log~cal and social effects of differential fertility* on the characteristics of populations. These questions arise because there is generally an inverse relation between fertility and socioeconomic status, measured in terms of occupational status, education, or income, and because there are differences in the fertility of the major races of man. There are also substantial dif- ferences in the fertility of the major religious groups. Maximum fertility is found among Moslems, with Hindus and Buddhists next. Christians as a group have lower fertility, and among Christians in the United States, Catholics have higher fertility than Protestants. In worldwide terms, how- ever, Catholics run the gamut from very low fertility, e.g., in North Italy, to the highest fertility in the world in some parts of Latin America. In general, Jews exhibit the lowest fertility of any of the world's major religious groups. In this context, the word 'fertility" is employed in its demographic usage, indicating the number of offspring produced per 1,000 of population, and not in the sense of the opposite to sterility.

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464 THE LIFE SCIENCES A few sweeping propositions can be ventured: 1. Many data are available that are descriptive of the differences in the fertility of broad socioeconomic, racial, and regional groups, but little is known about the significance of these differences for either the social or the biological heritage. 2. In biological terms, it is probable that differences in reproductive performances among individuals of varying characteristics within all groups are much more important than differences in the average performances among the highly heterogeneous social groupings for which data are readily available. 3. In the developed world, as birth rates have declined since the mid- nineteenth century, the inverse relation between socioeconomic status and fertility first became stronger and then weakened. The small-family pattern has tended to occur first in the urban upper classes and only later to spread throughout society. As governments in the newly developing countries mount national programs to spread the practice of family planning, it is likely that the trends in the lower social strata of the populations will follow those of the upper strata more closely. 4. In the white population of the United States the "class" differences narrowed substantially with the postwar rise of the birth rate, which was more pronounced in the urban and upper-class groups than in the rural and lower economic strata. The inverse relation remains, however, partly because of an earlier age at marriage in the lower economic groups. It is probable that much of the higher fertility of the lower status and income groups would disappear if contraceptive information and services were made readily available. 5. In the United States, the fertility of Negroes exceeds that of the white population, mainly as a correlate of their lower educational, economic, and social status. When similar educational, income, and occupational groups are compared, the differences are greatly reduced and even reversed. Prom a genetic viewpoint, differences in fertility among groups of people are important only when these groups differ in their genetic endowments. From the societal standpoint, only those genetic differences count that may bear on the intellectual, behavioral, and social attributes characteristic of man. Selection and: the Variability of Man Even without scientific knowledge of genetics, man created a great variety of genetically different strains of domesticated animals and plants by select

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BIOLOGY AND THE FUTURE OF MAN ing for desired types and breeding. The wild ancestors of cattle, dogs, chickens, wheat, and corn, for example, appeared rather uniform. Never- theless, deliberate breeding practice has shown that a great amount of concealed genetic variation was present beneath the apparent unifo~ity- variation that enabled man to select for traits that appeared desirable. Such selection led to the establishment of cattle specialized for milk or for meat production, the astonishing manifoldness of races in dogs, and chickens high bred for egg-laying or for meat yield. At the same time, selection led to disease resistance, heat tolerance, and other physiological states. Plant strains were selected for adaptation to many climatic and soil condi- tions, as well as for yields that surpass by far those attained in the wild state. But, in man, selection occurred without conscious direction. Different groups of mankind differ from one another in many ways; the significance of most of these differences is unknown or only incompletely understood. Why do the average body sizes of populations vary from the pygmies of Africa to the tall Watusi of the same continent, from the shorter Southern Mediterraneans to the taller Scots? Why do the facial features of Orientals differ from those of the Caucasians? It is possible that some of these dif- ferences arose by the chance sampling of genetic types in the distant past, followed by long periods of physical, hence genetic, isolation. Other dif- ferences have been presumed to be the result of natural selection. Dark pigmentation of the skin is an asset in the tropics, where it protects the tissues against excess ultraviolet radiation. Light pigmentation is an asset in northern regions, where enough ultraviolet light must penetrate the surface to transform dihydrocholesterol into vitamin D. Long limbs serve as radiators of heat in desert peoples, while short extremities conserve body heat in arctic climates. What is useful, natural selection preserves, and what is of negative value it rejects. While it is obvious that the racial groups of mankind differ from one another in specific ways, the multitude of differences in facial features, body build, height, and other physical as well as mental traits readily indi- cate the great heterogeneity of each major population group. Indeed, the extensive overlap of these groups with respect to many genetically deter- mined traits is as impressive as the differences that distinguish the groups. Moreover, the polymorphic nature of any human group and that of every other species studied intensely, e.g., cattle, chickens, flies has become dramatically clear in recent years. Every human group contains a great variety of genes for alternative blood substances, serum proteins, hemo- globin, and enzymes, and new polymorphisms are constantly added to our knowledge. Thus, in every population there are people belonging to blood group M, others to N. and still others to MN. Why should there be a 465

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466 THE LIFE SCIENCES variety of genes determining these properties instead of a single type best fitted to survival and therefore having become fixed by natural selection? What is the biological and sociological significance of polymorphism? The inability to answer these questions for most, if not all, human polymor- phisms indicates fundamental gaps in our understanding of the genetics of human populations. Selective forces must exist that operate to retain variety of genes rather than to eliminate all but one of each kind. How these forces act specifically, so as to enhance survival of a gene under certain genetic or environmental circumstances and to decrease its survival under other circumstances, is unclear and will have to be established in each individual case. If we do not know how we became extensively polymorphic in the past or how we retain polymorphism at present, we cannot expect to predict the genetic future. The complexity of selective forces is such that to gain the necessary understanding there are required longitudinal studies, from birth to death, of exceedingly large cohorts; analysis of the data will require the use of powerful computers. The biological insights to be so gained should eluci- date the causes of the great load of biological losses in the form of spon- taneous abortions, stillbirths, deaths before the end of the reproduction period, reduced fertilities, and infertility. Notwithstanding the complexity of genetic population dynamics, gross interference with natural conditions is clearly possible. It would not take many generations to breed Caucasians whose average adult body size is four feet or average Japanese of six feet. We could breed for obesity or leanness, blue eyes or black, wavy or wiry hair, and any one of the obvious physical attributes in which human beings vary. Presumably, we could also breed for mental performance, for special properties like spatial per- ception or verbal capacity, perhaps even for cooperativeness or disruptive behavior. Most of these traits vary not only genetically but also under the influence of environmental factors, as, for example, size and weight with food, or mental scores with impressed social attitudes and educational opportunities. This, however, does not negate genetic components in the determination of the variety of traits. The heritability of a trait, which is a measure of the part genes play in the observed variability of the trait, may be large or small. Although more research with respect to heritability of human traits is needed, it is abundantly clear that selection could be effective even with traits of quite low heritability. Although potentially able to select his own genetic constitution, man has not made use of this power. Selection is a harsh process. To make speedy progress, reproduction should be limited primarily to those who possess genotypes for the desired traits. But who will decide what is desirable? How much genotypic and phenotypic variability would be opti

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BIOLOGY AND THE FUTURE OF MAN 467 mat in the human society? Who would dare to prohibit procreation to a majority of men and women, limiting this activity only to an elite group? And to whom would society entrust such decisions? May we expect changes in attitudes of whole societies so that they would accept the self- control of human evolution at the cost of foregoing the private decisions of most people to propagate themselves in their own children? It is ex- tremely unlikely that such changes in attitudes will come soon. The future of man, however, may well extend over incomprehensibly long times, long enough not only to ponder these possibilities but also to explore them in actuality. In order to overcome some of the objections to all-out self-selection by man, the late H. J. Muller advocated partial selection for the betterment of mankind. Muller proposed deep-freeze storage of the sperm of the most distinguished men. Such storage was to extend over a long period, perhaps decades after the death of the sperm donors, in order to give perspective to the judgment of their being unusually distinguished. The sperm of those who withstood the test of time were then to be made available to married couples. The wife and the donor would become biological parents while the husband would, like an adoptive parent, influence the child by his personal attributes. This scheme has a low genetic efficiency as compared to procedures in animal breeding. Its emotional appeal, too, is limited. Yet its control over man's genetic future, granting its limitations, would be accomplished by methods that leave room for free choice. Moreover, the procedure is already employed in numerous cases of infertility of a husband, without, however, using the opportunity to choose unusually distinguished sperm donors. Careful selection of the mothers by an appropriate agency and subsequent inbreeding might, however, accomplish the goal of a "superior" breed of man exhibiting the criteria chosen, but this was not essential to Muller's suggestion since the loss of free choice diminishes the social acceptability of the scheme. A much more efficient and a most revolutionary way of selecting for specific human genotypes has been suggested on the basis of experiments with frogs and other amphibians experiments whose original purpose had nothing to do with plans for genetic selection. It is possible to remove the haploid nucleus (half the adult number of chromosomes) of a frog egg before fertilization, and, instead of fertilizing it with sperm, implant the diploid nucleus (a complete nucleus with a double set of chromosomes, one from each parent) of a body cell from a frog embryo. Such an egg can develop into an adult frog with the same genetic constitution as the frog embryo whose body cell provided the transplanted nucleus. If the method of nuclear transplantation with subsequent full development should become successful, utilizing the nuclei of body cells of adult individuals,

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468 THE LIFE SCIENCES and if it could be applied to man, a most powerful means of controlling the genetic constitution of future generations would become available. Since the nucleus of a body cell retains the totality of one's genes, a child pro- duced by an enucleated egg that had been supplied with the nucleus of an adult body cell would, genetically, be an identical twin of the donor of that body cell. Moreover, any desired number of genetic twins could be produced. It would require the collection of unfertilized eggs from the oviducts of many women, removal of the egg nuclei, and replacement by the nuclei of body cells of the chosen man or woman. This would be fol- lowed by return of the eggs to the uteri of women who then would undergo normal pregnancies. In this way one could produce multiple identical copies of any person judged admirable. Technically, it is still a long way from the use of frog eggs to the use of human eggs, but what can be done in frogs today will surely be possible in man tomorrow. The biological problem now is primarily one of skill and development of detailed procedures. The next step would probably be the extension of the techniques from amphibians to laboratory mammals. Once successful in mice or rabbits, there could be practical applications to animal breeding. Prize bulls or cows could be perpetuated by identical "offspring" derived from their body cells. From thence, technically, the steps toward potential human use would not be difficult, and if there were a strong wish to make such potentialities a reality, it could probably be accomplished within a few decades. At this time, there is need to ponder the personal and social implications of this biologically possible procedure. Powerful social forces would as surely resist adoption of such practice as they would a deliberately under- taken breeding program with selected human beings. At the present moment of extremely dangerous population growth, social pressures are best directed to lower reproduction, in general, without qualitative con- siderations. But one day, when populations are stable, world peace is the norm, and man's social and political institutions are sufficiently mature to assure that biological understanding will not be utilized to perpetuate in- justice or strengthen dictatorship but, rather, to expand human potential, man will be free to guide his own evolutionary destiny. There is no doubt that much of the seeming variability of mental, be- havioral, and social traits can be accounted for by graded differences in nongenetic factors such as wealth and poverty, intellectual stimulation and its absence, or environmental encouragement and discouragement, as well as malnutrition in early life. A major task before mankind is to see that these nongenetic factors are adjusted so that each individual realizes his genetic potential to the fullest. At the same time, however, while the per- formance of unchanged genotypes may be improved in this way, intensive

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BIOLOGY AND THE FUTURE OF MAN studies of the existing genetic variability should make possible the design of realistic blueprints for the control of man's biological makeup. These plans will rest on a future deeper understanding of the "gene pool," the genie content of populations quite apart from its actual existence in living individuals. In abstract terms, control of the genetic future of man consists of manipu- lation of the gene pool. In concrete terms, such manipulation is accom- plished by specified reproductive patterns of individuals. Although the hypothetical production of multiple identical copies, discussed above, may become technically feasible, there can be no certainty that a given geno- type, successful under one set of conditions, would be equally successful under different circumstances. The future of man is more likely to be rich and exciting, to progress to greater possibilities, by exploring the variety of the gene pool than by standardizing on some uniform Homo sapiens. Although it might be feasible, we forcefully reject the abhorrent thought of breeding subsets of humans specifically adapted to the performance of various tasks, thereby creating a highly efficient but antlike society. The brain of man has not increased significantly in size since his Cro- Magnon ancestor, perhaps not for many millennia before. When one day man accepts responsibility for his acknowledged power to control his own genetic destiny, the choice between various plans must be based on value judgments. When he begins to use the power to control his own evolution, man must clearly understand and define the values toward whose realiza- tion he is to strive. Man's view of himself has undergone many changes. From a unique position in the universe, the Copernican revolution reduced him to an inhabitant of one of many planets. From a unique position among orga- nisms, the Darwinian revolution assigned him a place among the millions of other species that evolved from one another. Yet Homo sapiens has overcome the limitations of his origin. He controls the vast energies of the atomic nucleus, moves across his planet at speeds barely below escape velocity, and can escape when he so wills. He communicates with his fellows at the speed of light, extends the powers of his brain with those of the digital computer, and influences the numbers and genetic constitution of virtually all other living species. Now he can guide his own evolution. In him, nature has reached beyond the hard regularities of physical phe- nomena. Homo sapiens, the creation of nature, has transcended her. From a product of circumstances, he has risen to responsibility. At last, he is Man. May he behave so! 469

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