 In 1956, and again in 1960, the National Academy of Sciences published a report that embodied the findings and recommendations of six committees established to study the biological effects of atomic radiation. In both years, the report was issued in two forms. One, a summary report directed to a reader with some modest background knowledge of biology. And the other report to the public designed to inform an intelligent but not scientifically educated citizenry about the elements of the problem. Professor Bentley Glass served as rapporteur for the committee on the genetic effects of radiation. On the basis of my own personal experience in committees, I would estimate that the text of the committee report is largely that of Professor Glass. Rapporteur always does all the work. I believe the reports to be exemplary, both in their presentation of technical material on a level appropriate to the audience and especially because of their sensitivity to the interaction of technical and scientific circumstances with society at large. I myself have used the report from time to time for the purpose of quotes from a section of the report entitled Responsibilities of Geneticists. I use it as an example of a exceedingly fine sample of the exercise of moral responsibility. Professor Glass was born in China in 1906. It is not possible to describe all stages of his academic career and all the activities at market. It's not possible because he'd go to sleep. He earned a PhD degree at the University of Texas in 1932 and has been associated with several institutions since then. Since 1947, he has been professor of biology at Johns Hopkins University, where he markedly contributes to the maintenance and strengthening of the tradition of excellence in the biological sciences that has always characterized Johns Hopkins. Professor Glass has been a vigorous spokesman for American science. He is a member of the board of directors of the American Association for the Advancement of Science and has been the vice president for the zoological section of that most influential organization. He has been an outstanding proponent of the responsible use of science and an opponent and an opponent of Kant, both within and without the academic community. His dedication to the integrity of the academic enterprise, both scientific and otherwise, is evidenced by his work within the American Association of University professors, of which he is a former president. Professor Glass will speak to this symposium both as a distinguished biologist and as a reflective citizen with opinions. The topic is the effect of changes in the physical environment on genetic change. Professor Glass. Thank you for those embarrassing words, Professor Cush. I shall try to live up to the standard you hold up for me, President Carlson, fellow participants, and members of the symposium. Evolution, for mankind or any other species, is constituted of changes in genetic makeup that provide better degrees of adaptation to the total environment. The physical environment is only a part of that total environment, and probably, except for setting the limits within which life can exist at all, it is the less important part. Once life had conquered the physical environment, first in the waters of the earth and later on dry land, and once the organism had developed that amazing capacity which it now demonstrates to regulate its internal chemical affairs in spite of external fluctuations in the environment, adaptation took on a different aspect. Then it was that the presence of living predators in the environment and of swarms of parasites, the agents of disease, became of paramount importance. The evolutionary value of social organization proved itself, whether founded on instinct, as in insects or on learned behavior. Man's intelligence, which we so fondly regard as the supreme product of organic evolution, is less a tool for coping with an inimical physical environment than it is one for regulating behavior in the context of the family, tribe, and nation. If these generalities be true, it must follow that minor alterations of the physical environment are indeed unlikely to provoke any radical change in the human genotype. Only a cataclysmic alteration of human circumstances might be expected to do so. And yet such is man that even the smallest modifications of our present genetic constitution in such essentially trivial aspects as skin color may strike us with consternation. And so we proceed to give the matter some consideration. The ways in which the physical environment may affect the human genotype are two. First, the frequency of occurrence of mutations and recombinations of existing varieties of genes may be altered. Secondly, the factors of the environment may impose new selective forces that alter the previous degrees of successful adaptation, of successful reproduction and transmission of particular genes so that some are favored and others are gradually eliminated. It is not necessary to devote much consideration to the place of recombination in the evolutionary process. That is not at all because recombination is unimportant, but simply because it is itself secondary to the origination of the genetic variations in the population through the process of mutation. Recombination may enable each new mutant gene to be tried out in natural selection, in company with a variety of modifiers, and so to find itself. No gene works alone in the complex control of metabolic and developmental processes. Each gene is thus known eventually by the company it keeps. Physical agents that are known to be capable of producing mutations, the more important aspect of this topic, I think, mutations of individual genes or fractures and rearrangements of the chromosomes that bear the genes, and at the same time are capable of penetrating the living barriers that rather effectively isolate the reproductive cells of human beings from external variations include three types of agents, ionizing high-energy radiations, high temperatures, and perhaps even cold shocks. I put that in for the benefit of the dwellers in Minnesota. And certain chemical agents, particularly those that act strongly upon deoxyribose, nucleic acid, or DNA, as we abbreviate it, the hereditary material itself. Analyses of the total range of detectable mutations produced by any of these physical agents in any of the experimental organisms subjected to genetic analysis from bacteriophages and bacteria to the higher plants and animals, without exception, agree in showing that the majority of induced mutations are harmful. The exact proportion of mutations which are harmful varies with the species, but it is always preponderant. In fruit flies and mice, it may comprise as high a proportion as 99 or even 99.9% of all mutations detected. It's not hard to see why that must, in fact, be so. At one level of analysis, the biochemical level, it is apparent that the usual effect of a mutation of any gene is to interfere with the formation of its primary protein product, an enzyme, or a structural protein, or to cause a loss of its biological activity. In other words, mutations tend to block specific genetically controlled steps in metabolism. And that is characteristically harmful. The broader level of consideration is that of the evolutionary process in the nature of its productions. Neither we humans nor any other organisms possess a large amount of useless chemical machinery. When any process, once useful, becomes by some internal or external change, to be no longer of use to its possessor, the inevitable occurrence of mutations will sooner or later remove it. This truth applies to useless structures which become vestigial organs and eventually disappear. It applies also to physiological activities. Thus, the capacity to detect odors has diminished vastly since man's ancestors came to rely more and more upon visual stimuli in the guidance of behavior. And it applies fully at the biochemical level, where we find that many substances, such as amino acids, so readily synthesized by bacteria and green plants, cannot be manufactured in our own cells. And that even some substances made by many animals not too distantly related to us, we are forced to call vitamins and to seek in our food. Perhaps if the food upon which man's ancestors subsisted in the past several million years had not regularly contained sufficient amounts of these substances, we today would have retained the capacity to synthesize them and so would not need them in our food. But here we are with our synthetic and over-processed foods and our vitamin pills in bottles. The reason why most mutations are harmful is therefore a simple consequence of the fact that we have over the ages evolved to a particular state of adaptation toward our physical and biological environments. No, we're not perfect in our adaptations, but neither do we possess a superfluity of useless biochemical and anatomical lumber. This truism has an important corollary. Genes useful in novel ways can arise only from the genes that already exist in the species. And these genes are already engaged in performing specific vital functions. Merely to substitute the new useful gene for an old gene serves no purpose. The new adaptation is lost in the swift and remorseless eradication of the mutant type, which has been despoiled of some vital function. Swift and easy the descent to a vernal. The path to the light, slow and rugged. Geneticists therefore in general believe that really new beneficial genes rarely, if ever, arise by substitution. The process is more complicated. It is one in which an existing gene must first become duplicated, so as to provide a dual locus. And then the evolution of one of these two duplicate genes can proceed in a new direction, while the other one continues to perform the vital function with which it is entrusted. Only in case the physical environment were to change so radically that genes once useful were no longer of any material consequence to the survival of the species, would a supply of genetic material for a rapid evolutionary change in new directions become available at the appropriate time, and this situation seems most unlikely. Evolution therefore cannot be speeded up in an adaptive direction simply by increasing the mutation rate. The harmful effects far outweigh the possibility of any benefit. The physical and chemical agents that produce mutations are blind and undiscriminating. They produce mutations at all genetic loci that are capable of mutating, and not merely at those that might provide some better adaptation. The important question to consider is therefore, how great a total genetic load of harmful mutations the population can bear, or under which it might alternatively succumb. Every harmful gene that arises through mutation must be eliminated from the population through natural selection, that is through the death or the failure to reproduce of some possessor. Else the frequency of the harmful gene will rise and the total genetic load will be increased. How may we understand this in specific terms? At the present time approximately four million births occur in the United States each year. Of these a considerable number bear some tangible defect or possess an inner defect that later in life becomes evident. Perhaps half of these defectives owe the defect wholly or in part to some genetic cause. The best current estimate which I've derived from data in the report of the United Nations Scientific Committee on the Effects of Atomic Radiation, in 1958 is that about 4% of all births carry a genetic defect tangible then or later in life. Some of these are chromosome anomalies such as the presence of a particular extra chromosome which might cause Mongoloid idiocy or a sexual aberration known as Kleinfelder's syndrome or the lack of a particular chromosome in its normal double dose. Thus disorders that affect intelligence and normal sexuality and that constitute several percent of all inmates of our mental institutions are of this nature. Translocations of portions of one chromosome to another sometimes with comparable physical and mental effects and probably always with an adverse effect upon the fertility of the bearer have in recent years been found to be far more frequent in the human population than was ever dreamed. Besides the chromosomal abnormalities there are single or multiple gene effects, our inborn errors of metabolism and our structural defects. These include such representative defects of the gastrointestinal tract as polyposis of the colon of the blood is hemophilia of immunity mechanisms agamoglobulinemia of kidney function as phenylketonuria of nervous and mental disorders as epilepsy and schizophrenia of muscular and skeletal defects as muscular dystrophy of endocrine disorders as diabetes and pituitary dwarfness and of reproductive disorders that engender sterility. These genetic defects are the fruit of the genetic load of the population. In theory, there is a very simple relationship between the frequency of the genetic mutations that produce detrimental genes and the equilibrium that exists between the influx of such mutations and their elimination by means of natural selection. Doubling the mutation rate will upset the existing equilibrium. The load of detrimental mutant genes carried in the population, its genetic load will then rise until the frequency of defective persons becomes just double the original frequency. Double the mutation rate, you eventually double the number of defective, genetically defective individuals born. That is because natural selection can act only upon the individuals in which the effect of the mutant gene is expressed. And for influx to balance efflux, a double mutation rate must be balanced by doubling the amount of elimination. Thus eventually, after the passage of perhaps 20 generations or more, a doubling of the mutation rate would increase the percentage of individuals with tangible genetic defects from 4% to 8%. And in a population the size of our present one, that would signify an increase from 160,000 to 320,000 defective babies born every year. If our population continues to increase at its present rate, thus reaching the size of the present population of China within the next century, the increased number of defective babies would amount to 1,280,000 annually. This measure is our yardstick for evaluating the effects of any general increase in the mutation rate. Of all mutagenic agents, atomic radiations have been studied most intensively. These radiations include x-rays and the radiations from naturally occurring radioactive substances upon Earth as well as the man-made products of nuclear fission and fusion reactions. There is background radiation in our normal physical environment, amounting to a gonadal, that is reproductive cell dose, of three to five runtkins in the duration of a single human generation of about 30 years. Approximately one fourth of this radiation comes from cosmic rays, which vary considerably with altitudes since the Earth's atmosphere effectively absorbs the radiation. At 15,000 feet, the cosmic radiation is more than five times as great as it is at sea level. About one half of the background radiation comes from rocks, soil, and building materials. The radiation from igneous rock is considerably greater than that from sedimentary rock, so that mountainous regions in general are more radioactive than coastal plains. Living in a stone house, a person receives more radiation than in a brick house, and there is still less in a frame house. Finally, about one fourth of the background radiation comes from radioactive substances, especially potassium-40, that are taken in with food and water and become internal emitters in the tissues of the body. A vast body of genetic evidence supports the firm conclusion that the frequency of simple gene mutations and the frequency of single chromosome breaks each increase linearly with an increase in dose of the radiation, and that there is no threshold below which mutations fail to be induced by radiation. My own experiments with the laboratory fruit fly, Drosophila melanogaster, have demonstrated that even a dose of five runtkins, no more than the human dose per generation from the physical background, increases the mutation rate as predicted. From this experiment, which was based on the detection of mutations in a total of 1,360,948 fruit flies, which entitles me, I think, to call this the mega-fly experiment, it may be calculated that a dose of six runtkins would double the number of mutations arising spontaneously in the fruit fly, and that the background radiation it actually receives accounts for less than 1,000 of the total spontaneous mutations. The proportion of spontaneous mutations accounted for by the background radiation would be greater in longer live species, but even in man it would be little above 5% of the total amount of the spontaneous mutation. It's to be emphasized that not all mutations arising spontaneously can possibly be produced by the radiation in the natural environment. The value of 60 runtkins for a dose that would double the number of spontaneous mutations is in good agreement with other estimates based on mutations induced by high energy radiation in bacteria, flowering plants and mice, range generally estimated to be between 30 and 80 runtkins. There is now also good evidence from my own as well as other laboratories that human and other primate and mammal cells grown in culture and subjected to x-rays undergo chromosome fracture at doses of 15 runtkins or less with a frequency of 3,500 of a break per 100 cells or one break per 300 cells per runtkin. Again, the relation of genetic effect to radiation dose is linear. Double the dose should double the number of chromosome breaks should double the number of mutations. This conclusion means in the plain language of the National Academy of Sciences Committee to which Professor Kush referred that any radiation dose however small can induce some mutations and that the genetic harm is proportional to the total dose. If this statement were exactly true it would remain simply for us to judge the genetic damage done by every sort of exposure to nuclear radiations solely by estimating the cumulative dose received by the gonads from the time of conception to the end of the reproductive portion of life. Thus from estimates of the population of the United States received on the average in 1956 a cumulative 30-year gonadal dose, dose to the reproductive organs of three runtkins for medical and dental diagnostic purposes. One might say that this dose was approximately equal to or slightly below the background radiation dose and might increase the spontaneous mutation frequency by perhaps 5%. Following the direction of attention to the undesirability of such exposures much has been done during these subsequent years since 1956 to reduce the dosage from medical and dental exposures through limitations in the use of fluoroscopy which supplied the heaviest diagnostic dosages through use of faster photographic films through better coning of the x-ray beam and better shielding of the patient, many other measures. The total accumulated exposure over a 30-year period may now be scarcely at an average of two runtkins per person for the population of the United States. There are complications however. During the past six years largely through experimental studies of mice exposed to radiation at the Oak Ridge National Laboratory it has been discovered that although the quality of the radiations makes little difference the rate at which they are administered is of very great importance. A low dose rate that is administered over a prolonged period of time produces far fewer mutations than the very same total dose administered at a high dose rate for example within a few seconds. Thus in experiments in which Chinese hamster corneal cells were treated in my own laboratory by J. Grant Bruin with doses of 50 and 100 runtkins at dose rates of 600 r per minute, 60 r per minute and two r per minute. The number of chromosome breaks produced was scarcely one third as great at the lowest dose rate as at the highest dose rate. Recent experiments by Bruin show that the difference is attributable to a repair mechanism that can operate when the radiation is received slowly but not when it is administered rapidly. We must therefore from now on reckon with dose rates as important parameters as well as the total doses received. Medical uses of x-rays and gamma rays from radium whether for diagnostic or therapeutic reasons are characteristically delivered at high dose rates and consequently do the greatest relative amount of biological damage. Background radiation likewise the direct radiation from fallout derived from nuclear weapons testing are on the other hand delivered at low often very low dose rates and may be expected to produce fewer mutations than would be estimated from the magnitude of the delivered dose. Radioactive isotopes whether natural or artificial such as the strontium 90 cesium 137 and iodine 141 in the latter case involves still another complication. Some of them become generally distributed throughout the tissues of the body. For example, cesium 137. Others become highly localized in particular organs. Strontium 90 almost wholly in the bones. The iodine 141 in thyroid gland. The genetic effects of these two isotopes will be slight indeed even though they're the damage they inflict upon the organs in which they become localized may be very great. Carbon 14 an isotope that is both natural and artificial represents a special case. Not only is it dispersed throughout the body it is extensively incorporated into the DNA of the chromosomes themselves both in somatic cells and in reproductive cells. Thus while cesium 137 is not involved in the normal metabolism of the body and is quite rapidly eliminated. Carbon 14 with a physical half-life of over a thousand years is a highly persistent genetic hazard. It has been estimated that the total genetic dose received from carbon 14 is about equal to that from cesium 137. Although the dose from carbon 14 will be spread over many more generations after the exposure to fallout. Delayed fallout. The fallout that is not local and in the immediate vicinity of an explosion. Occurring on a continental hemispheric or worldwide basis after nuclear weapons testing is of course at a low dose rate far below the two-tenths to eight-tenths runkins per minute which W. L. Russell found at the Oak Ridge Laboratory to be those levels at which the reduction of mutation by a low dose rate reaches a maximum. The total estimated fallout dose to the reproductive organs of persons in the United States from nuclear weapons exploded through 1962 has been estimated to be probably about 225 thousandths of one runkin. If we divide this estimate by at least three to allow for the fact that exposure will be at a low dose rate, it appears that the increase in the mutation frequency will amount to the equivalent of about 75 thousandths of one runkin, 75 millirunkins administered at a high dose rate as when ordinary X-rays are used. It would follow that the fallout from all past tests is producing about 1-800 as many mutations as occur spontaneously per generation. This would produce a small but not insignificant increase in the genetic load. Nuclear war, should it envelop us, would be an altogether different matter. The populations of the combatant or target nations in a nuclear war would receive not only the delayed fallout from the exploding atomic and hydrogen bombs but would also receive a very large amount of local fallout at a high dose rate. Fallout shelters, strong, relatively expensive, can be constructed to provide a hundred fold reduction in the fallout intensity, a reduction sufficient to lower the first day dose to less than 100 runkins. While some portion of this remaining exposure would be at a high dose rate, the average for even the first day would be at a low dose rate. Assume a nuclear war now of modest proportions. In relation to the size of the present stockpiles of weapons on both sides, that is. Let us say a 20,000 megaton exchange, which half might fall on the United States, of which roughly half is fission and half fusion. It has been estimated by experts, not by me, that such an attack on a protected population might leave as many as 50 million survivors in the United States, of whom half would probably be severely injured. The hail survivors would be forced into exposure to radiation outside of their shelters at least after the first month. It seems doubtful then that any survivor would accumulate less than a total of 200 to 300 runkins, equivalent to about 100 runkins at a high dose rate. What would be the genetic consequences of a probable exposure of 100 runkins to gonadal dose to the entire surviving population? Clearly enormous, more than doubling the spontaneous mutation rate. Genetically defective births would increase steadily for some generations, mounting toward a maximum level of about 10% of all births. Nevertheless, strictly from the genetic point of view, I do not foresee that such an increase could bring about an actual extinction of the population. The population might become extinct from other reasons, but we're talking just about the genetic effect. Experimental populations of fruit flies, mice, dogs, and pigs have been exposed to such doses in repeated generations without such an outcome. However, natural selection might be sharply increased as our ethical sympathies for the unfortunate became blunted by sheer inability to cope with the problem of medical aid and rehabilitation. It may be more important to consider the effects of delayed fallout on the people of the rest of the world in the event of an outbreak of nuclear war. Here one who looks at the problem without national sympathies may afford to be encouraging. The extrapolation from our knowledge of the fallout produced by past nuclear weapons tests involves simply a multiplication of the fallout through 1958 by two orders of magnitude or of the total to date by a factor of 40. 40 times 0.225 runkins is nine runkins. Even if our estimates have passed in present fallout, our inconsiderable error, we can conclude that the non-target countries in the same latitudes of the Northern Hemisphere will be subjected to only a fractional increase in the spontaneous mutation rate, about a 15% increase. In the Southern Hemisphere, the increase would scarcely rise to half of that. Thus, although every geneticist agrees that any increase whatsoever in the overall mutation rate is undesirable and will have detrimental effects, and though every defective child is a cause of agonizing heartbreak, it is not scientifically correct, in my opinion, to maintain that a nuclear war would necessarily lead to the genetic extinction of all human life on this planet. Not even if the nuclear war were double or triple the size predicated. And even if most of the nations of the earth were actually targets. Less horrifying is the problem of the risk as we enter the age of nuclear power of accidental exposures of the population to atomic radiations. There will of course always be a danger of accidents. Yet there is considerable reassurance in the monitoring of current operations which show that nuclear power plants of modern types can be operated safely with very little or no contamination of the surroundings. On the other hand, there is accumulating evidence that radioactive pollution of ocean waters at the mouth of the Columbia River has been produced by supposedly safe levels of radioactive wastes, constantly leaving the great atomic energy plant at Hanford. There is little knowledge at the present time of the tolerance for radioactive contamination within different ecological habitats, marine, freshwater, and terrestrial. Experiments conducted on underground nuclear explosives during the current partial weapons test ban have improved our understanding of the conditions that must be met to keep explosions from venting into the atmosphere. And before long, it may be possible to use subterranean explosions for digging the new Atlantic Pacific Canal in Central America. But much study must be devoted to the ecological effects of large subterranean radioactivity and the drainage of underground waters must be carefully explored. In one respect, the inevitable nuclear accidents of the future are less alarming than the fallout from atmospheric weapons tests. The genetic damage done to a population is a compound function of the dose, dose rate, and number of functioning gametes treated, either when mature or in the ancestral germline. For an acute dose, 1,000 rutkins administered to the reproductive cells of 100 persons is equivalent to 100R administered to the reproductive cells of 1,000 persons, to 10R administered to 10,000 persons, to 1R administered to 100,000 persons, or to 1 tenth R administered to 1 million persons. For this reason, the fallout from weapons tests, which affects virtually every person in the world, is far more significant than the smallness of the individual dose from fallout would seem to imply. While the effects of a nuclear accident, even though doses might range up to several hundred rutkins for some persons, will be spread to far smaller numbers of persons, perhaps a few hundred or 1,000 only. So much for ionizing radiations as a cause of mutations. Let's turn our attention now to temperature. Temperature may be the most important single factor in the production of mutations in nature. Long ago it was established that in the fruit-flied Rosofla melanogaster, the frequency of lethal mutation is increased two and a half times by an increase in temperature from 20 degrees to 30 degrees centigrade. Allowing for the fact that the length of a generation is about twice as long at the lower temperature, the actual increase per unit of time is five-fold. Mammals with their internal gonads and well-regulated body temperature might well seem to be exempt from such fluctuations in the mutation rate. And indeed, it may have been the importance of stabilizing the mutation rate even more than the value of regulating general biochemical and physiological processes that led to the evolution of a homeostatic regulation of body temperature. Yet our analysis must also reckon with the fact that in most species of mammals, including man, the testes of the male are slung in a pouch of skin outside the abdominal cavity. Here they are certainly subject to temperature variation. In 1957, Lars Ehrenberg and his associates in Stockholm performed an amusing experiment. They dressed 25 young male volunteers in kilts or skirts and allowed time for adjustment to the ambient outdoor temperature. Another 25 young males clad in their usual trousers served as controls. The average temperature inside the scrotum, measured by thermocouple, was found to be three and three-tenths degrees higher in the males wearing trousers than in those wearing kilts. Here the evidence rests. But if we suppose that in the human species, there is a relation of mutation rate to temperature, comparable to that observed in Drosophila, the conclusion would surely follow that high temperature is a major cause of detrimental mutations. Perhaps our leaders of fashion for both sexes have not recognized the possibilities of capitalizing on this biological relation. As for the chemical agents capable of producing mutations, most of them are rarely met with in the normal environment. Thus mustard gas or nitrogen mustard formaldehyde, nitrous oxide and ethylurethane are not commonly met in ordinary life. However, certain carcinogens are also mutagens and some of these may be found in smog. The common pesticides, now widespread contaminants of the environment of the United States are also suspect and have not been adequately tested for their mutagenic power. Metabolically, sugars and ethyl alcohol are convertible to acetaldehyde, which like formaldehyde may possibly react with the DNA molecule and alter it. But then, possibly there are barriers that prevent any access of acetaldehyde to the nucleus or perhaps there are enzymes which break it down so promptly that it cannot react in this way. We do not know. The same possibilities arise with respect to molecular analogues of the purine and pyrimidine bases of DNA and RNA and ribose nucleic acid. Artificial analogues are among the most potent laboratory mutagenic agents known. What then of naturally occurring purines or pyrimidines? For instance, consider the case of caffeine, which is a potent mutagen for bacteria. Although caffeine has not been proved to produce mutations in any multicellular organism, a derivative, 8-ethoxycafine, is a very strong mutagen and chromosome breaker. Perhaps our metabolic barriers keep caffeine out of the nuclei of cells. Perhaps it enters but is not mutagenic. Perhaps it produces mutations. We really do not know. And now I pass to the effects of changes in the physical environment upon natural selection. These changes probably have a much greater impact upon the nature of selection than they do upon rates of mutation and recombination. Selection is the primary creative force in the evolutionary process. The varieties of genes produced by mutation in their several combinations are the raw material out of which the conformation of the species is carved. Selection is the force that carves the raw material. Like a human sculptor, natural selection chips away the superfluous and the detrimental variants within the population. They either die before reproducing or reproduce less prolifically than competing hereditary types. The population thus becomes more uniform than it otherwise might be. The individual and the species become suitably adapted to their physical and biological environment. Whatever change may occur in future in our own physical environment will therefore require some re-adaptation of the genetic structure of man. Unless he can avoid this by insulating himself from the altered environment so as to maintain his own preferred circumstances with little or no change. Man would be foolish, however, to suppose that he can avoid every change that will have evolutionary consequences. Even now, certain prevailing conditions are greatly changing the nature and magnitude of selection pressures. One of these is the decrease in the geographic isolation that formerly operated to establish and conserve the various human races and ethnic subgroups. A second is the steadily increasing size of populations. Both of these factors tend to homogenize the world's populations. Although to say that by no means signifies that individual genetic differences will disappear. These will be conserved within the amalgamated populations even though the differences between the groups will largely vanish. My own studies conducted in part with C.C. Lee show the extent and rapidity with which this process is occurring in the present North American Negro population. This ethnic group first brought to the New World a mere three and a half centuries ago is now represented in our major cities by a population approximately 30% of whose genes are derived from white ancestry. The curve representing gene transfer from the white into the Negro population of the United States reveals interesting features. As time passes, the curve flattens out so that at the present rate it may take 75 or more generations, 2000 years or more to reach a final equilibrium. But that prediction will be true only if the past rate of gene flow which has been two and a half to 3% per generation is maintained. Social factors will surely predominate in altering the real outcome. Prejudice against mixed marriages may lessen. Illegitimate bursts of mixed matings might increase. The very existence of a more mixed population may speed further intermixture. On the other hand, the establishment of a caste system such as India's conquerors imposed on that land long ago in their endeavor to maintain their superior status might prove quite effective in maintaining ethnic distinctions. The geneticist cannot predict the future. He can only study the dynamics of the processes as they occur. The rapidly increasing size of Earth's human populations likewise has unescapable genetic effects. Mating becomes more random with respect to most traits and all recessive traits become for a time much rarer. The recessive genes will tend under cover to increase in the population and eventually having attained a much higher general frequency in the population will produce homozygotes again, individuals upon whom natural selection may act. Yet for the time being, presumably for as long as populations continue to grow, natural selection for or against the rarer recessive genetic traits is in abeyance. In another way, the growth and merging of human populations alters the nature of selection. It is only in quite small populations of a few hundred reproducing individuals that chance factors in the establishment or extinction of competing genes play any significant role. In a past not so remote prior to the advent of agriculture, most men were members of quite small hunting and gathering groups and mating was predominantly limited to the tribe. Under those circumstances, random genetic drift, that is runs of luck, probably played a considerable role in determining the fates of competing genes. And if some few bold adventurers, male and female, departed into the unknown to establish a new tribe across the seas or mountains, so smaller group could not possibly be representative of the group of origin in its full range of genetic variability. The foregoing causes are not the only ones operating to lessen the force of natural selection upon modern man. Selection may be subdivided into the two aspects of mortality and fertility. If a dominant genetic trait is to be passed on, its possessors must on the average reach the age of reproductive maturity and must on the average produce at least as many offspring as the possessors of the alternative trait. The principle is the same for recessive genes, but because these may be passed on by heterozygous persons who are carriers of the gene, but do not manifest the trait, the process is very much slower. Our ethics promote mercy, and our medicine and surgery preserve to the reproductive age numerous genetic types that in a more ruthless society and a more rigorous age would never have had children. Diabetes affords a conspicuous example, but there are many others. Simple defects of vision such as uncomplicated myopia may serve to make the point more sharply. In a primitive human society, keen distance vision must have been a necessity. Probably only after agriculture and needlework or handcraft developed could a nearsighted man pull his weight in the social group. Infants with defects were commonly exposed to the elements even in relatively modern societies. Then less than a thousand years ago, spectacles were invented, and the gene that produces myopia was no longer selected against, at least not very strongly. Today, nearly everyone wears spectacles. I do not know whether it is likely that in time, the gene that produces myopia will become universal, and it's a leal that permits normal vision will become extinct, perhaps not. Less persons with nearsighted vision are more fertile in reproduction than their competitors. Or our present normal vision is associated with some unsuspected, less efficient quality. But it is apparent that once we have created an environment in which glasses are a necessity of existence, we cannot readily reverse the process. Diabetes is no great physical disability, least it does not prevent reproduction or seem to impair fertility. But we have elected an environment in which insulin is abundant and available and we cannot turn the clock back. Thus our ethics and our medicine are reshaping our genetic nature. Whether we guide our evolution in the future consciously or not, it is quite clear that we are shaping it unconsciously in many ways. The tremendous reduction in mortality during the early years of life, which has been achieved by modern medicine and nutrition by surgery and by antibiotics, leaves every genetic type with little advantage or disadvantage in respect to others. Our evolution in the past has certainly included much selection for resistance to various infectious diseases, such as malaria, cholera, smallpox, plague, tuberculosis and the like. Such selection is now largely in abeyance. Instead, however, there is abundant scope for selection to occur, as James F. Crow has demonstrated, on the basis of differences in fertility. While the human reproductive potential, clearly not less than eight children per mother, is realized in some groups, reproduction is scarcely at the replacement level in others. Selection will favor those genotypes that produce the most children, no matter what their other characteristics may be. What I have just described is probably the biggest shift in the nature of human evolution that has ever occurred, and it is occurring just now. The shift may not, however, be very prolonged since the prospective stabilization of the world's population within a century or so should have the effect of greatly reducing any selection based on fertility differences. If every couple were to reproduce at a replacement level, there would be no selection for fertility differences at all. The elimination of selection based on mortality and also that based on fertility might leave Homo sapiens in an evolutionary status quo, except for the continued loss of whatever hereditary characteristics are no longer vital to him or to her. We may speculate gloomily that there will be many dysgenic effects resulting from the physical degeneration of structures no longer necessary because our instrumentation and our sources of power and locomotion will have made them useless. Our bodies bear witness to the elimination of the superfluous. We have already lost the use of the muscles of our ears. The rudimentary appendix wisdom teeth and the mere remnant of hair that crowns the head will not be with us long. Clothes and cooking have changed us a lot already. Dare we look a bit farther and envision a new race of humans who have vestigial legs since they walk so little and ride so much? Without mammary glands, this cow's milk and artificial substitutes have replaced the need of lactation, even without intelligence comparable to ours because thinking has been handed over to the computers. Will the man of tomorrow need to spend a large part of his day getting ready to face the world, putting on his spectacles and adjusting his hearing aid, inserting his teeth, adding his false hair, taking insulin shots in one arm and allergy shots in the other, topping it off with a tranquilizer before venturing to step into his car? All these alterations of the human phenotype are hardly to be regarded as dysgenic. If we can indefinitely maintain our social capacity to compensate for them, although the burden of social labor required for so unproductive an effort may be expected to increase constantly. It seems unlikely that new paths of evolution will open before us without some strong challenge of our present adaptation to our environment. For example, any further evolution of higher intellectual competencies than we now possess will not be possible unless the future physical environment or future human practices lead to greater reproduction of the mentally well-endowed. Yet we cannot define the well-endowed precisely either on the basis of present genetic knowledge, methods of personality and intelligence testing, or without knowing prophetically the nature of that future environment in which mortals will dwell. In general, biological evolution moves with glacial slowness. Man as a species may have originated more than a million years ago according to the latest revisions of prehistory made by the anthropologists. And certainly man has not changed perceptibly in the past 40,000 years. Although that latest period has seen such vast physical changes as the diminution of the rigor of the ice ages, the advent of more abundant food supplies through the introduction of agriculture, the rapidly increasing command of inanimate sources of power, and all the complex growth of a civilization based upon scientific technology. The best evidence existing at present regarding the speed of genetic adaptation to a new environmental situation comes from the presence in many tropical and subtropical human populations of relatively high frequencies of certain genes, otherwise adverse, such as those for sickle hemoglobin, thalassemia, and glucose-6-phosphate dehydrogenase deficiency. For these genes seem to owe their local abundance to their capacity to confer some degree of resistance toward falciparum malaria. It is reasonable to believe that falciparum malaria, like plague, is a disease of civilized agricultural mankind since it exists only in cleared country and where populations are fairly dense. If so, malaria as a human endemic disease can scarcely date back more than eight or 10,000 years, and a significant change in human heredity, a change of an adaptive kind, must be able to occur within that span of time, approximately 300 to 400 human generations. The man and woman of tomorrow are not really likely to be the caricatures of the man and woman of today I have previously sketched, unless we submit ourselves to the more extreme environments of the moon or of Mars as dwelling places. Even there, we are more likely to carry our terrestrial environment with all its conventional circumstances along with us than we are to adapt ourselves radically to novel conditions. Within a few decades in all probability, it will be experimentally feasible to grow human spermatozoan ova in the laboratory, to conduct selected fertilizations between desired types and to implant the young embryos in the wombs of foster mothers providing such can be found willing. Not only the selection of particular types, but also of what we might call genetic surgery may become possible. Professor Tatum will probably talk more about that. I say however that these things are feasible and possible. I do not say either advisable or wise. Within just a few years, we must decide whether to permit such human reproductive engineering. Yet at present, we do not comprehend our own genetic natures. We cannot distinguish the fit or better genotype from the worse. We do not agree upon our goals. Will it not be easier as well as wiser to select and shape the environment to which adaptation must be made than to change our own inmost nature for the better? I have, of course, but chosen another way of saying in conclusion that our cultural evolution has outstripped our biological evolution and is far more likely to dominate the future. So the ushers bring questions to the front of the hall where Professor Glass will try to answer 1.26% of the questions. Perhaps I could put our fellow panelists in a special position. If any of the panelists wants to raise hell, I think this is the time to do it. Can't raise hell. Your comments on thermal effects. How would you redesign the topless bathing suit? The better advantage? Does current evidence suggest that most or all translocations are deleterious? Probably so. The translocations which have been studied in other organisms characteristically cause semi-sterility. That is one half of the offspring of an individual carrying the translocation will die. There are probably some translocations that become established in populations that have less radical effects than that. Although the matter has not been studied for the human population. I know of a considerable number of cases of confirmed translocations found in individuals with monogloid mental deficiency or with one of the sexual abnormalities associated with translocations of the sex chromosomes. But the fact that this association occurs may simply result from the reason that most investigators find it easiest to examine the chromosomes of individuals who are in mental institutions. They don't usually object. And it's more difficult to carry out tests of the normal population. But there are other individuals well known who carry translocations without any apparent defects produced in themselves or in their children. We don't know whether it's affected their level of fertility or not. Will the immunization shots cause a mutation? Well, so far as I know, no kind of immunization phenomenon produces mutations. Will you and Dr. Reed discuss your statement that number of offspring in man equates with evolutionary success? A statement with which he differed this morning. Success, of course, can is a term that is capable of interpretation in a variety of ways. All the evolutionist usually means by evolutionary success is the increase of a particular genotype, the establishment rather than the extinction of a particular species. And in this particular sense, I think it's undeniable that the number of offspring of a particular type produced is the measure of evolutionary success. Would Dr. Reed want to comment on that? He agrees. What increase in mutation is predicted for the survivors of Hiroshima? The studies of the probable production of mutations in the irradiated survivors of the Hiroshima bomb have been very complicated to analyze as they would be in any human population subjected to irradiation. In the first place, it's been very difficult to determine what the average dose was among individuals at different distances from the hypo center of the explosion. Those measurements of dosage have recently been, or estimates have recently been considerably revised and improved and individuals have been divided up into categories, those who received perhaps 10 runkins, those who received between 10 and 50, those between 50 and 100, those who received from 100 to 500. The mutation that would be predicted, the amount of mutation would be different for each of these categories. So you can hardly make a generalization without saying something about the numbers of individual survivors in each of these groups. The method used has been to study the change in the sex ratio produced in the survivor, in the children of the survivors. If mutations are produced in the sex chromosomes, these will lead to a particular kind of shift in the sex ratio if the male parent was the irradiated person and the female parent received no radiation and a different kind of shift if the reverse was the case. The actual changes observed are in the expected directions. They're just barely on the borderline of statistical significance. Since they agree with the theory, we are inclined to say as geneticists that there is evidence that adverse mutations were produced in the survivors of the Hiroshima bomb. Is all genetic material capable of mutation? That is a very interesting question. We don't know. We cannot make any kinds of genetic studies until we have differences to observe. The differences always arise by mutation. If there is genetic material that can't mutate, if it's uniform throughout the species, there's nothing we know about it. We can only study the kinds of differences that do arise through mutations, and so we really can't answer that question. Is it possible to build up an immunity to radioactivity? That's also a very interesting question. In the short sense, in the sense of the individual who is exposed once, the answer is rather clearly no. On the contrary, individuals, whether mice or men, who have once been exposed to high energy radiations, are always more sensitive to a similar dose on a subsequent occasion than they were at the beginning. Thus, individuals who have once been exposed to radiation are never quite the same as if they had remained unexposed. On the average, their lives will be shorter, and they will be more susceptible to a variety of diseases, including especially malignancies of various kinds, such as leukemia and various kinds of cancer. But in terms of the species, probably it is possible to build up an immunity of a sort, of a degree to radioactivity. Different species are different in their sensitivity, and it is therefore reasonable to suppose that these differences came about in the course of their evolution from common ancestry. So possibly over a period of hundreds of thousands or millions of years, a species could build up a greater resistance to radioactivity, but meanwhile, the individuals would suffer severely. There are, of course, various methods of trying to produce artificial immunity of various grades to radioactivity by the use of certain kinds of chemical agents. Let's see, may I ask the management, how long will they continue in order that we may meet schedules? It is now 315, are you willing, or able? To what extent does your evaluation of the effects of fallout differ from the position held by Linus Pauling? In principle, I think do you agree with Professor Pauling's evaluation of the data concerning rate of production of defective babies owing to fallout? I have in the past differed with Professor Pauling in the interpretation of the data because I felt that his calculations based on the same raw data were in some respects what one might call marginal. When you're making estimates and there are many uncertainties about the value of each parameter that is being measured, you can either take what you think is a middle point in the range of estimated values or you can state the range or you can calculate a maximum level of take the upper limit of the range. And it has seemed to me that in some of his calculations Professor Pauling was more inclined always to take the upper limit. And so arrive at an estimate that was a kind of maximal figure rather than a most probable figure. Following various discussions in print and out of print, however, I find that following the latest publications of estimates of fallout and genetic damage published by the Federal Radiation Council in 1963, we're not as far apart on these matters as we once were. I think the important thing in this connection and I believe this is an important question is not to look at the particular figures, the actual numbers of defective babies that might be born if such and such a thing were to happen. The geneticists of the National Academy of Sciences Committee to which Professor Cush referred tried to avoid in so far as possible pinning their arguments to any exact figures. Geneticists agree that the great majority of all mutations are damaging. They agree that all radiation will produce mutations, even the smallest amounts. That in general, if you allow for differences in dose rate, the effects are linearly proportional to the dose given. And with those principles in mind, one can go on to say, of course, that the fallout received by the United States population from past weapons tests will produce defective babies in the future. And perhaps it isn't so important to argue about whether it's 300 defective babies or 1200. May the moderator use his prerogative, I think, to make one brief remark. Very good. My impression of the argument, the controversy between Mr. Pauling and Mr. Teller was the following. They were, let me say, I mean, adherents of Pauling's position as a moral man, let me state this, abdiceo, I too. The fact remains that they both used their status as eminent scientists. They used their scientific authority to support a particular political or social thesis about the matter of babies, how many babies, and so forth. Professor Glass did the following this afternoon. He said, something is going to increase, I forget all the numbers, by two-tenths of 1%. This amounts to, say, 12,000 babies. But think of the different emotional impact if something makes, if I tell you, look, a human activity is going to increase something by two-tenths of 1%. Do you move your money from one bank to another for two-tenths of a percent difference? Probably not. It doesn't sound like a big number. But if you are told, if you take the other identical figure, this is 12,000 deaths, my God, this is dreadful. You see, it's the emphasis which is put on figures which were not as far apart as the public was led to believe. Would you move your money from one bank to another if the interest amount is $12,000 a year more? Well, obviously, you're not fools. This is a point. I hope I haven't disagreed with you. Very good, no, you haven't, not at least. I presume you mean by 99.9% or 99% of harmful mutations that they are lethal or reduce reproductive fitness, and that is correct. Have any of the one-tenth to 1% been shown helpful in promoting longevity or fecundity relative to the wild type? Yes, this is what the experiments showed, that perhaps one in a thousand of the mutations that were detected actually improved the viability or the fertility of the possessor in comparison with the standard type, which was the beginning of the experiment. What is the specific effect of radiation upon the gene? Is there a change in the molecular structure of DNA? What is the locale of this change? I suspect that a professor will be talking about those matters in his lecture and I don't want to trespass further than I've already done upon his subject. Let me then answer the question very briefly by saying that the ions which are produced by high energy radiations will lead to chemical reactions, chemical changes in the DNA, either directly or indirectly, at specific points. The points being simply the parts of the molecule that are directly hit that absorb the radiant energy or that are in the near vicinity of a molecule that is hit and which is of such a character that the chemical change can then be transferred to the DNA molecule. There is no particular locale of this change other than that the radiation must strike the DNA molecule or produce a chemical change in the nuclei of the reproductive cells very close to the chromosomes. I think that is all we can manage in a tight schedule. I think we reconvene here at four o'clock, is that correct?