Mutations and Evolution

Darwin's theory of natural selection, which was published practically simultaneously with the establisment of the ATLANTIC, opened new worlds to science. Dr. Evelyn Witkin, a brilliant young biologist at State University of New York College of Medicine in New York City, tells how genetics, a branch of science not yet born in Darwin's day, has carried forward our understanding of evolution.

It can be readily demonstrated, first of all, that the adaptation to streptomycin does not come about by the mass conversion of the entire sensitive population, but rather is the result of the selective overgrowth of the culture by a few individuals that are able to multiply in its presence, while the division of the rest of the population is inhibited. It is for this reason that adaptation occurs only when the exposed population is large enough to contain at least one such individual. The critical question is this: how did these rare individuals acquire the properties that enabled them and their descendants to multiply in the presence of streptomycin?

This question has deep roots in biological controversy. It recalls, in a new form, the arguments over Lamarck's idea that modifications of the individual caused by environment can be inherited by descendants. Although Lamarckism has long since been disproved to the satisfaction of most biologists by repeated demonstrations that such inheritance just doesn't happen, the idea has persisted in bacteriology until very recently that microorganisms are somehow quite different from other plants and animals, and that permanent hereditary changes of an adaptive kind can be produced in bacteria directly as a result of the action of the conditions of life.

Two alternative hypotheses can be considered in planning experiments to determine the true origin of streptomycin-resistant variants. The first is that a small number of initially sensitive bacteria were modified as a direct result of the action of streptomycin, thereby acquiring permanent resistance. This would be an example of an adaptive hereditary change caused by the environment, as Darwin envisaged the origin of most hereditary variations. The second possibility is that the resistant individuals had already acquired the properties necessary for resistance before coming into contact with streptomycin, as a result of a mutation during the normal division of the sensitive population. In this case, the role of the antibiotic would be entirely passive, providing conditions that favor selectively the multiplication of those rare individuals present in the population that are already equipped, by virtue of the previous occurrence of a chance rearrangement of a particular gene, to withstand its inhibitory action.

During the past fifteen years, a great many experiments have been designed and conducted in a number of laboratories for the purpose of determining which of these hypotheses is correct. They have established beyond doubt that the second one is right, and that streptomycin-resistant variants originate by mutation, at a very low rate, during the growth of sensitive strains that have never been exposed to streptomycin. The proof depends upon the demonstration that the very first generation of resistant individuals in a culture, to which streptomycin has just been added already consists of related family groups, or clones, in just the way that would be predicted if their resistance were the consequence of a hereditary change that had taken place some generations back.

The development of resistance to streptomycin illustrates the way in which mutations provide the basis for adaptive changes in bacterial populations. Actually, any culture of Escherichia coli, apparently quite homogeneous when hundreds or even thousands of bacteria are compared, contains within it rare variants that differ from the predominant type in one or more of countless ways. When a suitable selective environment is provided, it can be shown that a culture contains mutants resistant to many antibiotics, to the action of radiation, to all sorts of chemicals that inhibit particular steps in metabolism — mutants that differ from the standard type in the sugars they can ferment, in their rate of growth, in the complexity of their nutritional requirements, in their antigenic properties, and in almost any characteristic for which a method of detection can be found.

In every case that has been carefully studied, these differences are found to originate without any contact with the conditions under which they happen to be advantageous, and their rates of occurrence are ordinarily not increased by such contact. This is true not only in bacterial cultures, where mutations can be demonstrated rapidly and dramatically. Natural populations of other plants and animals, including man, are known to contain mutations of many kinds that occur with no apparent causal relation to the conditions of growth.

Thus, in a way that Darwin could not have surmised, chance, through mutation, plays a most important part in evolution. It would be difficult indeed to imagine how a species could long survive, or progress in evolution, if it were dependent for its flexibility upon variations directly caused by the conditions of life. Quite aside from the fact that modifications produced in this way are not inherited, except in very special cases, it would require the intervention of some purposive and prescient agent to guarantee that previously unencountered conditions could typically provoke in the organism just those responses that are required to enhance adjustment.

Of course, the occurrence of a diversity of mutations in populations of bacteria and other organisms does not necessarily equip them to meet successfully every environmental challenge. Some strains of bacteria, for instance; are unable to adapt to streptomycin, since their spectrum of mutations does not include the particular modification of metabolism that is required for streptomycin resistance. Furthermore, since there are limits to the range of conditions that can support life, any sufficiently drastic changes, such as those that would take place in the center of a hydrogen bomb explosion, are not likely to prove conducive to the survival of any living thing.

Even within the range of more tolerable conditions, the suddenness of change is sometimes more decisive than its magnitude. For example, the bacterium Escherichia coli can be made resistant to streptomycin, penicillin, and chloromycetin, if the mutants resistant to each of these antibiotics are selected sequentially, but such a triply resistant strain cannot be obtained if the sensitive strain is exposed simultaneously to all three agents. This is explained by the negligible probability that any one individual in a finite population will have undergone mutation in three particular genes, each of which mutates very infrequently and independently of the others.

Observations of this kind, incidentally, although originally made in laboratories of genetics,, have found important applications in medical practice. Many people who have used antibiotics to combat infection have had the experience of dramatic relief of symptoms, only to be followed within a few days by a recurrence, this time failing to respond to the same antibiotic. Sometimes this can be explained by selection of a variant, present in the infecting population of bacteria, that is resistant to the antibiotic and that has its chance to multiply once the sensitive population is eliminated by the first round of treatment. In some cases, a physician will recommend the use of a combination of two or more unrelated antibiotics simultaneously, knowing that mutants resistant to more than one such drug are much less likely to be present. While the use of combinations of antibiotics is not always feasible for medical reasons, under certain conditions it has effectively prevented the occurrence of relapses caused by selection of resistant variants.

There is, of course, much more involved in the complicated saga of evolution than the simple picture of mutation and selection that accounts for bacterial adaptation to streptomycin. Nevertheless, the continuity of life from its first stirrings, and its steady progress toward higher levels of organization, has depended, and continues to depend, upon the reservoir of adaptive responsiveness that is provided initially by the mutations of genes.

Why, it may be asked, if mutations are the source of evolutionary progress, do we hear so much about the genetic dangers of radioactive fall-out, overexposure of the reproductive organs to clinical radiations, and the heightened radiation levels of the atomic age? We know that radiations increase considerably the frequency with which mutations of all sorts occur. Mutations, in themselves, are neither good nor bad. Streptomycin resistance is good for Escherichia coli in the presence of streptomycin, but when the antibiotic is removed, many of the resistant mutants are unable to grow, some of them actually requiring streptomycin for growth. Similarly, radiation-resistant mutants are at a distinct advantage in the presence of ultraviolet light or X rays, yet, in competition with the sensitive form when no radiation is present, they die out rapidly. At any stage in the history of a species, under natural conditions, the mutations that are occurring have undoubtedly occurred before, and most of those that are advantageous under the conditions then prevailing have already been established as part of the predominant gene complex. Thus most mutations are bound to be harmful in some way; the most frequently occurring mutations in the fruit fly are known to be those having lethal effects. Increased mutation rates as a result of exposure to unnatural amounts of radiation, therefore, are likely to be injurious, not only to the individual progeny of particular people, but to the vigor of mankind.

While the genetic hazards of radiation are of most immediate concern, there are more positive implications of the new knowledge of genetics and evolution for the future of humanity. The degree of control that has been achieved over environmental forces, and over the constitutional infirmities that would otherwise reduce the chances of survival and procreation of a significant segment of mankind, has already weakened the hitherto unchallenged power of natural selection. If man should one day choose to put to use the far greater power of his conscious and purposeful intervention, his biological future will be shaped by. his own hands. There are still undreamed-of possibilities in the multipotent clay that is his to mold.

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