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.

When Charles Darwin began his voyage around the world aboard H.M.S. Beagle, he shared with his contemporaries the almost unquestioned belief that every species of plant and animal then inhabiting the earth had originated in a separate act of creation. No other way had ever been found to explain the exquisite adaptations of structure and behavior by which each form of life seems so perfectly designed for its place in nature. By the end of the live-year journey, an altogether new and startling idea had begun to develop in the mind of the young naturalist. Today, less than a century after the publication of The Origin of Species, the theory of evolution has long been accepted as a fact of life.

The brilliance of Darwin's insight lay in his integration of two simple and seemingly unrelated biological truths, and in his projection of their inevitable consequences on a vast scale of time. One was that the individual members of a species are not all precisely alike, the differences among them tending to be inherited. The other, somewhat less obvious, was that the infinite expansion of populations is checked by limitations in the availability of food, and by other restrictive conditions of life. It follows directly, reasoned Darwin, that any inheritable trait that enhances the survival and fertility of an individual will he "naturally selected" — that is, will be transmitted to a larger fraction of the population in each succeeding generation. In this way, by the gradual accumulation of adaptive variations, the species now existing have evolved from earlier and more primitive progenitors, and owe their intricate mechanisms of adjustment not to purposeful planning but to the impassive operation of natural laws.

In the great upheaval of scientific thought that followed the announcement of the theory of evolution, the phenomena of heredity and variation were suddenly thrust into the forefront of biology. Almost' nothing was known of the way in which hereditary differences arise, and of the mechanisms of their transmission, but Darwin foresaw the development of a "grand and almost untrodden field of inquiry" in which the causes of variation and the laws of heredity would be discovered. Even as Darwin called upon the future to solve the mysteries of inheritance, Gregor Mendel was laying the foundation for the new science of genetics. Genetics has contributed richly to the synthesis of facts and ideas from almost every branch of the natural sciences that has been built upon Darwinism. As the diverse and intricate mechanisms of evolution have come to be understood, it has grown increasingly certain that the raw materials upon which they depend are the mutations of genes.

The hereditary endowment of a plant or animal is now known to be determined by a very special kind of material found primarily in the threadlike chromosomes that may be seen under the microscope in the nucleus of the cell. The invisible elements of which this material is composed, the genes, were once regarded as discrete particles strung along the chromosome like beads. Recent evidence has modified this concept considerably, and many geneticists now think of genes as chemically differentiated regions of the chromosome, not necessarily separated one from another by definite boundaries, but each having a distinctive structural pattern from which it derives a highly specific role in the metabolism of the cell.

Every cell in the body contains a set of chromosomes and genes, descended directly by a long line of cell divisions from the set originally constituted in the egg cell at fertilization. The human embryo develops into a person, rather than into, a tree or an elephant or a monstrosity, because the material carried in its chromosomes, its constellation of genes, initiates and guides a marvelously coordinated sequence of reactions that leads inevitably, under normal conditions, to the differentiation and growth of a human being.

Throughout the life of the individual, the genes, continue to exert their control over the complex chemistry of the cells and tissues of the body. As older tissue is gradually replaced by new tissue in the mature person, the food that is consumed is converted quite specifically into more of the very same individual, even though an identical diet, fed to a dog, would be transformed into more dog. We are a long way from understanding just how genes direct the manifold activities of living systems, but we know with growing certainty that the range of possible responses of any cell or organism to the conditions it may encounter is largely gene-determined.

All the members of our species have in common the basic genetic make-up that sets us apart from other forms of life. Nevertheless, no two individuals, with the exception of identical twins, have exactly the same heredity, which is another way of saying that every person possesses a unique pattern of chromosomal genes. Differences in skin pigmentation, eye and hair color, stature, and facial features are familiar hereditary traits by which individuals and groups of individuals differ from one another. These and the host of other inherited variations, from fingerprint patterns to blood types, are manifestations of the differences that exist in the structure and arrangement of the genic material.

Some hereditary variations, such as eye color, are known to depend upon differences in the state of a single gene. This does not imply that one gene, all by itself, is responsible for the formation of blue or brown pigment in the iris of the eye. It means that a change in this particular gene can alter the integrated functioning of the whole gene system so as to result in the production of a different kind of pigment. Other characteristics, such as height, depend upon the states of a relatively large number of genes.

Genes do not exist in a vacuum. They are always present in an environment that must be taken into account in understanding how they work. The environment within the cell and within the organism, and the more unpredictable environment outside, are intimately bound up with the functioning of genes and have varying degrees of influence upon the ultimate expression of heredity. A trait or characteristic is not, in itself, inherited. That which is determined by genes is the capacity to produce certain traits under certain conditions.

In the case of eye color, this distinction may seem unimportant, since an individual having the genetic constitution for blue eyes will have blue eyes under any environmental conditions.' Its meaning becomes evident, however, when we consider inherited characteristics that are more directly responsive to environmental variables. The Himalayan rabbit is a case in point. This rabbit has a pattern of white fur, with black fur at the extremities (ears, tips of paws, tail), and this pattern is passed along from generation to generation. If a patch of white fur from the back of such a rabbit is shaved off, and the new fur allowed to grow back while the animal is kept in a cool place, it will grow in black instead of white. Thus it is not the pattern itself that is inherited, but the capacity to produce black pigment at low temperatures and not at higher temperatures. Since the temperature at the extremities is normally lower than that of the rest of the body, the typical Himalayan pattern is obtained. Similarly, although stature is basically under the control of genes, it can be influenced significantly by nutritional factors.

Genes are remarkable not only for the way they direct the intricate pathways of metabolism and development. They have in addition, unique properties that give them special importance in biology, as the raw materials not only of evolution but probably of life itself. Genes have the ability to organize material from their surroundings into precise copies of their own molecular configurations, and they exercise this power every time a cell divides.

They are also capable of undergoing structural changes, or mutations; and once such a change has occurred, it is incorporated into the copies that the gene makes of itself. A single unit having these properties, and having also the ability to aggregate with other such units, would possess the essential features of a living being, capable of unlimited evolution through the natural selection of variant forms and combinations most efficient in reproducing themselves. Many biologists believe that life may have originated with the accidental formation of "naked genes," organic molecules able to duplicate their own structure, and their variations in structure, from materials available in the environment.

Although the chemical nature of genes is not yet known with certainty, one of the most important recent advances in genetics is the evidence that their definitive properties can be accounted for by the theoretical structure and behavior of the molecules of compounds known as desoxyribonucleic acids, or DNA. Chromosomes contain large amounts of DNA. Its molecules are very big, as molecules go, built up in long chains from only four kinds of simple chemical building blocks. The order in which these units occur, and the number of repetitions of similar groupings, are thought to be the basis of the specific activity of different regions of the chromosome — in other words, of genes. The study of the properties of these molecules provides a way to explain the mechanism by which genes duplicate themselves and reproduce the variations that they may undergo.

Mutations, as has already been suggested, are considered to be changes, on the molecular level, in the structure or organization of genes. A mutation in any gene is likely to be reflected in a modification of its contribution to the delicately interwoven pattern of control exercised by the whole constellation of genes, and may be detected by its effect on some physical or metabolic characteristic of the organism.

Mutations, in nature, are rather rare events, occurring usually with frequencies of from one in a thousand to one in a billion gene duplications. They have an extremely wide range of effects, from fatal disturbances of normal development to perceptible reductions of life expectancy, from striking changes in appearance to slight alterations of metabolism that can he detected only with sensitive laboratory instruments.

Mutations in man are responsible for the kinds of hereditary differences we have already discussed, and can produce, as well, such effects as early fetal death, stillbirth, diseases such as hemophilia and sickle cell anemia, color blindness and harelip. It seems quite possible that cancer, leukemia, and other malignant diseases may originate by the occurrence of mutations in body cells other than the reproductive cells.

Although the overall frequency of mutations can be increased considerably by exposure to radiations and a variety of chemicals, there is ordinarily no relation between environmental conditions and the kinds of mutations that occur. Mutations of all sorts arise in natural populations, with low but regular frequencies, in a way that is best explained by considering them to be the consequences of accidental molecular rearrangements, occurring more or less at random in the genetic material. X rays and other kinds of high-energy radiations increase the probability that these accidents or mutations will occur, but we do not know with certainty the causes of so-called "spontaneous" mutations. Natural radiations, such as cosmic rays, undoubtedly cause a fraction of them, but it has been estimated that the intensity of natural radiations is not sufficient to account for all the mutations that occur in plant and animal populations.

Darwin believed that the inheritable variations upon which natural selection acts are caused directly by the influence of the conditions of life upon the organism, or by the effects of use and disuse of particular body parts. Although he appreciated the difficulty of explaining how the environment can provoke appropriately adaptive modifications, and how such changes can be incorporated into the reproductive cells so as to be inherited, it seemed at that time even more difficult to imagine that they could arise by chance. How, then, does modern genetics propose that the orderliness of evolution can follow from accidental variations in the molecular structure of genes, occurring without relation to the demands of the environment?

We do not need to rely upon speculation to answer this question. The study of evolution has moved into the laboratory, and while it is not possible to duplicate here the kinds of changes that have required millions of years in nature, the elementary steps of evolution can be analyzed. For this purpose, the use of bacteria presents many advantages. This is particularly true since the mechanisms of heredity and variation, wherever studied in the plant and animal kingdoms, seem to be fundamentally alike. Genes and mutations are much the same, in their basic behavior, whether they are investigated in fruit flies, in maize plants, in man, or in microorganisms.

The bacterium Escherichia coli, a rod-shaped, one-celled organism normally found in the human intestinal tract, is widely used in research on heredity. It divides every twenty minutes under optimal conditions, and a single cell, placed in one cubic centimeter of culture medium, will produce overnight as many descendants as the human population of the earth. The recent discovery of a sexual process in this organism, as well as in some other kinds of bacteria, has made it possible to interbreed different strains and to apply many of the classical methods of genetic analysis that were developed in the study of higher forms. Escherichia coli is an ideal vehicle for the experimental study of "microevolution."

In the laboratory, a strain of this bacterium can be maintained almost indefinitely, under constant conditions, without undergoing any appreciable change in its characteristics. When the environment under which the bacteria are grown is changed, however, in a way that is somehow detrimental to the population, it will often adapt itself rapidly and effectively to the new conditions.

A good example of the way in which a bacterial culture may adapt to an unfavorable environment is the reaction of Escherichia coli to streptomycin. Most strains of this bacterium are sensitive to streptomycin, and are unable to multiply in the presence of even very small amounts of the antibiotic. Sensitivity to streptomycin is an inherited trait and is transmitted, unchanged, through countless generations. If a high concentration of streptomycin is added to the culture tube in which a sensitive strain is growing, the outcome depends upon the size of the population at the time. If the number of bacteria in the tube when the antibiotic is added is relatively small (a hundred or a thousand), multiplication will stop at once, and no further growth will take place in the tube, no matter how long it is incubated. If the population is large (a hundred million bacteria or more), the addition of streptomycin will arrest multiplication sharply, but incubation of the tube for a few days will almost always result in the ultimate appearance of a fully grown culture containing tens of billions of bacteria. When the bacteria in this culture are tested, they prove to be completely resistant to streptomycin, and are able to multiply vigorously in its presence. Further, we find that resistance to streptomycin is a stable, hereditary characteristic, transmitted indefinitely to the descendants of these bacteria.

Thus, by exposing a large population of streptomycin-sensitive bacteria to a high concentration of the antibiotic, the emergence of a genetically resistant strain can be brought about. This, indeed, is a strikingly adaptive change, and at first sight it may seem to substantiate the old idea that the environment can cause useful modifications that are then inherited. The careful study of the events leading to the appearance of a streptomycin-resistant strain proves without doubt that this is not so.

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