by Isaac Asimov
Generally, in complex animals, however, no form of cloning takes place naturally, and reproduction is exclusively sexual. Yet human interference can bring about the cloning of vertebrates.
After all, a fertilized egg is capable of producing a complete organism; and as that egg divides and redivides, each new cell contains a complete set of chromosomes just like the original set. Why should not each new cell possess the capacity of producing a new individual if isolated and kept under conditions that allow the fertilized egg to develop?
Presumably, as the fertilized egg divides and redivides, the new cells differentiate, becoming liver cells, skin cells, nerve cells, muscle cells, kidney cells, and so on, and so on. Each has very different functions from any other; and, presumably, the chromosomes undergo subtle changes that make this differentiation possible. It is these subtle changes that make the differentiated cells incapable of starting from scratch and forming a new individual.
But are the chromosomes permanently and irreversibly changed? What if such chromosomes are restored to their original surroundings? Suppose, for instance, that one obtains an unfertilized egg cell of a particular species of animal and carefully removes its nucleus. One then obtains the nucleus of a skin cell from a developed individual of that species and inserts it into the egg cell. Under the influence of the egg cell, designed to promote the growth of a developed individual, might not the chromosomes within the skin-cell nucleus experience a “fountain of youth” effect which will restore them to their original function? Will the egg, fertilized in this fashion, develop to produce a new individual with the same chromosome set as the individual whose skin cell has been used for the purpose? Will not the new individual so obtained be a clone of the skin-cell donor?
This removal and substitution of nuclei within a cell is, of course, an excessively delicate operation, but it was successfully carried through in 1952 by the American biologists Robert William Briggs and Thomas J. King. Their work marked the beginning of the technique of nuclear transplantation.
In 1967, the British biologist John B. Gurdon successfully transplanted a nucleus from a cell from the intestine of a South African clawed frog to an unfertilized ovum of the same species and from that ovum developed a perfectly normal new individual—a clone of the first.
It would be enormously difficult to repeat this procedure in reptiles and birds whose egg cells are encased in hard shells—that is, to keep those egg cells alive and functioning after the shell is in some way broken for nuclear penetration.
What about mammalian egg cells? These are bare but are kept within the mother’s body; they are particularly small and fragile, and microsurgical techniques must be further refined.
And yet nuclear transplantation has been successfully carried through in mice; and, in principle, cloning should be possible in any mammal, including the human being.
Genes
MENDELIAN THEORY
In the 1860s, an Austrian monk named Gregor Johann Mendel, who was too occupied with the affairs of his monastery to pay attention to the biologist’s excitement about cell division, was quietly carrying through some experiments in his garden that were destined eventually to make sense out of chromosomes. Abbé Mendel, an amateur botanist, became particularly interested in the results of cross-breeding pea plants of varying characteristics. His great stroke of intuition was to study one clearly defined characteristic at a time.
He would cross plants with different seed colors (green or yellow), or smooth-seeded peas with wrinkle-seeded ones, or long-stemmed plants with short-stemmed ones, and then would follow the results in the offspring of the succeeding generations. Mendel kept a careful statistical record of his results, and his conclusions can be summarized essentially as follows:
1. Each characteristic is governed by factors that (in the cases that Mendel studied) can exist in one of two forms. One version of the factor for seed color, for instance, will cause the seeds to be green; the other form will make them yellow. (For convenience, let us use the present-day terms. The factors are now called genes, a term put forward in 1909 by the Danish biologist Wilhelm Ludwig Johannsen from a Greek word meaning “to give birth to”; and the different forms of a gene controlling a given characteristic are called alleles. Thus, the seed-color gene possesses two alleles, one for green seeds, the other for yellow seeds.)
2. Every plant has a pair of genes for each characteristic, one contributed by each parent. The plant transmits one of its pair to a germ cell (a general term used to include both egg cells and sperm cells), so that when the germ cells of two plants unite by pollination, the offspring has two genes for the characteristic once more. The two genes may be either identical or alleles.
3. When the two parent plants contribute alleles of a particular gene to the offspring, one allele may overwhelm the effect of the other. For instance, if a plant producing yellow seeds is crossed with one producing green seeds, all the members of the next generation will produce yellow seeds. The yellow allele of the seed-color gene is dominant, the green allele, recessive.
4. Nevertheless, the recessive allele is not destroyed. The green allele, in the case just cited, is still present, even though it produces no detectable effect. If two plants containing mixed genes (that is, each with one yellow and one green allele) are crossed, some of the offspring may have two green alleles in the fertilized ovum; in that case, those particular offspring will produce green seeds, and the offspring of such parents in turn will also produce green seeds. Mendel pointed out four possible ways of combining alleles from a pair of hybrid parents, each possessing one yellow and one green allele. A yellow allele from the first parent may combine with a yellow allele from the second; a yellow allele from the first may combine with a green allele from the second; a green allele from the first may combine with a yellow allele from the second; and a green allele from the first may combine with a green allele from the second. Of the four combinations, only the last will result in a plant that would produce green seeds. If all four combinations are equally probable, one-fourth of the plants of the new generation should produce green seeds—as Mendel indeed found to be so.
5. Mendel also found that characteristics of different kinds-for instance, seed color and flower color—to be inherited independently of each other: that is, red flowers are as likely to go with yellow seeds as with green seeds. The same is true of white flowers.
Mendel performed these experiments in the early 1860s, wrote them up carefully, and sent a copy of his paper to Karl Wilhelm von Nägeli, a Swiss botanist of great reputation. Von Nägeli’s reaction was negative. Von Nägeli had, apparently, a predilection for all-encompassing theories (his own theoretical work was semimystical and turgid in expression), and he saw little merit in the mere counting of pea plants as a way to truth. Besides, Mendel was an unknown amateur.
It seems that Mendel allowed himself to be discouraged by von Nägeli’s comments, for he turned to his monastery duties, grew fat (too fat to bend over in the garden), and abandoned his researches. He did, however, publish his paper in 1866 in a provincial Austrian journal, where it attracted no further attention for a generation.
But other scientists were slowly moving toward the same conclusions to which (unknown to them) Mendel had already come. One of the routes by which they arrived at an interest in genetics was the study of mutations—that is, of freak animals, or monsters, which had always been regarded as bad omens. (The word monster came from a Latin word meaning “warning.”) In 1791, a Massachusetts farmer named Seth Wright took a more practical view of a sport that turned up in his flock of sheep. A lamb was born with abnormally short legs, and it occurred to the shrewd Yankee that short-legged sheep could not escape over the low stone walls around his farm. He therefore deliberately bred a line of short-legged sheep from his not unfortunate accident.
This practical demonstration stimulated other people to look for useful mutations. By the end of the nineteenth century, the American horticulturist Luther Burbank was making a s
uccessful career of breeding hundreds of new varieties of plants which were improvements over the old in one respect or another, not only by mutations, but by judicious crossing and grafting.
Meanwhile botanists tried to find an explanation of mutation. And in what is perhaps the most startling coincidence in the history of science, no fewer than three men, independently and in the very same year, came to precisely the same conclusions that Mendel had reached a generation earlier. They were Hugo De Vries of Holland, Karl Erich Correns of Germany, and Erich von Tschermak of Austria. None of them knew of each other’s or Mendel’s work. All three were ready to publish in 1900. All three, in a final check of previous publications in the field, came across Mendel’s paper, to their own vast surprise. Ail three did publish in 1900, each citing Mendel’s paper, giving Mendel full credit for the discovery, and advancing his own work only as confirmation.
GENETIC INHERITANCE
A number of biologists immediately saw a connection between Mendel’s genes and the chromosomes seen under the microscope. The first to draw a parallel was an American cytologist named Walter Stan borough Sutton, in 1904. He pointed out that chromosomes, like genes, come in pairs, one of which is inherited from the father and one from the mother. The only trouble with this analogy was that the number of chromosomes in the cells of any organism is far smaller than the number of inherited characteristics. Man, for instance, has only twenty-three pairs of chromosomes and yet certainly possesses thousands of inheritable characteristics. Biologists therefore had to conclude that chromosomes are not genes. Each chromosome must be a collection of genes.
In short order, biologists discovered an excellent tool for studying specific genes. It was not a physical instrument but a new kind of laboratory animal. In 1906, the Columbia University zoologist Thomas Hunt Morgan, who was at first skeptical of Mendel’s theories, conceived the idea of using fruit flies (Drosophila melanogaster) for research in genetics. (The term genetics was coined in 1902 by the British biologist William Bateson.)
Fruit flies had considerable advantages over pea plants (or any ordinary laboratory animal) for studying the inheritance of genes. They bred quickly and prolifically, could easily be raised by the hundreds on little food, had scores of inheritable characteristics that could be observed readily, and had a comparatively simple chromosomal setup—only four pairs of chromosomes per cell.
With the fruit fly, Morgan and his co-workers discovered an important fact about the mechanism of inheritance of sex. They found that the female fruit fly has four perfectly matched pairs of chromosomes so that all the egg cells, receiving one of each pair, are identical so far as chromosome makeup is concerned. However, in the male fruit fly, one of each of the four pairs consists of a normal chromosome, called the X chromosome, and a stunted one, the Y chromosome. Therefore, when sperm cells are formed, half have an X chromosome and half a Y chromosome. When a sperm cell with the X chromosome fertilizes an egg cell, the fertilized egg, with four matched pairs, naturally becomes a female. On the other hand, a sperm cell with a Y chromosome produces a male. Since both alternatives are equally probable, the number of males and females in the typical species of living things is roughly equal (figure 13.4). (In some creatures, notably various birds, it is the female that has a Y chromosome.)
Figure 13.4. Combinations of X and Y chromosomes.
This chromosomal difference explains why some disorders or mutations show up only in the male. If a defective gene occurs on one of a pair of X chromosomes, the other member of the pair is still likely to be normal and can salvage the situation. But in the male, a defect on the X chromosome paired with the Y chromosome generally cannot be compensated for, because the latter carries very few genes. Therefore the defect shows up.
The most notorious example of such a sex-linked disease is hemophilia, a condition in which blood clots only with difficulty, if at all. Individuals with hemophilia run the constant risk of bleeding to death from slight causes or of suffering agonies from internal bleeding. A woman who carries a gene that will produce hemophilia on one of her X chromosomes is very likely to have a normal gene at the same position in the other X chromosome. She will therefore not show the disease. She will, however, be a carrier. Of the egg cells she forms, half will have the normal X chromosome and half the hemophiliac X chromosome. If the egg with the abnormal X chromosome is fertilized by sperm with an X chromosome from a normal male, the resulting child will be a girl who will not be hemophiliac but who will again be a carrier; if it is fertilized by sperm with a Y chromosome from a normal male, the hemophiliac gene in the ovum will not be counteracted by anything in the Y chromosome, and the result is a boy with hemophilia. By the laws of chance, half the sons of hemophilia carriers will be hemophiliacs; half the daughters will be, in their turn, carriers.
The most eminent hemophilia carrier in history was Queen Victoria of England. Only one of her four sons (the oldest, Leopold) was hemophiliac. Edward VII—from whom later British monarchs descended—escaped, so there is no hemophilia now in the British royal family. However, two of Victoria’s daughters were carriers. One had a daughter (also a carrier) who married Czar Nicholas II of Russia. As a result, their only son was a hemophiliac; this circumstance helped alter the history of Russia and the world, for it was through his influence on the hemophiliac that the monk Gregory Rasputin gained power in Russia and helped bring on the discontent that eventually led to revolution. The other daughter of Victoria had a daughter (also a carrier) who married into the royal house of Spain, producing hemophilia there. Because of its presence among the Spanish Bourbons and the Russian Romanoffs, hemophilia was sometimes called the royal disease, but it has no particular connection with royalty, except for Victoria’s misfortune.
A lesser sex-linked disorder is color-blindness, which is far more common among men than among women. Actually, the absence of one X chromosome may produce sufficient weakness among men generally as to help account for the fact that, where women are protected against death from childbirth infections, they tend to live some three to seven years longer, on the average; then men. That twenty-third complete pair makes women the sounder biological organism, in a way. (Recently, it has been suggested that the male’s shorter life span is due to smoking, and that women, now smoking more as men smoke less, are catching up in death rate.)
The X and Y chromosomes (or sex chromosomes) are arbitrarily placed at the end of the karyotype, even though the X chromosome is among the longest. Apparently chromosome abnormalities are more common among the sex chromosomes than among the others. The reason may be not that the sex chromosomes are most likely to be involved in abnormal mitoses, but perhaps that sex-chromosome abnormalities are less likely to be fatal, so that more young manage to be born with them.
The type of sex-chromosome abnormality that has drawn the most attention is one in which a male ends up with an extra Y chromosome in his cells, so that he is XYY, so to speak. It turns out that XYY males are difficult to handle. They are tall, strong, and bright but are characterized by a tendency to rage and violence. Richard Speck, who killed eight nurses in Chicago in 1966, is supposed to have been an XYY. A murderer was acquitted in Australia in October 1968 on the grounds that he was an XYY and therefore not responsible for his action. Nearly 4 percent of the male inmates in a certain Scottish prison have turned out to be XYY, and there are some estimates that XYY combinations may occur in as many as 1 man in every 3,000.
There seems to be some reason for considering it desirable to run a chromosome check on everyone and certainly on every newborn child. As is the case of other procedures, simple in theory but tedious in practice, attempts are being made to computerize such a process..
CROSSING OVER
Research on fruit flies showed that traits are not necessarily inherited independently, as Mendel had thought. It happened that the seven characteristics of pea plants that he had studied were governed by genes on separate chromosomes. Morgan found that where two genes governing two different characteri
stics are located on the same chromosome, those characteristics are generally inherited together (just as a passenger in the front seat of a car and one in the back seat travel together).
This genetic linkage is not, however, unchangeable. Just as a passenger can change cars, so a piece of one chromosome occasionally switches to another, swapping places with a piece from it. Such crossing over may occur during the division of a cell (figure 13.5). As a result, linked traits are separated and reshuffled in a new linkage. For instance, there is a variety of fruit fly with scarlet eyes and curly wings. When it is mated with a white-eyed, miniature-winged fruit fly, the offspring will generally be either red-eyed and curly-winged or white-eyed and miniature-winged. But the mating may sometimes produce a white-eyed, curly-winged fly or a red-eyed, miniature-winged one as a result of crossing over. The new form will persist in succeeding generations unless another crossing over takes place.
Figure 13.5. Crossing over in chromosomes.
Now picture a chromosome with a gene for red eyes at one end and a gene for curly wings at the other end. Let us say that, in the middle of the chromosome’s length, there are two adjacent genes governing two other characteristics. Obviously, the probability of a break occurring at that particular point, separating these two genes, is smaller than the probability of a break coming at one of the many points along the length of the chromosome that would separate the genes at the opposite ends. By noting the frequency of separation of given pairs of linked characteristics by crossing over, Morgan and his co-workers, notably Alfred Henry Sturtevant, were able to deduce the relative locations of the genes in question and, in this way, worked out chromosome maps of gene locations for the fruit fly. The location, so determined, is the locus of a gene.
