Molecular Biology: Nucleic Acid. Viruses and Genes

But even as the protein molecule came under control, it was suddenly, and quite surprisingly, replaced by another type of substance as the prime "chemical of life." The importance of this new substance made itself felt, first of all, through a line of research brought into play by the question of the nature of the filtrable virus.

The nature of the virus remained a puzzle for a generation. It was known to cause disease and methods were developed to counter it in this respect, but the thing itself, rather than merely its effects, remained unknown.

Eventually, filters were developed that were fine enough to hold back the virus and from that it could be estimated that the virus particles, whatever they were, while very much smaller than even the smallest known cells, were still larger than even very large protein molecules. They proved thus to be structures that were intermediate between cells and molecules.

It was the electron microscope that finally revealed them as objects that could be sensed. They proved to cover a large range of sizes, from tiny dots not very much bigger than a large protein molecule, to sizable structures with regular geometrical shapes and with an apparent internal organization. The bacteriophages were among the largest viruses for all that they preyed on such small organisms, and some of them were tailed, like tiny tadpoles. Above the virus range and yet Still smaller than even the smallest ordinary bacteria were the "rickettsia" (named for Ricketts because microorganisms of this type caused Rocky Mountain fever, the disease that bacteriologist had investigated.)

The question was thus raised as to whether this group of organisms, which seemed to fill the range between the smallest cells and the largest molecules, were alive or not. A startling development that seemed to militate against the hypothesis that they were alive came in 1935. The American biochemist, Wendell Meredith Stanley (1904- ), then working with extracts of tobacco mosaic virus, was able to obtain fine needlelike crystals. These, when isolated, proved to possess all the infective properties of virus, and in high concentration. In other words, he had crystalline virus and a living crystal was a concept that was quite difficult to accept.

On the other hand, might it not be conjectured that the cell theory was inadequate and that intact cells were not after all the indivisible units of life. The virus was much smaller than a cell and, unlike cells, did not possess the capacity for independent life under any circumstances. Yet it managed to get inside cells and once there it reproduced itself and behaved in certain key respects as though it were alive.

Might there not be, then, some structure within the cell, some subcellular component that was the true essence of life; one that controlled the rest of the cell as its tool? Might a virus not be that cellular component broken loose, somehow, waiting only to invade a cell and take it over from its rightful "owners"?

If this were so, then such subcellular components ought to be located in normal cells, and the logical candidates for the honor seemed to be the chromosomes. In the first years of the twentieth century, it became plain that the chromosomes carried the factors governing the inheritance of physical characteristics and so they controlled the rest of the cell as the key subcellular component would be expected to do. The chromosome, however, was far larger than the virus.

But there were far fewer chromosomes than there were inheritable characteristics, so that it could only be concluded that each chromosome was made up of many units, perhaps thousands, each of which controlled a single characteristic. These individual units were named "genes" in 1909 by the Danish botanist, Wilhelm Ludwig Johannsen (1857-1927), from a Greek word meaning "to give birth to."

In the first decades of the twentieth century, the individual gene, like the individual virus, could not be seen, and yet it could be worked with fruitfully. The key to such work came when the American geneticist, Thomas Hunt Morgan (1866-1945), introduced a new biological tool in 1907, a tiny fruit fly, Drosophila melanogaster. This was a small insect, capable of being bred in large numbers and with virtually no trouble. Its cells, moreover, possessed but four pairs of chromosomes.

By following fruit-fly generations, Morgan discovered numerous cases of mutations, thus extending to the animal kingdom what De Vries had discovered among plants. He was further able to show that various characteristics were linked; that is, inherited together. This meant that the genes governing such characteristics were to be found on the same chromosome, and this chromosome was inherited, of course, as a unit.

But linked characteristics were not eternally linked. Every once in a while, one was inherited without the other. This came about because pairs of chromosomes occasionally switched portions ("crossing over"), so that the integrity of an individual chromosome was not absolute.

Such experiments even made it possible to locate the spot on the chromosome at which a particular gene might exist. The greater the length of chromosome separating two genes, the greater the likelihood that crossing over at a random spot would separate the two. By studying the frequency with which two particular linked characteristics were unlinked, the relative positions of the genes could be established. By 1911, the first "chromosome maps" for fruit flies were being drawn up.

One of Morgan's students, the American geneticist, Hermann Joseph Muller (1890- ), sought a method for increasing the frequency of mutations. In 1919, he found that raising the temperature accomplished this. Furthermore, this was not the result of a general "stirring up" of the genes. It always turned out that one gene was affected, while its duplicate on the other chromosome of the pair was not. Muller decided that changes on the molecular level were involved.

He therefore tried X rays next. They were more energetic than gentle heat, and an individual X ray striking a chromosome would certainly exert its effect on a point. By 1926, Muller was able to show quite clearly that X rays did indeed greatly increase the mutation rate. The American botanist, Albert Francis Blakeslee (1874- ), went on to show, in 1937, that the mutation rate could also be raised by exposure to specific chemicals ("mutagens"). The best example of such a mutagen was "colchicine," an alkaloid obtained from the autumn crocus.

Thus, by the mid-1930s, both viruses and genes were losing their quality of mystery. Both were molecules of approximately the same size and, as it quickly turned out, of approximately the same chemical nature. Could the genes be the cell's tame viruses? Could a virus be a "wild gene"?