Molecular Biology: Nucleic Acid. The Importance of DNA

Once viruses were crystallized, it became possible to analyze them chemically. They were protein, of course, but a particular variety of protein; a variety called "nucleoprotein." The advance of staining methods made it possible also to work out the chemical nature of individual subcellular structures, and it turned out that the chromosomes, too (and therefore the genes), were nucleoprotein.

A nucleoprotein molecule consists of protein in association with a phosphorus-containing substance known as "nucleic acid." The nucleic acids were first discovered in 1869 by a Swiss biochemist, Friedrich Miescher (1844-1895). They were so named because they were first detected in cell nuclei. Later, when they were found to exist outside the cell nucleus, too, it was too late to change the name.

The nucleic acids were first studied in detail by a German biochemist, Albrecht Kossel (1853-1927), who, in the 1880s and thereafter, broke nucleic acids down into smaller building blocks. These included phosphoric acid and a sugar he could not identify. In addition, there were two compounds of a class called "purines" with molecules made up of two rings of atoms, including four nitrogens. These Kossel named "adenine" and "guanine" (and they are sometimes referred to simply as A and G). He found also three "pyrimidines" (compounds with a single ring of atoms, including two nitrogens), which he named "cytosine," "thymine," and "uracil" (C, T, and U).

A Russian-American chemist, Phoebus Aaron Theodor Levene (1869-1940), carried matters further in the 1920s and 1930s. He showed that in the nucleic acid molecule, a phosphoric acid molecule, a sugar molecule, and one of the purines or pyrimidines formed a three-part unit which he called a "nucleotide." The nucleic acid molecule is built up of chains of these nucleotides, as proteins are built up of chains of amino acids. The nucleotide chain is built up by connecting the phosphoric acid of one nucleotide to the sugar group of the neighboring nucleotide. In this way a "sugar-phosphate backbone" is built up, a backbone from which individual groupings of purines and pyrimidines extend.

Levene further showed that the sugar molecules found in nucleic acids were of two types: "ribose" (containing only five carbon atoms instead of the six carbon atoms in the better-known sugars) and "deoxyribose" (just like ribose except that its molecule possessed one fewer oxygen atom). Each nucleic acid molecule contained one type of sugar or the other, but not both. Thus, two types of nucleic acid could be distinguished: "ribosenucleic acid," usually abbreviated RNA; and "deoxyribosenucleic acid," usually abbreviated DNA. Each contained purines and pyrimidines of only four different varieties. DNA lacked uracil and possessed only A, G, C, and T. On the other hand, RNA lacked thymine, and possessed A, G, C, and U.

The Scottish chemist, Alexander Robertus Todd (1907- ), confirmed Levene's deduction in the 1940s by actually synthesizing various nucleotides. Biochemists did not at first attach special importance to nucleic acids. Protein molecules were, after all, found in association with a variety of nonprotein adjuncts, including sugars, fats, metal-containing groups, vitamin-containing groups, and so on. In every case, it was the protein that was considered the essential portion of the molecule with the nonprotein section quite subordinate. Nucleoproteins might be found in chromosomes and in viruses, but it was taken for granted that the nucleic acid portion was subsidiary and that the protein was the thing itself.

Kossel, in the 1890s, made some observations, however, which, by hindsight, we can see to be most significant. Sperm cells consist almost entirely of tightly packed chromosomes and carry the chemical substances that include the complete "instructions" by which the father's share of inherited characteristics are passed on to the young. Yet Kossel found sperm cells to contain very simple proteins, much simpler ones than those found in tissues, whereas the nucleic acid content seemed to be the same in nature as those in tissues. This might make it seem more likely that the inheritance instructions were included in the sperm's unchanged nucleic acid molecules rather than in its grossly simplified protein.

Biochemists remained unmoved, nevertheless. Not only was faith in the protein molecule unshakable but, through the 1930s, all evidence seemed to point to the fact that nucleic acids were quite small molecules (made up of only four nucleotides each) and therefore far too simple to carry genetic instructions.

The turning point came in 1944 when a group of men headed by the American bacteriologist, Oswald Theodore Avery (1877-1955), were working with strains of pneumococci (pneumonia-causing bacteria). Some were "smooth" strains (S), possessing an outer capsule about the cell; while others were "rough" strains (R), lacking such a capsule.

Apparently the R strain lacked the ability to synthesize the capsule. An extract from the S strain added to the R strain converted the latter into the S strain. The extract could not itself bring about the formation of the capsule but, apparently, it produced changes in the R strain that made the bacteria themselves capable of the task. The extract carried the genetic information necessary to change the physical characteristics of the bacteria. The totally startling part of the experiment came with the analysis of the extract. It was a solution of nucleic acid and nucleic acid alone. No protein of any kind was present.

In this one case at least, nucleic acid was the genetic substance, and not protein. From that moment on it had to be recognized that it was nucleic acid after all that was the prime and key substance of life. Since 1944 also saw the introduction of the technique of paper chromatography, it might fairly be termed the greatest biological year since 1859 when The Origin of Species was published.

In the years since 1944, the new view of nucleic acid has been amply con6rmed, most spectacularly perhaps through work on viruses. Viruses were shown to have an outer shell of protein, with a nucleic acid molecule in the inner hollow. The German-American biochemist, Heinz Fraenkel-Conrat (1910- ), was able, in 1955, to tease the two parts of the virus apart and put them together again. The protein portion by itself showed no infectivity at all; it was dead. The nucleic acid portion by itself showed a bit of infectivity; it was "alive," though it needed the protein portion to express itself most efficiently.

Work with radioactive isotopes showed clearly that when a bacteriophage, for instance, invaded a bacterial cell, only the nucleic acid portion entered the cell. The protein portion remained outside. Inside the cell, the nucleic acid not only brought about the manufacture of more nucleic acid molecules like itself (and not like those native to the bacterial cell), but also protein molecules to form its own shell, its own characteristic protein, and not that of the bacterial cell. Certainly there could no longer be any doubt that the nucleic acid molecule, and not protein, carried genetic information.

Virus molecules contained either DNA or RNA or both. Within the cell, however, DNA was found in the genes exclusively. Since the genes were the units of heredity, the importance of the nucleic acid resolved itself into the importance of DNA.