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Science and Scientists The Genetic Code The Science After years of work by many molecular biologists, Marshall W. Nirenberg succeeded in unraveling the mystery of the genetic code. The Scientists Marshall W. Nirenberg (b. 1927), an American biochemist and cowinner of the 1968 Nobel Prize in Physiology or Medicine J. H. Matthaei, a German postdoctoral fellow Francis Crick (b. 1916), an English biologist and cowinner of the 1962 Nobel Prize in Physiology or Medicine George Gamow (1904-1968), a Russian theoretical physicist and cosmologist The Structure of Proteins It had been confirmed by 1944 and accepted by 1952 that nucleic acids somehow carried the blueprint of proteins, but it took James D. Watson and Francis Crick's discovery of the molecular structure of deoxyribonucleic acid (DNA) to suggest how the necessary process of information storage, replication, and transmission might occur. Their model served to fix the course of subsequent research that would eventually lead to a deciphering of the genetic code and an understanding of the relationship between protein and the genetic material. Proteins make up most cellular structures and also serve as "catalysts" (substances that cause chemical change to occur without changing their own composition). Proteins play a role in almost all chemical reactions in living organisms. Proteins are also "polymers" (molecular chains composed of similar chemical units called monomers) that are made of amino acids, of which there are twenty main types. The linear sequence of amino acids is the primary structure of the protein molecule, and their order causes the molecule to fold into a three-dimensional form. That form is the most important factor in determining the function of the molecule. DNA is composed of four different types of links, which are called "nucleotides" or "bases." These links are attached to a backbone made up of alternating phosphate and sugar groups. Two chains usually intertwine in a characteristic double-helical (double-spiral) form so that the bases pair up in a regular fashion. The four major types of bases are adenine (A), guanine (G), thymine (T), and cytosine (C); these bases join by means of hydrogen bonds so that A's always pair with T's and G's always pair with C's. Ribonucleic acid (RNA) has a similar structure, except that uracil (U) replaces thymine (T). Gamow's Diamond Code In 1953, George Gamow, a theoretical physicist who had been inspired by the Watson-Crick DNA model, came up with an idea that would define the discussion of the genetic coding problem. Noting the four-base linear structure of DNA and the linear primary structure of proteins, he theorized that the order of the DNA determined the protein structure. He reasoned that the problem was to determine how the four-letter "alphabet" of nucleic acid bases could be formed into "words" that would translate into the twenty-letter alphabet of amino acids. If the words were one letter long, then four nucleotides could code for only four amino acids. Two-letter sequences could combine to code for only sixteen. That meant that a three-letter sequence, which would make possible sixty-four combinations (called "codons"), was therefore the minimum required to code for twenty amino acids. Gamow proposed an ingenious three-letter solution, the "diamond" code, which was based on what he took to be twenty types of diamond-shaped pockets (into which he thought the amino acids could fit) formed by the bases in the double helix. This proposal spurred interest in the coding problem, and a flurry of theoretical work followed. Missing Punctuation Gamow's diamond code immediately ran into mechanical and chemical difficulties. For example, the model required that protein production take place in the cell nucleus, but evidence suggested that it took place in the cytoplasm. Also, in order to fit the spacing of the diamonds to typical amino-acid spacing, the code had to be fully overlapping; that is, each code letter in a chain would be used in three codons in a row. This overlapping structure, however, ruled out certain sequences that were known to exist. A variety of other overlapping codes were suggested, but it was eventually shown to be impossible for a fully overlapping structure to work. If the code was overlapping and was to be read as a series of triplets, then the problem of punctuation arose. Unless there was something that functioned like a comma, there was no way for the cell to know where a triplet began. To avoid this problem, creative attempts were made to devise codes that included "nonsense" triplets that did not correspond to any amino acid, and there was some excitement when mathematical permutations of this approach were discovered that produced codes with exactly twenty "sense" combinations. This approach, however, implied that DNA molecules in all species should have more or less the same composition, but it was discovered that they actually could vary tremendously. Breaking the Code In the summer of 1961, at the Fifth International Congress of Biochemistry in Moscow, Marshall W. Nirenberg, a young researcher from the National Institutes of Health in Bethesda, Maryland, reported that he and his associate J. H. Matthaei had shown experimentally that the triplet UUU was a codon for the amino acid phenylalanine. The first word of the genetic code had been translated. Nirenberg and Matthaei had discovered how to add an RNA message to a test-tube system that synthesized proteins to determine which amino acid was synthesized by it. The technique involved extracting the protein-synthesis machinery (ribosomes, messenger RNA, and enzymes) from Escherichia coli, the common bacteria that inhabits the human intestine. Such extracts, when given an energy source, are called "cell-free systems"; these systems are able to incorporate amino acids into protein. Cell-free systems had been developed by other researchers several years earlier, but they were unreliable because the enzymes and the messenger RNA disintegrated rapidly. Nirenberg and Matthaei had increased the systems' stability by adding a chemical that allowed them to freeze the systems for storage without causing loss of activity. The twenty amino acids, radioactively labeled with carbon 14, were added to the systems. When these ingredients were mixed, only very little incorporation of amino acid into protein occurred. Next, the artificial RNA message (UUU) was added. This produced an eight-hundredfold increase in the activity level; an amino acid had been incorporated into the protein. Subsequent tests showed that the amino acid was phenylalanine. After Nirenberg's 1961 discovery, work proceeded rapidly. By the following year, Crick's laboratory had confirmed that the code was indeed a triplet code. Nirenberg and other researchers had correctly decoded thirty-five of the triplets by 1963. A new test developed in Nirenberg's laboratory increased the number of triplets by fifty, and by 1966, all but three of the sixty-four possible triplets had been assigned to a corresponding amino acid. The final three triplets (UAA, UAG, and UGA) were revealed to be "chain terminators"--punctuation that specified the end of an amino acid "sentence"--and this brought the coding problem, as it was originally conceived, to a final solution. Impact From a theoretical standpoint, the near universality of the code supports the hypothesis that all forms of life on Earth are related to one another by common evolution; at some point very early in the evolution of life, a single successful chemistry emerged, and all subsequent variation has been built upon that structure. From the standpoint of applied science, the universality of the code simplifies the technology of bioengineering, since it allows bits of DNA from one organism to be spliced into that of another organism. The impact of this technology, which was made possible by building upon the sorts of techniques developed to elucidate the genetic code, is only beginning to be felt. It has given rise to many new legal and ethical problems that have not yet been resolved. See Also Cloning; DNA Fingerprinting; DNA Sequencing; Double-Helix Model of DNA; Gene-Chromosome Theory; Giant Mice; Human Genome; Mendelian Genetics; RNA's Catalytic Activity. Further Reading Crick, Francis. What Mad Pursuit: A Personal View of Scentific Discovery. New York: Basic Books, 1988. Haseltine, William A. "The Genetic Code." In The Microverse, edited by Byron Preiss and William R. Alschuler. New York: Bantam Books, 1989. Lappé, Marc. Broken Code: The Exploitation of DNA. San Francisco: Sierra Club Books, 1984. Lewin, Benjamin. Genes III. 3d ed. New York: John Wiley & Sons, 1987. Nirenberg, Marshall W. "The Genetic Code: II." Scientific American (March, 1963): 80-94. Ycas, M. The Biological Code. Amsterdam: North-Holland, 1969. Robert T. Pennock |
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