Cracking the Genetic Code

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Cracking the Genetic Code

Overview

"Cracking" the genetic code was one of the most exciting discoveries of the twentieth century. Although philosophers and early scientists had long pondered the nature of inheritance, it was not until 1953 that James Watson (1928- ) and Francis Crick (1916- ) announced that they had determined that the code for life resides in the molecular structure of deoxyribonucleic acid (DNA). This announcement began a frenzy of investigation that still continues today. One of the hottest topics in science at the end of the twentieth century is molecular biology.

Many scientists have added to the knowledge of the genetic code. In 1955 Mahlon B. Hoagland (1921- ) isolated transfer ribonucleic acid (tRNA) while Robert Holley (1922-1993) described the complete structure of tRNA in 1965. In 1956 George Palade (1912- ), working with the small structures (organelles) within the cytoplasm of the cell, discovered ribosomes, the protein factories of the cell. In 1967 Charles Yanofsky (1927- ) and Sydney Brenner (1927- ) described the organization of base groups that make up a protein. Marshall Nirenberg (1912- ) and his team cracked the genetic code with a description of how the base pairs are related to twenty amino acids. These scientists laid the foundation for biotechnology and genetic engineering.

Background

A few scientists in the 1800s argued that the nature of living organisms could be reduced to basic chemistry and physics. Most were resigned to the prospect that the mystery of life and its mechanisms would never be solved. While a Swiss scientist in 1869 isolated the chemical DNA from pus cells, he did not recognize the importance of his finding.

At the beginning of the twentieth century, scientists had determined that nucleic acids were in all cells. Likewise, they knew that cells had three key ingredients: a ribose or deoxyribose sugar, a phosphate, and bases made of nitrogen and carbon. In 1938 Warren Weaver used the term "molecular biology" for the first time in an annual report to the Trustees of the Rockefeller Foundation. The foundation was supporting research into x-ray crystallography, which became instrumental in cracking the genetic code.

The 1940s, including the events of World War II, encouraged a new frenzy of scientific thinking that led to exciting discoveries in many fields, ranging from nuclear physics to biochemistry. In 1944 O.T. Avery (1877-1955) and his colleagues identified a substance, named deoxyribonucleic acid, that was able to change one strain of bacteria into another. The science of molecular biology was built on the work of scientists such as Walther Flemming (1843-1905), who studied cell processes, and Hugo de Vries (1848-1935), who investigated mutations. While the discovery of DNA was eclipsed by developments in nuclear technology, the study of reproduction, inheritance, and growth was taking off.

Impact

In 1951 a young post-doctoral fellow named James Watson came to the Cavendish Laboratories in Cambridge, England, where he met physicist-turned-biologist Francis H.C. Crick. The two immediately became focused on the problem of DNA structure. Using x-ray diffraction, a technique that shows chemical structure, they studied the protein coat of the tobacco mosaic virus but made no great progress.

At another laboratory at King's College, London, Rosalind Franklin (1920-1958) and Maurice Wilkins (1916- ) had taken great diffraction pictures of DNA. All, however, was not well between the two colleagues, who disliked each other. When Wilkins showed Watson one of the pictures they had made of the double helix, Watson immediately recognized the parameters he needed to establish the structure of DNA.

Franklin died of cancer in 1958 at the age of 37, but her work helped illuminate the way toward the double helix. Crick praised her key experimental work and acknowledged that he and Watson had benefited from her criticism, which, while it offended them, caused them to rethink their procedures.

While the existence of four DNA bases—adenine (A), thymine (T), cytosine (C), and guanine (G)—had already been established, Watson looked at how the pairs fit together. Fiddling with models, he showed that adenine and thymine are held together by a hydrogen bond and that this pair was identical in shape to the guanine-cytosine pair. From looking at the x-ray pictures of the structure, he deduced that the pairs were the like the rungs of a ladder. The base pairs that unzip and rezip form the key to DNA replication. For example, rung by rung, CA-T would have a complementary strand, G-T A. When these pairs unzip, each of the two separate helixes forms a template upon which is built a new double helix.

On February 28, 1953, Crick strolled into the Eagle pub in Cambridge, England, and casually announced he and Watson had just completed a model for the secret of life. What caught the attention of scientists as well as the public was the model of the double helix, which presented to the world a tangible picture of what the molecule of life looked like. Although the two scientists wrote an account that was published in the journal Nature, it was the picture of the twisted ladder made of colored balls (representing atoms) that excited the world. In 1962 Watson, Crick, and Wilkins were awarded a Nobel Prize for their work.

In 1954 George Gamow (1904-1968) published the first theoretical consideration of a genetic code, suggesting that amino acids fit into the "holes" on the DNA. Other scientists were also investigating the relationship.

With the double helix established, Crick turned his attention to finding out how nucleotide sequences in DNA make up the sequences of amino acids in proteins. Amino acids have a nitrogen base or NH₂ radical. In 1954 he founded the ribonucleic acid (RNA) Tie Club, a group of scientists determined to find out how RNA coded for the amino acid sequences. Crick suggested that amino acids are attached to adapter molecules before being attracted to a nucleic acid molecule. In 1957 Crick and Gamov worked out the "central dogma," explaining how DNA makes a protein. The central theme of this idea is the "sequence hypothesis," which states that the order of pairs on the DNA determine a specific amino acid. They also suggested information goes only in one direction: from DNA to RNA to protein.

By the early 1950s, researchers had realized that RNA carries information from structures called codons to build proteins. Codons consist of three base pairs (for example, C-A-T) located on the DNA within the cell nucleus. RNA carries the codon instructions from the cell's nucleus into the cytoplasm, where ribosomes use this information to assemble amino acids into proteins. Biochemist Paul Berg (1926- ) had determined that the combining of amino acids into proteins involved adenosine triphosphate (ATP), but it was unknown how the amino acids recognized the coding.

While Crick and Watson were working in England, other scientists on the other side of the Atlantic Ocean were also conducting research. In 1956 Mahlon Hoagland (1921- ) and a team at Harvard stumbled onto the idea that amino acids attach not to RNA on the ribosome but instead to locations on small, soluble molecules called transfer RNA (tRNA), which, in turn, attach to the ribosomal RNA. This discovery fit Crick's theory that amino acids attach to an adapter molecule.

Examining how the genetic code controls synthesis of proteins, American biochemist Robert Holley began his research on RNA after studying with James F. Bonner at the California Institute of Technology in 1956. By 1960 Holley and colleagues had shown that tRNA provides instructions for the assembly of amino acids into proteins. This discovery was independent of Hoagland. Holley's team developed techniques to separate tRNA from the cell. By 1965 Holley had established how tRNA incorporates the amino acid alanine to form specific proteins. First, he determined the sequence of the nucleotides by digesting the molecule with enzymes, identifying the resulting pieces, and then figuring out how these pieces fit back together. All tRNA molecules have been determined to have similar structures. Marshall Nirenberg built a strand of tRNA comprised only of the base uracil. Calling the strand "poly U," he discovered that UUU is the codon for the amino acid phenylalanine. This finding was the first step in setting up the code for other amino acids. In 1966 the genetic code was cracked when Nirenberg and his team announced that a specific sequence of three nucleotide bases (a codon) determined each of twenty amino acids. Holley, along with Nirenberg and Har Gobind Khorana (1922- ), shared the Nobel Prize in physiology or medicine in 1968 for their studies of amino acids and proteins.

Charles Yanofsky, an American geneticist, worked with a bacterium, Esherichia coli (E. coli),to show that the sequence of nitrogen-containing bases of the genetic structure has a linear correspondence to the amino acid sequence of proteins. (An amino acid always has an NH₂ radical.) His establishment of the co-linearity of gene and protein structures was built upon by other scientists to establish the genetic code.

From 1960 to 1964, South-African born biologist Sydney Brenner teamed up with Crick to study the genetics of bacterial viruses called bacteriophages. Studying carefully chosen mutations, they found information on the number of nucleotides that form the cores of amino acids. Using sophisticated detection methods, they found that a particular type of nucleotide forms a codon, which specifies an amino acid. Brenner was also a member of the first scientific team to introduce messenger RNA (mRNA), which carries the information that specifies a particular protein product.

From the Watson-Crick model of the DNA double helix in 1953, the gene emerged as a continuous string of information. The gene is organized so that three base pairs, or codons, hold the information for amino acids, which form proteins. By 1969 molecular biologists thought that they had found all the major players in the genetic code, but their discoveries were only the beginning.

EVELYN B. KELLY