History Nature of the Gene
The Molecular Gene
Genetic material was understood in the mid-twentieth century to have two key chemical properties: the ability to catalyze reactions to make more genetic material and the ability to catalyze reactions to make a wide array of chemical products found in organisms of all sorts. For most biologists, proteins were the only molecules that seemed to have the ability to play so many specific roles. Researchers naturally focused their attention on the protein component of chromosomes.
The realization that the nucleic acid (DNA) portion of the chromosome was actually the hereditary material was the consequence of two sets of experiments. In 1941 Oswald Avery, Colin MacLeod, and Maclyn McCarty extended work by Fred Griffith on the transformation of nonvirulent bacteria into virulent bacteria. Working from the premise that some hereditary chemical component of the virulent bacteria was transforming the nonvirulent bacteria, these researchers isolated DNA and proteins from the virulent bacteria in order to determine which was the "transforming principle." The surprising result that DNA caused transformation contributed to growing interest in DNA, but DNA was not widely accepted as the genetic material until much later.
In 1952 Alfred Hershey and Martha Chase used radioactive labels to follow DNA and proteins. Hershey and Chase worked with bacteriophages—viruses that infect bacteria. Bacteriophages are composed of proteins and DNA. To determine which was the genetic material, Hershey and Chase created DNA-specific labels and protein-specific labels using radioactivity. They were then able to determine that only DNA was injected into the bacteria to provide the genetic blueprint for the next generation of viruses. This elegant experiment was soon followed by the discovery of the structure of DNA by James Watson and Francis Crick. The double helix structure for DNA immediately suggested a mechanism for its own replication. Thus, by 1953 DNA was identified as having the key catalytic properties required of the genetic material.
At about the same time, the physicist-turned-geneticist Seymour Benzer was using bacteriophages to show that genes were not indivisible units; rather, they could break and recombine within their structures. This focused even more attention on the molecular nature of the gene. An understanding of recombination led slowly to a more dynamic view of genes and chromosomes, exemplified by Barbara McClintock's discovery that some genetic elements are mobile, moving from place to place around the chromosomes. In the early 1960s, Francois Jacob showed that bacterial gene expression is controlled by several noncoding DNA segments. Jacob developed the concept of the operon, a set of coding genes controlled by a common set of regulatory regions.
Identifying DNA as the molecular basis of the genetic material sparked interest in cracking the DNA code and determining how it specifies its products. Reconciling the structure of the DNA sequence with its function became a central preoccupation of molecular genetics.
Ever since Morgan, the gene as a hereditary unit had been a unit of structure and function. Morgan's particulate gene theory, however, had begun to dissolve in the late 1930s, as it became clear that rearrangements in the chromosome could alter genetic function. Various units of structure and function were suggested (enzymes, polypeptides, etc.) in the wake of the particulate gene, but the discovery of the genetic code suggested that the molecular gene could be identified as a continuous coding sequence of DNA.
While most coding sequences lead to the formation of a temporary RNA intermediate (messenger RNA) that is then translated into protein, some sequences code for RNA molecules that are not translated but are functional themselves (ribosomal RNA, transfer RNA, and a host of small nuclear RNAs). The discovery of noncoding sequences (introns) within coding regions (exons) further complicated any simple formulation of the structure-function relationship, as did the growing understanding of regulatory regions, which may or may not be located near the coding regions. Finally, recent discoveries indicate that exons can be joined in different ways in different tissues and that this alternative splicing allows a single set of exons to code for a group of related protein products. By the end of the twentieth century genes could be seen as sequences of DNA (that may be interrupted by noncoding introns) that code for RNA products, many of which are translated into proteins (or a group of related proteins).
SEE ALSO ALTERNATIVE SPLICING; CHROMOSOMAL THEORY OF INHERITANCE, HISTORY; DELBRüCK, MAX; DNA STRUCTURE AND FUNCTION, HISTORY; GENE; INHERITANCE PATTERNS; QUANTITATIVE TRAITS; MEIOSIS; MENDEL, GREGOR; MORGAN, THOMAS HUNT; MULLER, HERMANN.
Carlson, Elof. The Gene: A Critical History. Philadelphia: W. B. Saunders, 1966.
Portin, Petter. "The Concept of the Gene: Short History and Present Status." The Quarterly Review of Biology 69 (1993): 173-223.
Sturtevant, Alfred H. A History of Genetics. New York: Cold Spring Harbor Press,2001.
Access Excellence. The National Health Museum. <http://www.accessexcellence.com/AB/GG/HERSHEY.gif>.