The
first clues regarding the function of genes appeared in 1902 when the English
physician Archibold Garrod found that alkaptonuria, a rare disorder, was seen
in families and was associated with the absence of an enzyme. In 1909, he
predicted that the ability to synthesize specific enzymes was inherited and
that the inability to produce such enzymes resulted from an inborn error of
metabolism—a prediction that was biochemically validated in 1952.
Although
the biochemical aspects of Garrod’s findings were appreciated, its genetic
implications were neglected into the 1930s. Geneticists of the time believed
that genes were pleiotropic—that is, each gene had multiple primary effects. In
1941 at Stanford University, geneticist George Beadle and biochemist Edward
Tatum tested the concept that gene action could be examined in discrete
biochemical steps, which they evaluated in Neurospora crassa, a bread mold.
They exposed Neurospora to X-rays, causing mutations and changes in their
nutritional needs, which differed from the non-irradiated, wild type. For their
limited nutritional requirements, molds use metabolic pathways to synthesize
all the other materials they require to survive. Beadle and Tatum found that
the mutant molds were unable to survive on a minimal growth media because they
were unable to manufacture arginine, an essential amino acid. The researchers
concluded that the multistep biochemical pathway that synthesized arginine was
defective because it lacked the enzyme required for its synthesis.
Beadle
and Tatum determined that the radiation-induced mutation produced a defect in a
specific gene, resulting in a failure to produce a specific enzyme, and
proposed the one gene-one enzyme hypothesis: the function of a gene is to
dictate the production of a particular enzyme. Widely accepted at the time, it
represented a unifying concept in biology, provided the first insights into the
function of genes, and led to the emergence of biochemical genetics, for which
Beadle and Tatum were awarded the 1958 Nobel Prize. Subsequent findings
revealed that this hypothesis was an oversimplification, and that genes not
only dictate enzyme synthesis but also structural proteins (such as collagen)
and transfer RNA (tRNA).
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