The One Gene/One Enzyme Hypothesis
Beadle and Tatum's 1941 Breakthrough
Gene therapy for inherited diseases may be one of the most beneficial results of the biotechnology revolution. Many such diseases, including hemophilia and cystic fibrosis, result when a single defective gene causes the production of a non-functional protein. Gene therapy attempts to replace the defective genes with normal ones, allowing the patient to produce the necessary protein and function normally. The first human gene therapy test (still in progress) involves a girl suffering from severe immune problems due to a defective gene for the enzyme adenosine deaminase (ADA). Doctors have attempted to treat her by removing some of her bone marrow cells, inserting functional ADA genes into these cells, and then putting the "corrected" cells back in place.
The basis of gene therapy rests on our understanding of the relationship between genes and proteins - between genotype and phenotype. The concept that a gene is responsible for the production of a specific protein was first proposed in 1909 by Archibald Garrod, an English physician. Garrod was interested in inherited human diseases, particularly what he called "inborn errors of metabolism." He suggested (correctly) that alkaptonuria - an inherited condition in which the urine is colored dark red by the chemical alkapton - results from a single recessive gene, which causes a deficiency in the enzyme that normally breaks down alkapton. Although Garrod published a book and several papers on the subject, his work was generally ignored until the early 1940's, when it was rediscovered by the American geneticists, George Beadle and Edward Tatum.
Beadle and Tatum set out to provide experimental proof of the connection between genes and enzymes. They hypothesized that if there really was a one-to-one relationship between genes and specific enzymes, it should be possible to create genetic mutants that are unable to carry out specific enzymatic reactions. To test this theory, they exposed spores of Neurospora crassa (a bread mold) to X-rays or UV radiation and studied the resulting mutations. The mutant molds had a variety of special nutritional needs. Unlike their normal counterparts, they could not live without the addition of particular vitamins or amino acids to their food. For example, normal Neurospora requires only one vitamin (biotin), but mutants were created that also required thiamine or choline.
Genetic analysis showed that each mutant differed from the original, normal type by only one gene. Biochemical studies showed that the mutants seemed to be blocked at certain steps in the normal metabolic pathways. Their cells contained large accumulations of the substance synthesized just prior to the blockage point - just as Garrod's patients had accumulated alkapton.
As Beadle and Tatum had predicted, they were able to create single gene mutations that incapacitated specific enzymes, so that the molds with these mutations required an external supply of the substance that the enzyme normally produced, and the substance that the enzyme normally used, piled up in the cell. These results led them to the one gene/one enzyme hypothesis, which states that each gene is responsible for directing the building of a single, specific enzyme.
Subsequent work has led to further refinement of this hypothesis. We now appreciate that not all genes code for enzymes - they may instead direct the building of structural proteins, such as the collagen in our skin, or the keratin in our hair. Also, many proteins are made of more than one polypeptide chain - hemoglobin consists of four polypeptide chains of two different types, and each of the two chain types is controlled by a different gene. Thus, given what we know now, a more accurate way to summarize Beadle's and Tatum's results is: one gene-one polypeptide.
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