Launching the Age of Biochemical Genetics, withNeurospora: the Work of George Wells BeadleAn Inositolless Mutant Strain of Neurospora and Its Use in Bioassays(Beadle, G. W. (1944) J. Biol. Chem. 156, 683–690)George Wells Beadle (1903–1989) grew up on a 40-acre farm near the small town of Wahoo,Nebraska. Beadle might have become a farmer himself had it not been for the influence of hishigh school science teacher, Bess MacDonald, who persuaded him to enroll at the Universityof Nebraska College of Agriculture. After earning a B. S. in 1926, Beadle remained at Ne-braska to obtain an M. A. with Franklin D. Keim. Through his work with Keim, Beadle becameinterested in fundamental genetics and was persuaded to apply to graduate school at CornellUniversity rather than return to the farm.Beadle entered Cornell in 1927 and joined Rollins Adams Emerson’s laboratory to work on thecytogenetics of maize. Over the next 5 years he published 14 papers dealing with his investiga-tions on maize, all initiated while he was a graduate student at Cornell. With the completion ofhis graduate work in 1931, Beadle headed off to the California Institute of Technology to workwith future Nobel laureate Thomas Hunt Morgan. There he became interested in Drosophila andbegan doing research on genetic recombination. In 1934, Boris Ephrussi, a Rockefeller Founda-tion Fellow from Paris, came to Morgan’s laboratory at Caltech to study Drosophila genetics.Beadle and Ephrussi teamed up and began examining eye pigment development in Drosophilaafter devising a method for larval embryonic bud transplantation. These studies were performedin Ephrussi’s laboratory in Paris. From these experiments, they proposed that eye color changesin mutant strains of Drosophila could be caused by inactivation of specific proteins, acting in asingle biosynthetic pathway. This suggested that development could be broken down into a seriesof gene-controlled biochemical reactions and laid the foundation for the one gene-one enzymetheory that Beadle would eventually propose and make famous.The idea that specific proteins were produced by specific genes was first alluded to in 1909by Sir Archibald Garrod, an English physician. Garrod proposed that alkaptonuria, an inher-ited condition in humans in which the urine is black due to the presence of homogentisic acid,was associated with a recessive gene, Garrod called them Factors, in some way responsible forthe further metabolism of homogentisic acid. In 1958 others showed that the liver of a patientwith alkaptonuria was without measurable homogentisic acid oxidase activity (1). However,the first explicit articulation of the one gene-one enzyme phrase, and probably the concept,would have to wait until the 1940s when Beadle and biochemist Edward L. Tatum performedseveral experiments, with a simpler organism, that confirmed the direct relationship betweenone gene and one enzyme.In 1937 Beadle accepted an appointment as Professor of Biological Sciences at StanfordUniversity and invited Tatum to join him as a research associate. While auditing a course thatTatum was teaching on comparative biochemistry, Beadle learned that although microbialspecies share the same basic biochemistry, they differ in their nutritional requirements. Hereasoned that if these differences were genetic in origin, it should be possible to induce genemutations that would produce new nutritional requirements. This would allow identificationof the genes governing biochemical reactions that form known products.For his experimental organism, Beadle chose the red bread mold Neurospora crassa, whoselife cycle had been characterized, making it an ideal organism for genetic study. He and TatumTHE JOURNAL OF BIOLOGICAL CHEMISTRY Vol. 280, No. 12, Issue of March 25, p. e9, 2005© 2005 by The American Society for Biochemistry and Molecular Biology, Inc. Printed in U.S.A.ClassicsA PAPER IN A SERIES REPRINTED TO CELEBRATE THE CENTENARY OF THE JBC IN 2005JBC Centennial1905–2005100 Years of Biochemistry and Molecular BiologyThis paper is available on line at http://www.jbc.org 141 at University of California, Berkeley on January 17, 2007 www.jbc.orgDownloaded fromknew from the studies of others that Neurospora could grow on a minimal medium composedof a sugar, salts, and the one vitamin, biotin. Then they used x-rays to attempt to produceNeurospora mutants that had lost the ability to grow on their minimal medium. Beadle oncerecalled upon reflecting on these experiments, “We believed so thoroughly that the gene-enzyme reaction relation was a general one that there was no doubt in our minds that wewould find the mutants we wanted. The only worry we had was that their frequency might beso low that we would get discouraged and give up before finding one” (2).The 299th mutagenized culture they tested proved to be the lucky one. It did not grow intheir minimal medium, but it did survive and grow when vitamin B6was added. To prove thata single gene had been mutated, Beadle and Tatum performed a genetic cross between themutant strain and a wild type strain and tested cultures derived from the eight single sporesthat were the progeny of a single meiosis. Their tests showed that cultures from four progenyspores required vitamin B6whereas the other four did not, confirming that a single gene hadbeen mutated (3). Before long, mutants requiring amino acids, purines, and pyrimidines werealso found, and the science of biochemical genetics was born.In the Journal of Biological Chemistry (JBC) Classic reprinted here, Beadle discusses someof the practical applications in the isolation and characterization of one of his Neurosporamutants. He and Tatum had produced five Neurospora strains that required inositol fornormal growth and had established that each of these mutants was altered in the same gene.Because mutant growth rate was a function of inositol concentration, Beadle reasoned that anyone of these mutants could be used to assay for inositol. In the Classic, Beadle focuses on onestrain and shows that his bioassay is reproducible and fairly precise at quantitatively esti-mating inositol concentrations in a variety of natural materials.Beadle and Tatum’s Neurospora investigations further showed that the biosynthesis of anyone substance is dependent upon the function of a set of nonallelic genes. A mutation in anyof these genes results in loss of synthesis due to the presumed inactivation of a single enzymecatalyzing a reaction in a
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