Launching the Age of Biochemical Genetics, with Neurospora: theWork of George Wells Beadle
Year: 2005
Type: article
Abstract: An 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 smalltown of Wahoo, Nebraska. Beadle might have become a farmer himself had it notbeen for the influence of his high school science teacher, Bess MacDonald, whopersuaded him to enroll at the University of Nebraska College of Agriculture.After earning a B. S. in 1926, Beadle remained at Nebraska to obtain an M. A.with Franklin D. Keim. Through his work with Keim, Beadle became interested infundamental 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'slaboratory to work on the cytogenetics of maize. Over the next 5 years hepublished 14 papers dealing with his investigations on maize, all initiatedwhile he was a graduate student at Cornell. With the completion of hisgraduate work in 1931, Beadle headed off to the California Institute ofTechnology to work with future Nobel laureate Thomas Hunt Morgan. There hebecame interested in Drosophila and began doing research on geneticrecombination. In 1934, Boris Ephrussi, a Rockefeller Foundation Fellow fromParis, came to Morgan's laboratory at Caltech to study Drosophilagenetics. Beadle and Ephrussi teamed up and began examining eye pigmentdevelopment in Drosophila after devising a method for larvalembryonic bud transplantation. These studies were performed in Ephrussi'slaboratory in Paris. From these experiments, they proposed that eye colorchanges in mutant strains of Drosophila could be caused byinactivation of specific proteins, acting in a single biosynthetic pathway.This suggested that development could be broken down into a series ofgene-controlled biochemical reactions and laid the foundation for the onegene-one enzyme theory that Beadle would eventually propose and makefamous. The idea that specific proteins were produced by specific genes was firstalluded to in 1909 by Sir Archibald Garrod, an English physician. Garrodproposed that alkaptonuria, an inherited condition in humans in which theurine is black due to the presence of homogentisic acid, was associated with arecessive gene, Garrod called them Factors, in some way responsible for thefurther metabolism of homogentisic acid. In 1958 others showed that the liverof a patient with alkaptonuria was without measurable homogentisic acidoxidase activity (1LaDu B.N. Zannoni V.A. Laster L. Seegmiller J.E. J. Biol. Chem. 1958; 230: 251-260Abstract Full Text PDF PubMed Google Scholar). However,the first explicit articulation of the one gene-one enzyme phrase, andprobably the concept, would have to wait until the 1940s when Beadle andbiochemist Edward L. Tatum performed several experiments, with a simplerorganism, that confirmed the direct relationship between one gene and oneenzyme. In 1937 Beadle accepted an appointment as Professor of Biological Sciencesat Stanford University and invited Tatum to join him as a research associate.While auditing a course that Tatum was teaching on comparative biochemistry,Beadle learned that although microbial species share the same basicbiochemistry, they differ in their nutritional requirements. He reasoned thatif these differences were genetic in origin, it should be possible to inducegene mutations that would produce new nutritional requirements. This wouldallow identification of the genes governing biochemical reactions that formknown products. For his experimental organism, Beadle chose the red bread moldNeurospora crassa, whose life cycle had been characterized, making itan ideal organism for genetic study. He and Tatum knew from the studies ofothers that Neurospora could grow on a minimal medium composed of asugar, salts, and the one vitamin, biotin. Then they used x-rays to attempt toproduce Neurospora mutants that had lost the ability to grow on theirminimal medium. Beadle once recalled upon reflecting on these experiments,“We believed so thoroughly that the gene-enzyme reaction relation was ageneral one that there was no doubt in our minds that we would find themutants we wanted. The only worry we had was that their frequency might be solow that we would get discouraged and give up before finding one”(2Beadle G.W. Genes and chemical reactions inNeurospora.From Nobel Lectures, Physiology or Medicine1942-1962. Elsevier Publishing Co., Amsterdam1964Google Scholar). The 299th mutagenized culture they tested proved to be the lucky one. Itdid not grow in their minimal medium, but it did survive and grow when vitaminB6 was added. To prove that a single gene had been mutated, Beadleand Tatum performed a genetic cross between the mutant strain and a wild typestrain and tested cultures derived from the eight single spores that were theprogeny of a single meiosis. Their tests showed that cultures from fourprogeny spores required vitamin B6 whereas the other four did not,confirming that a single gene had been mutated(3Beadle G.W. Tatum E.L. Genetic controlof biochemical reactions in Neurospora..Proc. Natl. Acad. Sci. U.S. A. 1941; 27: 499-506Crossref PubMed Google Scholar). Before long, mutantsrequiring amino acids, purines, and pyrimidines were also found, and thescience of biochemical genetics was born. In the Journal of Biological Chemistry (JBC) Classicreprinted here, Beadle discusses some of the practical applications in theisolation and characterization of one of his Neurospora mutants. Heand Tatum had produced five Neurospora strains that required inositolfor normal growth and had established that each of these mutants was alteredin the same gene. Because mutant growth rate was a function of inositolconcentration, Beadle reasoned that any one of these mutants could be used toassay for inositol. In the Classic, Beadle focuses on one strain and showsthat his bioassay is reproducible and fairly precise at quantitativelyestimating inositol concentrations in a variety of natural materials. Beadle and Tatum's Neurospora investigations further showed thatthe biosynthesis of any one substance is dependent upon the function of a setof nonallelic genes. A mutation in any of these genes results in loss ofsynthesis due to the presumed inactivation of a single enzyme catalyzing areaction in a multistep biosynthetic pathway. Beadle summarized this conceptin an historic article in 1945 in which he claimed that “a given enzymewill usually have its final specificity set by one and only one gene”(4Beadle G.W. Biochemical genetics..Chem. Rev. 1945; 37: 15-96Crossref Scopus (62) Google Scholar). This statement eventuallybecame known as the “one gene-one enzyme” theory of geneaction. However, when Beadle first presented this theory few scientists acceptedthe concept that one gene specifies the sequence of one enzyme. This was duein part to the widespread belief in the pleiotropic action (multiple effects)of genes, which was somewhat correct since single gene mutations often hadmultiple consequences. Several scientists still suspected that genes governedonly trivial biological traits whereas important characteristics weredetermined by cytoplasmic interactions involving as yet unknown mechanisms.The one gene-one enzyme theory was eventually verified and accepted, whensubsequent investigations by others established that genetic material was DNAand that DNA had a double helical structure, and determined how geneticmaterial is replicated and how it functions in protein synthesis. Tatum later applied their methods to produce bacterial mutants. Using thesemutants, Tatum's graduate student, Joshua Lederberg, demonstrated geneticrecombination in Escherichia coli, thereby founding the field ofbacterial genetics. In 1958, Beadle, Tatum, and Lederberg shared the NobelPrize in Physiology or Medicine for their pioneering studies withNeurospora and E. coli. In 1946 Beadle returned to Caltech, succeeding Morgan as chairman of theDivision of Biology. He continued to work in the laboratory untiladministrative demands absorbed all of his time. He published his lastexperimental paper on Neurospora in 1946, after which his scientificwritings consisted of reviews, lectures, historical essays, and aprize-winning book for young people he wrote with his wife Murial calledThe Language of Life: an Introduction to the Science of Genetics(5Beadle G.W. Beadle M.B. TheLanguage of Life: an Introduction to the Science of Genetics. Doubleday and Co., Inc., New York1966Google Scholar). In 1961 Beadle leftCaltech to become president of The University of Chicago. After retiring in1968, he resumed research, returning to a problem he studied during hisCornell days—the origin ofmaize. 1All biographical information on George Wells Beadle was taken from Refs.6Horowitz N.H. Biographical Memoirof George Wells Beadle. 59. National Academy of Sciences, Washington, D.C.1990: 26-53Google Scholar and7Beadle G.W. Recollections.Annu.Rev. Biochem. 1974; 43: 1-13Crossref PubMed Scopus (14) Google Scholar. Additional information onGeorge Wells Beadle can be found in the biography written by Paul Berg andMaxine Singer (8Berg P. Singer M. GeorgeBeadle, an Uncommon Farmer. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY2003Google Scholar).1All biographical information on George Wells Beadle was taken from Refs.6Horowitz N.H. Biographical Memoirof George Wells Beadle. 59. National Academy of Sciences, Washington, D.C.1990: 26-53Google Scholar and7Beadle G.W. Recollections.Annu.Rev. Biochem. 1974; 43: 1-13Crossref PubMed Scopus (14) Google Scholar. Additional information onGeorge Wells Beadle can be found in the biography written by Paul Berg andMaxine Singer (8Berg P. Singer M. GeorgeBeadle, an Uncommon Farmer. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY2003Google Scholar)., 2We thank Charles Yanofsky, Emeritus Professor of Biological Sciences atStanford University, and Paul Berg, Emeritus Professor of Biochemistry atStanford University Medical School, for their assistance in writing this JBCClassic Introduction.2We thank Charles Yanofsky, Emeritus Professor of Biological Sciences atStanford University, and Paul Berg, Emeritus Professor of Biochemistry atStanford University Medical School, for their assistance in writing this JBCClassic Introduction.
Source: Journal of Biological Chemistry
Language: English
Subfield: History and Philosophy of Science
Field: Arts and Humanities
Domain: Social Sciences
Open Access status: hybrid
Estimated APC paid: $3,430
OpenAlex ID: W1579336294