One gene-one enzyme hypothesis
The one gene-one enzyme hypothesis is the idea that gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...

s act through the production of enzymes, with each gene responsible for producing a single enzyme that in turn affects a single step in a metabolic pathway
Metabolic pathway
In biochemistry, metabolic pathways are series of chemical reactions occurring within a cell. In each pathway, a principal chemical is modified by a series of chemical reactions. Enzymes catalyze these reactions, and often require dietary minerals, vitamins, and other cofactors in order to function...

. The concept was proposed by George Beadle and Edward Tatum in an influential 1941 paper on genetic mutations in the mold Neurospora crassa
Neurospora crassa
Neurospora crassa is a type of red bread mold of the phylum Ascomycota. The genus name, meaning "nerve spore" refers to the characteristic striations on the spores. The first published account of this fungus was from an infestation of French bakeries in 1843. N...

, and subsequently was dubbed the "one gene-one enzyme hypothesis" by their collaborator Norman Horowitz. It is often considered the first significant result in what came to be called molecular biology
Molecular biology
Molecular biology is the branch of biology that deals with the molecular basis of biological activity. This field overlaps with other areas of biology and chemistry, particularly genetics and biochemistry...

. Although it has been extremely influential, the hypothesis was recognized soon after its proposal to be an oversimplification. Even the subsequent reformulation of the "one gene-one polypeptide" hypothesis is now considered too simple to describe the relationship between genes and proteins.


Although some instances of errors in metabolism
Inborn error of metabolism
Inborn errors of metabolism comprise a large class of genetic diseases involving disorders of metabolism. The majority are due to defects of single genes that code for enzymes that facilitate conversion of various substances into others...

 following Mendelian inheritance
Mendelian inheritance
Mendelian inheritance is a scientific description of how hereditary characteristics are passed from parent organisms to their offspring; it underlies much of genetics...

 patterns were known earlier, beginning with the 1902 identification by Archibald Garrod
Archibald Garrod
Sir Archibald Edward Garrod KCMG, FRS was an English physician who pioneered the field of inborn errors of metabolism.- Education and Personal Life :...

 of alkaptonuria
Alkaptonuria is a rare inherited genetic disorder of phenylalanine and tyrosine metabolism. This is an autosomal recessive condition that is due to a defect in the enzyme homogentisate 1,2-dioxygenase , which participates in the degradation of tyrosine...

 as a Mendelian recessive
In genetics, the term "recessive gene" refers to an allele that causes a phenotype that is only seen in a homozygous genotype and never in a heterozygous genotype. Every person has two copies of every gene on autosomal chromosomes, one from mother and one from father...

 trait, for the most part genetics could not be applied to metabolism through the late 1930s. Another of the exceptions was the work of Boris Ephrussi
Boris Ephrussi
Boris Ephrussi , Professor of Genetics at the University of Paris, was a Russo-French geneticist from the Ephrussi family.His father, Samuil Osipovich Ephrussi, was a chemical engineer; his grandfather, Joseph Ephrusi , was the founder of a banking dynasty in Kishinev. He published two papers in...

 and George Beadle, two geneticists working on the eye color pigments of Drosophila melanogaster
Drosophila melanogaster
Drosophila melanogaster is a species of Diptera, or the order of flies, in the family Drosophilidae. The species is known generally as the common fruit fly or vinegar fly. Starting from Charles W...

fruit flies in the Caltech laboratory of Thomas Hunt Morgan
Thomas Hunt Morgan
Thomas Hunt Morgan was an American evolutionary biologist, geneticist and embryologist and science author who won the Nobel Prize in Physiology or Medicine in 1933 for discoveries relating the role the chromosome plays in heredity.Morgan received his PhD from Johns Hopkins University in zoology...

. In the mid 1930s they found that genes affecting eye color appeared to be serially dependent, and that the normal red eyes of Drosophila were the result of pigments that went through a series of transformations; different eye color gene mutations disrupted the transformations at a different points in the series. Thus, Beadle reasoned that each gene was responsible for an enzyme acting in the metabolic pathway of pigment synthesis. However, because it was a relatively superficial pathway rather than one shared widely by diverse organisms, little was known about the biochemical details of fruit fly eye pigment metabolism. Studying that pathway in more detail required isolating pigments from the eyes of flies, an extremely tedious process.

After moving to Stanford University
Stanford University
The Leland Stanford Junior University, commonly referred to as Stanford University or Stanford, is a private research university on an campus located near Palo Alto, California. It is situated in the northwestern Santa Clara Valley on the San Francisco Peninsula, approximately northwest of San...

 in 1937, Beadle began working with biochemist Edward Tatum to isolate the fly eye pigments. After some success with this approach—they identified one of the intermediate pigments shortly after another researcher, Adolf Butenandt
Adolf Butenandt
Adolf Friedrich Johann Butenandt was a German biochemist and member of the Nazi party. He was awarded the Nobel Prize in Chemistry in 1939 for his "work on sex hormones." He initially rejected the award in accordance with government policy, but accepted it in 1949 after World War...

, beat them to the discovery—Beadle and Tatum switched their focus to an organism that made genetic studies of biochemical traits much easier: the bread mold Neurospora crassa
Neurospora crassa
Neurospora crassa is a type of red bread mold of the phylum Ascomycota. The genus name, meaning "nerve spore" refers to the characteristic striations on the spores. The first published account of this fungus was from an infestation of French bakeries in 1843. N...

, which had recently been subjected to genetic research by one of Thomas Hunt Morgan's researchers, Carl C. Lingegren. Neurospora had several advantages: it required a simple growth medium
Growth medium
A growth medium or culture medium is a liquid or gel designed to support the growth of microorganisms or cells, or small plants like the moss Physcomitrella patens.There are different types of media for growing different types of cells....

, it grew quickly, and because of the production of ascospore
An ascospore is a spore contained in an ascus or that was produced inside an ascus. This kind of spore is specific to fungi classified as ascomycetes ....

s during reproduction it was easy to isolate genetic mutants for analysis. They produced mutations by exposing the fungus to X-ray
X-radiation is a form of electromagnetic radiation. X-rays have a wavelength in the range of 0.01 to 10 nanometers, corresponding to frequencies in the range 30 petahertz to 30 exahertz and energies in the range 120 eV to 120 keV. They are shorter in wavelength than UV rays and longer than gamma...

s, and then identified strains that had metabolic defects by varying the growth medium; if the synthesis of a particular nutrient (such as an amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...

 or vitamin
A vitamin is an organic compound required as a nutrient in tiny amounts by an organism. In other words, an organic chemical compound is called a vitamin when it cannot be synthesized in sufficient quantities by an organism, and must be obtained from the diet. Thus, the term is conditional both on...

) was disrupted by mutation, that mutant strain could be grown by adding the necessary nutrient to the medium. Following their first report of three such auxotroph mutants in 1941, Beadle and Tatum used this method to create series of related mutants and determined the order in which amino acids and some other metabolites were synthesized in several metabolic pathways.

The nutritional mutants of Neurospora also proved to have practical applications; in one of the early, if indirect, examples of military funding of science
Military funding of science
The military funding of science has had a powerful transformative effect on the practice and products of scientific research since the early 20th century...

 in the biological sciences, Beadle garnered additional research funding (from the Rockefeller Foundation
Rockefeller Foundation
The Rockefeller Foundation is a prominent philanthropic organization and private foundation based at 420 Fifth Avenue, New York City. The preeminent institution established by the six-generation Rockefeller family, it was founded by John D. Rockefeller , along with his son John D. Rockefeller, Jr...

 and an association of manufacturers of military rations) to develop strains that could be used to assay
An assay is a procedure in molecular biology for testing or measuring the activity of a drug or biochemical in an organism or organic sample. A quantitative assay may also measure the amount of a substance in a sample. Bioassays and immunoassays are among the many varieties of specialized...

 the nutrient content of foodstuffs, to ensure adequate nutrition for troops in World War II
World War II
World War II, or the Second World War , was a global conflict lasting from 1939 to 1945, involving most of the world's nations—including all of the great powers—eventually forming two opposing military alliances: the Allies and the Axis...


The hypothesis and alternative interpretations

In their first Neurospora paper, published in the November 15, 1941, edition of the Proceedings of the National Academy of Sciences
Proceedings of the National Academy of Sciences
The Proceedings of the National Academy of Sciences of the United States of America, usually referred to as PNAS, is the official journal of the United States National Academy of Sciences...

, Beadle and Tatum noted that it was "entirely tenable to suppose that these genes which are themselves a part of the system, control or regulate specific reactions in the system either by acting directly as enzymes or by determining the specificities of enzymes", an idea that had been suggested, though with limited experimental support, as early as 1917; they offered new evidence to support that view, and outlined a research program that would enable it to be explored more fully. By 1945, Beadle, Tatum and others, working with Neurospora and other model organisms such as E. coli, had produced considerable experimental evidence that each step in a metabolic pathway is controlled by a single gene. In a 1945 review, Beadle suggested that "the gene can be visualized as directing the final configuration of a protein molecule and thus determining its specificity." He also argued that "for reasons of economy in the evolutionary process, one might expect that with few exceptions the final specificity of a particular enzyme would be imposed by only one gene." At the time, genes were widely thought to consist of proteins or nucleoproteins (although the Avery-MacLeod-McCarty experiment
Avery-MacLeod-McCarty experiment
The Avery–MacLeod–McCarty experiment was an experimental demonstration, reported in 1944 by Oswald Avery, Colin MacLeod, and Maclyn McCarty, that DNA is the substance that causes bacterial transformation...

 and related work was beginning to cast doubt on that idea). However, the proposed connection between a single gene and a single protein enzyme outlived the protein theory of gene structure. In a 1948 paper, Norman Horowitz named the concept the "one gene-one enzyme hypothesis".

Although influential, the one gene-one enzyme hypothesis was not unchallenged. Among others, Max Delbrück
Max Delbrück
Max Ludwig Henning Delbrück was a German-American biophysicist and Nobel laureate.-Biography:Delbrück was born in Berlin, German Empire...

 was skeptical only a single enzyme was actually involved at each step along metabolic pathways. For many who did accept the results, it strengthened the link between genes and enzymes, so that some biochemists thought that genes were enzymes; this was consistent with other work, such as studies of the reproduction of tobacco mosaic virus
Tobacco mosaic virus
Tobacco mosaic virus is a positive-sense single stranded RNA virus that infects plants, especially tobacco and other members of the family Solanaceae. The infection causes characteristic patterns on the leaves . TMV was the first virus to be discovered...

 (which was known to have heritable variations and which followed the same pattern of autocatalysis
A single chemical reaction is said to have undergone autocatalysis, or be autocatalytic, if the reaction product itself is the catalyst for that reaction....

 as many enzymatic reactions) and the crystallization of that virus as an apparently pure protein. By the early 1950s, most biochemists and geneticists considered DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...

 the most likely candidate for physical basis of the gene, and the one gene-one enzyme hypothesis was reinterpreted accordingly.

One gene-one polypeptide

By the early 1950s, advances in biochemical genetics—spurred in part by the original hypothesis—made the one gene-one enzyme hypothesis seem very unlikely (at least in its original form). Beginning in 1957, Vernon Ingram
Vernon Ingram
Vernon M. Ingram, Ph.D., FRS was a German American professor of biology at the Massachusetts Institute of Technology.-Biography:Ingram was born in Breslau, Lower Silesia...

 and others showed through protein fingerprinting
Protein fingerprinting
Protein fingerprinting can refer to any of the several methods for identifying or differentiating proteins:*Peptide mass fingerprinting, a method developed in 1993 that uses protein mass spectrometry following SDS-PAGE...

 that genetic variations in proteins (such as sickle cell hemoglobin) could be limited to differences in just a single polypeptide chain in a multimeric protein, leading to a "one gene-one polypeptide" hypothesis instead. According to geneticist Rowland H. Davis, "By 1958 – indeed, even by 1948 – one gene, one enzyme was no longer a hypothesis to be resolutely defended; it was simply the name of a research program."

Presently, the one gene-one polypeptide perspective cannot account for the various spliced versions in many eukaryote organisms which use a spliceosome
A spliceosome is a complex of snRNA and protein subunits that removes introns from a transcribed pre-mRNA segment. This process is generally referred to as splicing.-Composition:...

 to individually prepare a RNA transcript depending on the various inter- and intra-cellular environmental signals. This splicing was discovered in 1977 by Phillip Sharp and Richard J. Roberts
Richard J. Roberts
Sir Richard "Rich" John Roberts is a British biochemist and molecular biologist. He was awarded the 1993 Nobel Prize in Physiology or Medicine with Phillip Allen Sharp for the discovery of introns in eukaryotic DNA and the mechanism of gene-splicing.When he was 4, his family moved to Bath. In...

Possible anticipation of Beadle and Tatum's results

Historian Jan Sapp
Jan Sapp
Jan Sapp is an historian of biology at York University, Canada. His writings focus especially on evolutionary biology beyond the traditional neo-Darwinian framework, and emphasize the fundamental importance of symbiosis and horizontal gene transfer in heredity and evolution...

 has suggested that German geneticist Franz Moewus
Franz Moewus
Franz Moewus was a German biologist who studied the algae Chlamydomonas, one species of which is named for him . His work was later called into question due to other scientists being unable to reproduce his results.- References :* Excerpt from J.D. Watson, Genes, Girls and Gamow...

 generated similar results before Beadle and Tatum's celebrated 1941 work. Working on the algae Chlamydomonas
Chlamydomonas is a genus of green algae. They are unicellular flagellates. Chlamydomonas is used as a model organism for molecular biology, especially studies of flagellar motility and chloroplast dynamics, biogenesis, and genetics...

, Moewus published, in the 1930s, results that showed that different genes were responsible for different enzymatic reactions in the production of hormones that controlled the organism's reproduction. However, these results were challenged by others who found the data 'too good to be true' statistically, and the results could not be replicated.
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