Hermann J. Muller and the Induction of Genetic Mutations

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Hermann J. Muller and the Induction of Genetic Mutations

Overview

Hermann J. Muller (1890-1967) made many contributions to the understanding of genetic mutation, the gene, and radiation genetics, but he is primarily remembered for his demonstration that mutations could be artificially induced by x rays. Muller began his research career in the famous "fly room" of Thomas Hunt Morgan (1866-1945), who established the chromosome theory of heredity. When Muller began his research, the term "mutation" was applied indiscriminately to many different phenomena. Muller helped narrow the definition to its present meaning: an inheritable change in a specific gene. In 1946 Muller won the Nobel Prize for physiology or medicine for the induction of genetic mutations with x rays. He also established the laws of radiation genetics, demonstrating the relationship between the radiation dose and the frequency of gene mutations and chromosomal rearrangements.

Background

Thomas Hunt Morgan and his research associates in the fly room at Columbia University proved that genes are located on the chromosomes in a specific linear sequence. During this period of exciting discoveries, Morgan's students included Hermann J. Muller, Alfred H. Sturtevant, Calvin B. Bridges, and Curt Stern. Morgan won the Nobel Prize in 1933 for his contributions to the chromosome theory of heredity. Sturtevant remembered their days in the fly room as a time of friendship and cooperation, but others reported signs of interpersonal differences and tensions. Muller in particular seemed to feel that he did not receive proper credit for his work at Columbia and he accused Morgan of sabotaging his professional advancement.

Morgan and his students used the fruit fly Drosophila melanogaster for both breeding experiments and cytogenetics, because it has only four pairs of chromosomes per nucleus and scores of easily recognizable inheritable traits. Although Drosophila seemed a promising model for saltative evolution (the sudden appearance of new character traits leading the formation of new species), the "fly group" did not find mutations that established new species. In 1926 Morgan published The Theory of the Gene to summarize developments in genetics since the rediscovery of Mendel's laws. Based on statistical studies of inheritance in Drosophila, Morgan assigned five principles to the gene: segregation, independent assortment, crossing over, linear order, and linkage groups.

Critics of Mendelian genetics often pointed to the kinds of mutants studied by the fly group as evidence that mutations were basically pathological and could not, therefore, play an important role in evolution. Morgan and his colleagues admitted that the kinds of traits studied in the laboratory were generally deleterious, but they believed that there might be many subtle, undetected mutations that were physiologically advantageous. The mutations investigated by Morgan's fly group did not support Hugo de Vries's (1848-1935) hope that new species could be created in one step. When de Vries gave a lecture in the United States in 1904, he suggested that the recently discovered "curie rays" produced by radium might be used to induce mutations in plants and animals. Shortly afterwards, Morgan made some attempts to induce "Devriesian mutations" in various animals, including Drosophila, by subjecting them to radium, acids, alkalis, salts, sugars, and proteins. These experiments did not produce either significant macromutations or new species and Morgan decided that his results were not worth publishing.

Impact

Work in Morgan's laboratory had demonstrated the value of mutants in genetic analysis, but the natural rate of mutation was too slow for direct studies of the process. To overcome this obstacle, Hermann Joseph Muller attempted to find methods that would increase the mutation rate. At that time, the term "mutation" was indiscriminately used to describe any sudden appearance of a new genetic type. Muller discovered, however, that some mutations were caused by Mendelian recombination, some were abnormalities in chromosome distribution, and others were changes in individual genes. He argued that in the interests of scientific clarity the definition of the term mutation should be limited to inheritable changes in specific genes. Muller tested various agents in his attempts to increase the frequency of mutations and proved that x rays could induce mutations in Drosophila.

Muller's discovery of the mutagenic effect of x rays established the new field of radiation ge netics, and the presentation of his report at the Fifth International Congress of Genetics in Berlin in 1927 received international attention. When Muller began his research, Drosophila geneticists had discovered about 100 spontaneous mutations. Using x rays, Muller produced several hundred mutants in a short time. Most of these induced mutations were stable over many generations and behaved like typical Mendelian factors when subjected to breeding tests.

Muller had been interested in the sciences, particularly evolution, while he was still a high school student. Majoring in genetics at Columbia University, he came under the influence of Morgan and Edmund B. Wilson (1856-1939). He earned his B.A. from Columbia in 1910 and enrolled in Cornell Medical School. Because of his interest in the possibility of consciously guided human evolution, Muller decided to join Morgan's Drosophila group so that he could select research topics that would provide a better understanding of the processes of heredity and variation. He earned his Ph.D. in 1915 for research on the mechanism of crossing over by following the interrelationships of many linked genes. At the same time, he undertook a sophisticated analysis of variable, multiple-factor characters by using "marker genes." This work provided further confirmation of chromosomal inheritance and the stability of the gene and led to Muller's theory of balanced lethals. Known for his ingenuity in experimental design, Muller clarified obscure aspects of chromosome behavior and genetic mapping and established the principle of the linear linkage of genes in heredity.

After three years at the Rice Institute in Houston, Texas, and a brief return to Columbia as an instructor, Muller became a member of the faculty of the University of Texas at Austin, where he remained until 1932. Although Muller felt isolated in Texas, the years that he spent in Austin were remarkably productive and culminated in the induction of genetic mutations through the use of x rays in 1926. Muller exposed fruit flies to x rays and proved that ionizing radiation produces mutations both within individual genes and as larger chromosomal aberrations. Later studies showed that other forms of radiation and various chemicals can also cause chromosomal aberrations and mutations in individual genes. Such mutagenic agents have been associated with aging, cancer, and genetic diseases.

Although he was elected to the National Academy of Sciences in 1931, he continued to feel isolated and depressed by tension related, at least in part, to his relationship with Morgan. In 1932 he suffered a nervous breakdown and took an overdose of sleeping pills. His personal and professional problems as well as pressure caused by his outspoken defense of radical ideas and socialist causes expedited his decision to leave Texas.

Working with Nikolai Timofeeff-Ressovsky (1900-1981) at the Kaiser Wilhelm (now Max Planck) Institute in Berlin, Muller tried to gain insights into the physical nature of the genetic material by bombarding it with radiation. These experiments led Timofeeff-Ressovsky and Max Delbrück to propose the "target theory" of mutation. Because of the growing threat of Nazism, Muller left Germany in 1933 and accepted Nikolai Ivanovitch Vavilov's (1887-1943) invitation to work as senior geneticist at the Institute of Genetics of the Academy of Sciences of the USSR. Muller and Vavilov, an eminent Russian geneticist, fought against the growth of Lysenkoism, a pseudoscientific form of "Marxist biology" established by Trofim Denisovich Lysenko (1898-1976). Thoroughly disillusioned by the losing battle against Lysenkoism, Muller left Russia. From 1937 to 1940, at the Institute of Animal Genetics in Edinburgh, Muller studied the chromosomal basis of embryonic death from radiation damage. World War II forced Muller to return to the United States. In 1945, after completing a study of the relationship between aging and spontaneous mutations, he became professor of zoology at Indiana University, where he continued his research on radiation-induced mutations, genetic analysis, and the mechanism by which radiation induces its biological effects. He remained at Indiana University until his death.

The Nobel Prize in physiology or medicine was awarded to Muller in 1946 for his research into the effects of x rays on mutation rates, but his interest in genetics went far beyond laboratory studies of the fruit fly. Muller used the publicity generated by his Nobel Prize to campaign against medical, industrial, and military abuse of radiation. After World War II, he was a leader of the radiation protection movement and he applied his expertise to the problem of radiation sickness. To raise awareness of the dangers of radiation, he published estimates of spontaneous and induced mutation rates in humans. He formulated the modern concept of spontaneous gene mutation, noting that most mutations are detrimental and recessive and involve accidental physical-chemical effects on the genetic material; he, therefore, concluded that the gene was the basis of evolution. Muller published more than 300 scientific articles. His books include The Mechanism of Mendelian Heredity, Out of the Night—a Biologist's View of the Future, and Genetics, Medicine and Man. He was a founder of the American Society of Human Genetics.

Although he remained a socialist, he was a vocal critic of Lysenko and resigned from the Soviet Academy of Science in 1947 as a protest. He was also interested in biology education, especially genetics and evolution, in secondary schools. Even as a college student, Muller had demonstrated a deep interest in evolution and human genetics, including a concern for the preservation and improvement of the human gene pool. Most mutations, he noted, were stable, deleterious, and recessive. Knowledge of mutation, therefore, had profound implications for eugenics and human reproduction.

Muller often condemned the mainline eugenics movement in the United States, calling it a pseudoscientific dogma based on racial and class prejudices that served the interests of fascists and reactionaries. Eugenic theory generally claimed that since civilized societies no longer permitted the natural elimination of the unfit by starvation and disease, such societies had to limit the reproduction of the unfit and encourage the fit to procreate. This approach assumed that inherited biological factors caused people to be unfit. Muller's commitment to eugenics was very strong, but his ideas were more subtle and complex than those who promoted the mainline creed. He called for detailed studies of twins in order to assess the possibility that nurture as well as nature affected human development. Muller believed that a true science of eugenics should guide human biological evolution in a positive direction. Indeed, he saw eugenics as a special branch of evolutionary science. As indicated by the "Geneticists' Manifesto," signed by Muller and about 20 other scientists, geneticists should encourage a rational change in attitudes towards sex and procreation in order to improve the human gene pool for the sake of future generations.

Because civilized societies had blunted the force of natural selection, Muller feared that undesirable genes would accumulate in the human gene pool until the pool became excessively burdened by defective genes. Muller expressed his concern in a 1949 presidential address on "Our Load of Mutations" to the American Society of Human Genetics. He argued that modern medicine and technology allowed defective genes to accumulate and, therefore, reduced the evolutionary fitness of advanced nations. Geneticists should guide civilized nations towards voluntary eugenic reproductive controls. People with defective genes should refrain from further burdening the gene pool. Those with a good genetic endowment should be encouraged to participate in positive eugenic programs, including "germinal choice"; suitable women should be artificially inseminated with sperm donated by great men. In order to be sure that the men involved were truly worthy, Muller suggested collecting and storing semen from promising candidates and using it only after history had passed its judgment on them.

Deliberately and consciously, Muller used his scientific successes to act as a gadfly to the scientific community and the eugenics movement. He raised serious questions about the dangers of ionizing radiation as well as the wisdom and propriety of attempting to apply eugenic measures to human beings. Muller's discovery of x-ray-induced mutations has had a profound impact on research in essentially every branch of genetics as well as on evolutionary theory and medicine.

LOIS N. MAGNER