The 2000 GSA Honors and Awards

The 2000 T. H. Morgan Medal Essay: H. J. Muller and the Nature of the Gene

Corresponding author: Evelyn M. Witkin, Princeton, NJ 08540.

GENETICS was at a turning point in the early 1940s. The classical period had matured and was ripe for the transition to the molecular era. Geneticists had established that a gene has a precise location on a particular chromosome. They had explained the transmission of genes in heredity, and their recombinations, by the dance of the chromosomes in meiosis. They had characterized and mapped hundreds of mutants in Drosophila, mice, maize, and other organisms. A good many of the complexities and subtleties of heredity had yielded to their analysis, including sex linkage, crossing over, nondisjunction, pleiotropy, position effects, epistasis, and quantitative inheritance. The neo-Darwinian "new synthesis" had united genetics and Darwinian evolution, which had long been considered incompatible. The gene itself, however, remained almost as abstract and operational a concept as the "factor" had been to Mendel. Most of the geneticists of the Morgan school, and indeed, most classical geneticists, had felt no need to concern themselves with the chemical basis of genes or mutations.

The beginning of molecular genetics is usually marked by the "one-gene one-enzyme" hypothesis of George Beadle and Edward Tatum, by Max Delbruck's choice of bacteriophage as a way to understand the gene, or by Salvador Luria's demonstration, with Delbruck, that bacteria have real genes and are suitable material for genetics. There was also Erwin Schrodinger's 1944 book, What Is Life, which attracted so many physicists to genetics. Taken together, all of these served powerfully to focus attention on the need to solve the mysteries of gene structure, gene replication, and gene action at the molecular level (JUDSON 1979 ). The discovery of sex in bacteria (LEDERBERG and TATUM 1946 ) turned Escherichia coli into a model system for genetics. The revolution was off and running.

Like most revolutions, this one was foreshadowed by earlier precursors. Most notably, Archibald Garrod concluded that each of the individual Mendelian gene mutations responsible for certain human hereditary diseases had inactivated a particular metabolic enzyme (GARROD 1909 ). By 1920, the gene's remarkable autocatalytic capability had become the subject of attention and speculation. But throughout the '20s and '30s one geneticist, Hermann J. Muller, thought more deeply, wrote more extensively, and spoke more passionately about the nature of the gene than anyone else. Indeed, Muller laid the conceptual foundation of molecular biology to an extent that is not generally recognized. E. O. Wilson has said that progress in a field of science is measured by how soon its founders are forgotten. Perhaps, but H. J. Muller's pioneering contributions to gene theory deserve to be remembered.

By the age of nineteen, in 1909, Muller had already become committed to genetics and to the chromosome theory of heredity. He was then an undergraduate at Columbia University studying with cytologist Edmund B. Wilson. His avid reading of physiologist Jacques Loeb's books convinced him of the physicochemical basis of biological phenomena. This conviction strongly influenced his thinking as he began, not much later, to develop a theory of the gene (CARLSON 1981 ).

Muller, a brilliant young maverick full of enthusiasm and bursting with ideas, went on to do graduate work on Drosophila under Thomas Hunt Morgan in Columbia's famous "fly room." He made major contributions to the work of that historic group and became one of the coauthors of Morgan's classic The Mechanism of Mendelian Heredity. In 1915, armed with his new Ph.D., he accepted a position in Texas and initiated an independent and radically new line of research. He decided to study the individual gene and its mutations as a way to gain information about gene structure. His idea that one ought to be able to measure mutation rates seemed bizarre to Morgan's group, who were used to depending on pure luck to find an occasional mutant. Muller was later awarded the Nobel Prize in Medicine for his discovery in1927 that X rays induce mutations in Drosophila, a discovery that depended on his first developing an ingenious method to detect and quantify lethal mutations. It was his conviction that genes must be extraordinarily stable chemical structures, and his intense desire to understand that structure, that led him to consider high-energy radiation as a likely mutagen.

The depth and prescience of Muller's thinking about the nature of the gene are already evident in a remarkable speech that he delivered to the American Association for the Advancement of Science in 1921 and published a year later (MULLER 1922 ). He had been developing his concept of the gene for over a decade, and here he distilled its most salient features. Some of them are briefly summarized below.

The size and complexity of the gene:
Muller concluded that the gene is ultramicroscopic in size. He estimated its maximum size by dividing the known length of one of the large Drosophila chromosomes by the minimum number of genes known to be contained on it. He believed that the gene must be complex in structure, based in part upon its extraordinary capacity for autocatalysis and also upon the existence of multiple alleles, which indicated that a gene can exist in several different stable states.

The gene as the basis of life:
That the gene is the basis of life was a theme of Muller's from his earliest writings. He believed that genes "play a fundamental role in determining the nature of all cell substances, cell structures and cell activitities" thereby affecting the character of the entire organism. This was far from appreciated in the '20s, even by most geneticists, and certainly not by most other biologists. Genetics was widely seen as a peripheral subdiscipline of biology, concerned primarily with the heredity and variation of superficial traits. Whereas today we might more accurately say that life depends upon the coexistence of nucleic acids and proteins, Muller's early recognition of the pivotal and pervasive role of genes was a profound insight.

The relation between gene and character:
Because a pair of genes, in some cases, determines the presence or absence of an enzyme or of a certain agglutinin in the blood, Muller pointed out, it would be absurd to conclude that the gene itself is an enzyme or an agglutinin. He believed that the relation between gene and character is highly complex and depends upon "an intricate and delicately balanced system of reactions, caused by the interaction of countless genes." Every aspect of an organism's structure or activities may therefore become altered in some way when this reaction system is perturbed by a mutation in any of the component genes. Muller was led toward this position when he found that numerous modifier genes, mapping far from a particular mutation, could alter the expression of the mutant phenotype. It would be many years before it became the prevailing view in genetics.

Mutable autocatalysis:
The most distinctive property of the gene, said Muller, is its capacity for self-propagation, or autocatalysis, whereby it converts some of the surrounding cytoplasmic material into an end product identical with itself. This reaction "is in each instance a rather highly localized one, since the new material is laid down by the side of the original gene." (At the time, of course, it was not known that the gene's apparent self-propagation requires the participation of numerous extragenic elements such as enzymes and other proteins.)

The self-duplicating capacity of the gene had been noted many times by others, but Muller recognized and emphasized an aspect of this property that had not been appreciated. He pointed out that the most remarkable aspect of the gene's autocatalytic capacity is that it duplicates its changes. A change in the gene—a mutation—results not in the destruction of its autocatalytic power but in a modification of the autocatalytic process that now duplicates the altered gene. Since this phenomenon, which he called "mutable autocatalysis," persists through change after change in the gene, it must depend upon "some general feature of gene construction, common to all genes, which gives each one a general autocatalytic power—a `carte blanche'—to build material of whatever specific sort it itself happens to be composed of." How easily this 1921 inference of Muller's translates into the biochemical language of DNA!

The central issue in genetics:
The most fundamental question of genetics, Muller asserted, is how to explain "the general principle of gene construction that permits this phenomenon of mutable autocatalysis." This formulation of the field's prime challenge had no great impact at the time, nor did it take center stage until some 20 years later, when Delbruck and his phage group, and then Schrodinger, defined the central issue in genetics in much the same way. Delbruck, who met Muller at a conference in Denmark in 1933, may have been familiar with some of his ideas. Schrodinger, a physicist who had probably not read Muller's papers, may have assumed that this was the conventional wisdom in genetics, as indeed by 1944, thanks largely to Muller, it had come to be. Elof Carlson, in an article on Muller's contributions to gene theory (CARLSON 1971 ), has called What Is Life "an unacknowledged physical paraphrase of Muller."

Genetics and evolution:
Perhaps the most far-reaching conclusion that Muller described in his 1921 speech was that the gene's unique capacity for mutable autocatalysis "lies at the heart of organic evolution, and hence of all the vital phenomena which have resulted from evolution." He asserted that any materials having this capacity would automatically evolve, becoming at first different from other inorganic matter, and then increasing in the "complexity, diversity and so-called `adaptation' of the selected mutable material." Thus, Muller was an early neo-Darwinian, evoking mutable autocatalysis as the key to the origin and evolution of life, at a time when many leading geneticists, including Morgan and Bateson, were not convinced that Mendelian genetics had any relevence to evolution as Darwin envisaged it. They could not reconcile the kinds of mutations they were observing with Darwin's idea that evolutionary change occurs gradually through the cumulative natural selection of small variations. Muller, however, noted that, in Drosphila, "the smaller character changes occur oftener than the larger ones ... and this raises the question of how many mutations are absolutely unnoticed, affecting no character, or no detectable character, to any appreciable extent at all."

Bacteriophage as an approach to the gene:
Near the end of his talk, Muller called attention to the recent discovery of a "striking phenomenon, which must not be neglected by geneticists. This is the d'Herelle phenomenon." In 1917, d'Herelle had discovered a self-propagating filterable substance capable of dissolving dysentary bacilli, later identified as bacteriophage. Muller pointed out that the d'Herelle substance met the definition of an autocatalytic substance, and since it existed in different varieties, must share with the gene the capacity for mutable autocatalysis. He said "... if these d'Herelle bodies were really genes, fundamentally like our chromosomal genes, they would give us an utterly new angle from which to attack the gene problem. It would be very rash to call these bodies genes, yet there is no distinction between genes and them. Hence we cannot categorically deny that perhaps we may be able to grind genes in a mortar and cook them in a beaker after all. Must we geneticists become bacteriologists, physiological chemists and physicists, simultaneously with being zoologists and botanists? Let us hope so."

Muller went on to write a great many papers, expanding and refining his ideas about the nature of the gene and fleshing them out with vast amounts of data (MULLER 1962 ). In 1927, he published his landmark paper demonstrating the power of X rays to induce lethal, semilethal, and visible mutations in Drosophila (MULLER 1927 ). It had taken him years to develop the stocks and crosses necessary to detect and quantify induced lethal mutations. This article created worldwide excitement, brought Muller worldwide recognition and broadly extended the influence of his thinking. Important as this and others of his later articles were, the article based on his 1921 speech remains noteworthy for its avant garde perceptions and insights. It can be read as an early prologue to the drama of molecular biology.

In later years, Muller could still cut to the heart of a new phenomenon in genetics. When Avery, McCleod, and McCarty, in 1944, showed that the Pneumococcus transforming factor was DNA, Muller, like most geneticists, was not immediately convinced that this result established DNA as the material of the gene. But OLBY 1974 reports that in 1946, at a conference in New York, when Delbruck described a similar result he had obtained with bacteriophage, Muller put forward the following idea: "To my mind, this suggests strongly that in both Delbruck's and Avery's cases what really happens is a kind of crossing over between chromosomes or protochromosomes of the killed inducer strain and those of the viable strain." That, of course, is precisely what happens in transformation.

Muller's research output was prodigious. He was preeminent in the fields of mutagenesis and radiation biology. He was also a committed humanist, who worked actively for world peace, for limiting nuclear proliferation, for the improvement of humanity through genetics, and against all forms of authoritarianism. He lived until 1967 and so had the deep satisfaction of seeing Watson and Crick and Wilkins and Franklin take up his challenge and show how mutable autocatalysis follows from the structure of DNA.

Author's note: I read Muller's 1922 paper in the library of Columbia's Department of Zoology during the first year of my graduate work there. It transformed the way I thought about the gene and was largely responsible for my decision to work on mutagenesis.

LITERATURE CITED

CARLSON, E. A., 1971  An unacknowledged founding of molecular biology: H. J. Muller's contributions to gene theory, 1910–1936. J. Hist. Biol. 4:149-170[Medline].

CARLSON, E. A., 1981 Genes, Radiation and Society: The Life and Work of H. J. Muller. Cornell University Press, Ithaca, NY/London.

GARROD, A., 1909 Inborn Errors of Metabolism. Oxford University Press, London.

JUDSON, H. F., 1979 The Eighth Day of Creation: The Makers of the Revolution in Biology. Simon & Schuster, New York.

LEDERBERG, J. and E. L. TATUM, 1946  Novel genotypes in mixed cultures of biochemical mutants of bacteria. Cold Spring Harbor Symp. Quant. Biol. 11:113-114.

MULLER, H. J., 1922  Variation due to change in the individual gene. Am. Nat. 56:32-50.

MULLER, H. J., 1927  Artificial transmutation of the gene. Science 66:84-87.

MULLER, H. J., 1962 Studies in Genetics. University of Indiana Press, Bloomington.

OLBY, R., 1974 The Path to the Double Helix. University of Washington Press, Seattle.

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