An Interview with Manuel Varela and Ann F. Varela:  Hermann Joseph Muller—the Realm of Genetic Mutations

Dec 5, 2020 by

Hermann Joseph Muller - Wikipedia
Hermann Joseph Muller

“To say that a man is made up of certain chemical elements is a satisfactory description only for those who intend to use him as a fertilizer.”

— Hermann Joseph Muller

Michael F. Shaughnessy

1) Like so many other famous scientists, Hermann J. Muller was born in New York City, allowing him access to Columbia University and rich cultural life. When was he born, and interestingly enough—who were some of his relatives?

Nobel Laureate Hermann Joseph Muller would be widely known for his groundbreaking studies in the 1920s that X-rays could artificially induce mutations in the fruit fly. He would also help to shed new light on the nature of the gene. On December 21, 1890, Hermann Muller was born to Hermann Joseph Muller Sr. and Frances Lyons Muller in New York City. In this city, his parents were born. Sadly, Muller’s father died before his son’s tenth birthday. Muller’s parents greatly influenced their son’s character regarding respect for nature and empathy towards humankind.

Muller married his first wife, formerly Jessie Marie Jacobs, a mathematics instructor, in 1923; Jessie had taken her Ph.D. from the University of Chicago. They had one son, David Eugene. With the birth of David, Jessie was consequently dismissed from her teaching position. In 1939, he married Dorothea (“Thea”) Kantorowicz; Thea had been rescued from a concentration camp at the bequest of Prince Carl of Sweden and provided a haven at Edinburgh, where she and Muller met. They have one daughter, Helen Juliette, who is presently professor emerita at the University of New Mexico (UNM) in Albuquerque, NM. Interestingly, Dr. Helen Muller has a daughter who is a faculty at UNM.

Hermann Muller earned his B.A. degree in 1910 and a master’s degree in 1911 at Columbia University. Muller attended the Medical School of Cornell University in 1911 and studied metabolism for about a year.

Muller later joined Morgan’s group back at Columbia in the “Fly Room” in 1912. His focus was on Drosophila genetics and mapping based on Morgan’s experiments. There he wrote a succession of papers on the mechanism of crossing-over of genes. Muller obtained his Ph.D. in 1916. His dissertation launched the principle of the linear linkage of genes in heredity.

In 1915, Muller spent three years in the biology department at the Rice Institute in Houston, Texas. Then, Muller was an instructor for a short time back at Columbia. By 1920, he was an associate professor and later a professor at the University of Texas in Austin until 1932. Muller’s research at UT Austin was his most prolific. Muller devoted about a year at the Kaiser Wilhelm (Max Planck) Institute in Berlin, Germany. He explored the various physical representations for mutations in genes after undergoing a nervous breakdown in 1932 due to personal anxieties.

Throughout his life, Muller thought scientists should be active in educating the public. Muller has contributed over 300 articles to the scientific publications of scholarly societies on biological subjects. His notable books include Genetics, Medicine and Man with C. C. Little and L. H. Snyder, 1947, The Mechanism of Mendelian Heredity with T. H. Morgan and others, 1915 and 1922, and Out of the Night – a Biologist’s View of the Future, published in several editions in 1935, 1936, and 1938.

2) Drosophila melanogaster—the fruit fly—seemed to intrigue Muller (as well as many other scientists). Can you give us the big picture of why Drosophila is so integral to a lot of scientific research?

The common fruit fly, also known by its species name Drosophila melanogaster, became the prime laboratory organism for the early studies of genetics at the beginning of the 20th century.

One might have envisaged easily culturable and manipulatable microbes, like bacteria or viruses that infect bacteria, to be good targets for genetic research. Such advances in genetics using bacteria and phages would not be forthcoming for another 35 years. Early geneticists and molecular biologists made genuine advances in gene expression, replication, and regulation by exploiting bacteria and phages. As members of the famous Phage Group would gladly have attested, scientific advances in genetics did emerge by conducting infections of bacteria with phages and their mathematical analyses of mutants. However, these later new developments would first require acceptance of Mendelian genetics and a better understanding of the biological and chemical natures of the gene. Mendel’s gene factors were either poorly understood or not believed. Phages and bacteria would eventually shed their light on the gene structure but not until their heyday, starting in the 1930s and reaching their peak in the mid-1960s.

Meanwhile, in the early 1900s, it was realized that the fruit fly held certain advantages that the bacteria and phages lacked. On the one hand, bacteria and phages suffered from a lack of clearly visible characteristics. As a group of extremely diverse microorganisms, the bulk of the bacteria and phages had a relatively small number of shapes and other features. With a microscope and chemical stains, investigators could discern only a few bacterial shapes, like rods or spheres. The colors, such as the Gram stain, could reveal that the bacteria either kept or lost the color when washed with an alcohol solution. Thus, the categories of the clear were limited to Gram-positive versus Gram-negative. Likewise, the chemical stain called carbol fuchsin could show whether bacteria were only acid-fast.

While certainly simple in their chemical composition, the bacteriophages were, nevertheless, too tiny to be observed without requiring sophisticated microscopy equipment. The electron microscope had not yet been invented at the turn of the 20th century. During the early advent of genetics, virtually little was known about the nature of Mendel’s factors, i.e., genes and their roles in inheritance, generation of new organismal structures and growth stages, and their propagation into the next generation. At this early juncture, it was not even clear that genetics followed the rules put forth by Gregor Mendel.

On the other hand, the fruit flies harbored distinctive advantages that made them desirable subjects for exploring the nature of the gene. The fruit flies had easily observable phenotypic forms, such as their morphologies and developmental stages. The different types of fly traits were numerous. The organisms, while small, were not nearly as tiny as their bacterial and bacteriophage counterparts. The fruit flies had eyes with different colors, wings with various shapes, and varying sizes and shapes of thoraxes and abdomens. See Figure 63. These traits could be observed with a loupe or a simple microscope. Notably, the morphological structures and forms could be enumerated. The numerical data could be evaluated scientifically. In short order, the fly investigators would break open the field of genetics.

File:Drosophila melanogaster ♀ (38978426500).jpg

https://commons.wikimedia.org/wiki/File:Drosophila_melanogaster_%E2%99%80_(38978426500).jpg

Figure 63. Drosophila melanogaster. (Labels added.)

The flies had discernable male and female structures, and the flies could easily be mated. The generation times were short, on the order of 10 to 12 days. New generations of flies could readily be produced, and their characteristics studied. The mating of any two flies with specific traits could result in a new generation of hundreds of progenies. Their numbers could be tallied, and their fly traits could be connected to genes on particular locations on their chromosomes.

The fruit flies were readily culturable using simple supplies, like glass vials, and culture media, like bananas and agar, both of which were easily attainable. The ease of manipulating fruit flies was made further possible by their relatively cheap costs to maintain in the laboratory.

The importance of the Drosophila melanogaster in the attainment of new knowledge regarding the gene cannot be overstated. Because early investigators had chosen the fruit fly with which to study genetics, significant advances became possible. For example, early investigators assigned specific genes to individual fly traits, like eye color, etc. As time went by, many fly traits were assigned to particular genes. Further, the locations of the trait-specifying genes were traced to precise locations within the fly chromosomes. The gene locations were used as markers to follow their connections (linkages) along the various fly chromosomes. Early geneticists exploited the gene linkages to track gene movements to new locations in the same or different fly chromosomes. See Figure 64. Eventually, a detailed genome map showing each of the 15,682 genes of the fruit fly genome would be constructed. The knowledge of genes and the traits they conferred would become significant for embryology and cell and molecular biology.

https://commons.wikimedia.org/w/index.php?search=drosophila+chromosome&title=Special:Search&go=Go&ns0=1&ns6=1&ns12=1&ns14=1&ns100=1&ns106=1&searchToken=aoxg29g0i8a8tp9i4tw0gd85c#%2Fmedia%2FFile%3ADrosophila_chromosomes.png

Figure 64. Drosophila chromosomes.

One key finding in more recent times has to do with the human immune system and fly genes. An immunity component in flies and humans is called a toll-like receptor. It is embedded in the plasma membrane of a white blood cell called the phagocyte, such as macrophages. The term “toll” arises from the German derivation meaning “fantastic, weird, or strange,” which was used to describe mutant flies with bizarre structural features. In the fruit fly, the toll proteins function in embryonic development. In flies that lack the gene for the toll proteins, the structural components are strange in appearance. Other sources indicate that a toll protein functions to protect fruit flies from fungal infection.

In humans, toll-like receptors bind to surface components of microbial pathogens, like bacteria and viruses. The toll-like receptor binding to the flagellin, lipopolysaccharides, or peptidoglycan molecules of infectious pathogens will stimulate the immune system. The toll-like receptors specifically bind to the pathogens’ surface components, generally called pathogen-associated molecular patterns (PAMP). Upon binding PAMP to toll-like receptors, induction occurs for inflammation, adaptive immunity, and programmed cell death—also called apoptosis.

Molecular biological breakthroughs were garnered by evaluating gene movements, gene mapping, gene expression, and trait determination in the fly genome. These developments would lead to genome projects for many living organisms. Eventually, in 2003, the human genome would be completely mapped. Even the complete nucleotide sequences for each of the human genes would be determined. While over a hundred years in the offing, these sorts of scientific advances had their origins with early genetic studies of the fruit fly chromosomes.

3) I think it worthy of mention that his doctoral advisor was Thomas Hunt Morgan—What did the two of them investigate?

Muller would take his Ph.D. degree in 1915 after having completed his dissertation work in the legendary Fly Room of Professor Thomas Hunt Morgan at Columbia University.

During the academic years 1910 to 1915, Muller was a graduate student. He worked as an instructor at Cornell Medical College until 1912, taking a subway and eating lunch on the run from Columbia to Cornell and back to Columbia to take courses and work in the Fly Room. In the evening, Muller taught English to international students, periodically arriving home late into the night. It was an exhausting schedule. During these early years, Muller’s activities in Morgan’s Fly Room were minimal, and Muller often speculated on genetics rather than conduct experiments. In 1912, Muller took an assistantship position to teach an introductory course at Columbia. The new schedule permitted time to do experiments in Morgan’s Fly Lab.

In Morgan’s lab at Columbia, Muller and a precocious undergraduate named Alfred Henry Sturtevant developed a rivalry. Morgan had hired Sturtevant to work in the Fly Room as a bottle-washing undergraduate. Morgan had conceived the idea that breaks in paired fly chromosomes permitted reciprocal exchanges in genetic material. Sturtevant then suggested that these genetic exchange frequencies potentially allowed one to measure the physical distances between genes with conferred fly traits. Sturtevant would work with another brilliant Fly Room member named Calvin Blackman Bridges. Together, they would begin the construction of the first genome map of the fruit fly.

In the lab, Muller was known as a theoretician, proposing new experiments for Bridges and Sturtevant and a harsh critic of their work. The Fly Room during this era was extremely productive. However, with four strong-willed and intelligent personnel in a small laboratory workspace, Morgan, Sturtevant, Bridges, and Muller created an air of tension, if not outright conflict. Sturtevant’s animosity towards Muller would spill over into his (Sturtevant’s) personal memoir—electing to omit his membership as a Fly Room participant. Muller would write to Sturtevant, reminding him of his presence, even pointing out Muller’s lab desk location, lest Sturtevant should forget in case of future memoirs.

In graduate school, Muller worked with Sturtevant to examine what happened when two genes were located far apart along a fly chromosome. They determined that the crossover numbers’ frequencies for the exchanged genetic material should increase by at least two-fold. As Muller considered the numbers of genes involved in these crossovers, he reasoned that the predicted exchange frequencies occurred faithfully if the outermost genes were sufficiently far apart along the chromosomes. However, the expected exchange frequencies failed to materialize if the genes were close to each other. Therefore, Muller hypothesized the notion of “Interference,” which held that the adjacent genes’ mechanical tension was alleviated by crossover. Thus, the loss of such mechanical tension between paired chromosomal elements prevented, i.e., interfered with, any additional genetic exchanges. In other words, interference involved inhibition of crossing over by another previous crossover event. Any genetic crossovers that did not obey these rules concerning near versus distantly located genes were considered “Coincidence.” A coincident event was the ratio of the proper double-crossovers frequencies to those theoretically predicted and considered independent crossovers. Muller termed this new phenomenon as the “Law of Linear Linkage.” Muller had tried to distinguish his findings from those of Sturtevant and Morgan, who called their recombination events only as “crossing over.”

Another project involving Muller in the Morgan laboratory was abnormally shaped and truncated fruit fly wings. Muller studied genes that affected wings’ structures using adjacent genetic elements along the fly chromosome as markers. In conducting his genetic analyses, Muller discerned that genes specifying fly wings were located on different chromosomes. Muller considered these additional elements as modifiers. This work would prove essential to the idea the specific fly structures, i.e., their wings, were dictated by more than one gene. Muller would locate genes for wings on the X chromosome and the second and third fly chromosomes. In later years, Muller would expand on these findings. He proposed that these multi-genes formed part of a more extensive network of distantly-located genes. They all played a role in specifying a single structural component of the fly—i.e., their wings. It seemed that clustering of a set of genes for one function, like flying, or structure, such as a wing or two, did not transpire. Such indeed would later be the case for structure-function relationships in prokaryotes.

Another accomplishment of Muller in Morgan’s Fly Room involved chasing flies to prevent inadvertent sterilization by repeated ether exposure. Muller had adopted a technique for transferring flies by suction, using a fine glass-fashioned nozzle affixed to a rubber tube. Muller would then insert his glass nozzle through the cotton stoppers that covered the vials of flies and chase the desired flies. Once the nozzle was near the sought-after fly, Muller would quickly inhale and capture the fly. Muller prevented inhaling flies with a fine mesh attached to the glass nozzle. Then Muller would dispense the caught fly into a new vessel by quickly exhaling.

Another project conducted by Muller in Morgan’s laboratory concerned providing an additional line of evidence for the so-called chromosome theory. It held that discrete genes occupied specific locations within distinct chromosomes. According to Mendel’s concepts, the theory predicted that during meiosis, when sperm and egg sex cells are produced, the chromosomes’ behavior could account for genetic and trait inheritances. Muller reasoned that the chromosome theory predicted a one-to-one correlation between the chromosome number and lengths and the linkage map numbers and their sizes. Muller would be fortunate to precisely find these kinds of correlations between genes that specified bent wing structures and their various gene linkage groups.

Muller and Morgan were starkly contrasting figures. They seemed to clash from the very beginning of Muller’s graduate school experience, during his first year. According to Muller, Morgan’s lectures in the classroom were disorganized, chaotic, and poorly developed. Muller was prone to speculation before conducting experiments. In contrast, Morgan maintained a degree of skepticism until supporting or refuting data were available. Initially, during this early fly genetics research, Muller had been a proponent of Mendelian genetics while Morgan had sound disbelief. Morgan became a reluctant advocate of Mendel’s model only later on after a significant amount of supporting data had accumulated—most of it originating in Morgan’s Fly Room. Muller had incorrect disbelief in Morgan’s data in favor of sex determination and Darwin’s evolution theories.

Muller seemed to clash with other members of Morgan’s Fly Room at Columbia, especially in who received the credit for specific scientific discoveries that emanated from the famous lab. For instance, the credit for gene crossing over from one chromosome location to another went primarily to Morgan. Similarly, Bridges got much of the credit for the theory of nondisjunction, i.e., the idea that individual adjacent chromosomes failed to separate during the process of meiosis when forming sex cells. Furthermore, the credit for the concept of gene mapping would fall to Sturtevant. Muller had felt that he deserved credit for his ideas that he had proposed during the various group discussions in the Fly Room. Muller had felt slighted for having been excluded from such credit in Morgan, Bridges, and Sturtevant’s writings. The rift between Muller and members of the Fly Room would last most of their lifetimes.

However, Muller would be a bona fide co-author of the famous genetics book called The Mechanism of Mendelian Heredity, published in 1915. Muller had written the sections on the relationships between the gene and traits, linear gene linkages, the correlation between the linear links of genes along the chromosome, and the linkage maps. The book would become a fundamental contribution to the field of classical genetics in the 20th century.

4) Muller was on the faculty at the University of Texas from 1920 until 1932, a long time indeed—what were his accomplishments there?

After his contract at Columbia was not renewed, Muller moved to Austin, TX, where Dr. John T. Patterson, chair of the Zoology department, hired him. In Austin, Muller would start on the faculty as an associate professor at the University of Texas. In 1926, he would discover that X-rays produced mutations, a discovery for which Muller would earn the 1946 Nobel Prize in the categories of physiology or medicine.

The progress early on at Austin, however, can best be described as a slow start. He had to apply for funding to assemble a new laboratory dedicated to Drosophila melanogaster genetics. Muller had poor luck in finding new spontaneously occurring fruit fly mutants. Furthermore, many of the mutants he did find were of the lethal kind, a situation he had predicted by their absence in genetic ratios. While he found that the deadly mutations were recessive, Muller nevertheless deemed them harmful to the fruit flies’ livelihood.

During this period, he attended a eugenics conference, a controversial field. The discipline aimed at improving the gene pool of humans and other organisms by selective breeding for “positive desirable” traits while discouraging “undesirable negative” ones—the so-called “feeblemindedness” trait comes to mind. While such studies were considered a positive avenue for improving the human condition, the field was unfortunately absconded by less than positive society elements, such as racism.

Unfortunately, eugenics thinking was fraught with shortsightedness and flaws in science and logic. The field of eugenics would suffer many problems. The adoption by Germany’s Nazi Party of the eugenics movement during the 1930s and early 1940s would prove that racism and mass murder were some of the most notorious of unanticipated outcomes. Perhaps these dire consequences were not easily predictable in the 1920s.

History informs us that the concept, adoption, and practices of eugenics is flawed. The selection of “desirable” traits would have the unintended consequences of lowering the gene pool’s diversity. Many diverse characteristics would certainly be needed for the species to survive new changes in environmental conditions. Ethics and morality aside, a so-called desirable eugenic organism, with all of its “positive traits” and none of the “negative” ones, would be less able to meet new challenges in ever-changing situations. Such an engineered eugenic organism would eventually die out. Another major inherent problem with eugenics involved the flawed thinking that certain desirable and undesirable traits were genetically determined, illogically excluding a nurturing environment’s contribution.

Thomas Hunt Morgan was an outspoken opponent of eugenics and would remain so for the entirety of his life. In contrast, while an early proponent of eugenics, Muller would nevertheless disassociate himself from the movement after learning of the prejudices associated with eugenics and their inevitable anti-immigration stance. Such a turnaround would place him in serious trouble with the eugenicists.

In 1923, Muller had begun using radium and X-rays to sterilize the fruit flies’ sex cells specifically. The approach was meant to produce an appropriate genetic background for his lethal mutants and studies of their gene function effects. Muller also learned about the use of X-rays for altering the crossing over frequencies. In his hands, the X-rays did not significantly alter these exchanges in a meaningful way. Another project by Muller and his assistant A. L. Dippel involved X-rays in enhancing the detachment of chromosomes that had presumably undergone Morgan’s nondisjunction phenomenon. However, the experimental effort suffered from a misinterpretation of the resulting data. Their X-ray treatment failed to detach fruit fly chromosomes, and Muller later retracted the publication.

In 1926, he turned his attention to the effect of radiation and mutation. Initially, Muller subjected several of his mutant fruit flies to very high doses of X-ray radiation to sterilize them. One of these mutants, called ClB, would become famous. The ClB fruit fly mutant possessed a crossover suppressor (C) trait. The mutant was recessive lethal (l), and its eyes were bar-shaped (B), a dominant trait. The results were astonishing! Muller observed an enhancement in the induction of mutations on the order of 150 times the background number of spontaneous mutations. He quickly dispatched a manuscript to the journal Science, and the article appeared in print in 1927. Because the sensational paper had little in the way of numerical data, Morgan had feared that Muller had “hanged himself.”

Muller’s later work, which provided further details, revealed a mapping analysis of the X-ray-induced mutations, comparing with spontaneous background mutations. Many of the newly induced mutations were dominant in their ability to kill embryos. Furthermore, Muller showed that the X-rays conferred structural changes in the fruit fly chromosomes, such as inversions, deletions, and gene translocations. Naturally occurring differences in chromosome structures like these were exceedingly rare, and Muller now had hundreds, due to X-rays. In 1932, Muller was world-famous for his mutation discovery work dealing with fruit flies and X-ray radiation.

However, several incidents during the year would significantly affect Muller’s career. One incident concerns his involvement in publishing a newspaper called The Spark sponsored by a left-wing communist-based organization called the National Student League. The students and Muller became surveillance targets of the Federal Bureau of Investigation (FBI). Undercover FBI agents had infiltrated the communist-based organization. The students and Muller’s activities were the topics of an FBI report. Muller’s association with the project had been made known to Dr. H.Y. Benedict, president of the University of Texas at Austin. Such literature on the campus had been expressly banned. Rather than suffering an embarrassing dismissal, Muller would quietly go on a sabbatical to Berlin, Germany.

Meanwhile, a problematic second situation was brewing. In 1932, Muller would commence a series of criticisms leveled at eugenics. He argued that the eugenicists ignored the nurturing environment’s contribution, such as social conditions and economic status, on the individual’s condition or successes. Muller elaborated that it would be complicated to sort out the precise contributions between genetics versus environmental components. Muller also stated that overt sexism in the American workforce would circumvent any progress towards that which the eugenics movement aimed. The pushback from the eugenicists was swift and harsh. Muller’s keynote address to the next eugenics conference was severely curtailed to just 10 minutes to say a few words. The accompanying paper that was to have been published in the conference proceedings was now relegated to the appendix.

Nevertheless, Muller’s shortened speech and the paper was given a broad audience in the press. The presentation was the beginning of the end for the eugenics movement. In ten years, it would be dead.

A third incident was Muller’s disappearance on the 10th of January 1932. Muller was reported to have left his laboratory to head for home, but he never showed up that evening. According to biographer Elof Axel Carlson, Muller went into the wooded area. He wrote what may be considered a suicide note with instructions for publishing his book Out of the Night. He consumed a bottle of sleeping pills. The next morning, Muller was found “dazed but well” by a “posse” of students who searched for him when Muller failed to show up for his university lecture that morning.

Another incident involved Muller and a disastrous speech at a Cornell University scientific conference in Ithaca, New York. During Muller’s address to the attendees of the Sixth International Congress of Genetics, they reported that Muller seemed nervous and spoke incoherently with long pauses. He continually searched for scraps of paper and had a disorganized set of notes. Matters were not helped because the rumors of his breakdown, marital problems, and his fiasco with The Sparks affair circulated beforehand amongst the conference-goers. Thomas Hunt Morgan was in the room and was noted to have said, “Something is wrong with Muller.”

In the texts of the accompanying scientific works, Muller would nevertheless show that he was able to exploit his new mutants to study the effects of gene deletions. In so doing, he would learn a great deal about gene function. Despite his setbacks, Muller’s mutant work dominated much of the genetics research for the duration of the 1920s and 1930s.

5) I find it interesting that Julian Huxley lured Muller to the Rice Institute in Houston. What kind of work did he do there?

Indeed, Julian Sorell Huxley was the grandson of Thomas Henry Huxley, who was a famous evolutionary biologist. In 1912, the younger professor J.S. Huxley became chair of the biology department at Rice. In 1914 offered a post to Muller, who had yet to acquire his Ph.D. from Columbia. Starting in 1915, Muller would spend three years at the Rice Institute in Huston as a biology department member. Huxley was eager to recruit a member of Morgan’s Fly Room group. The new appointment at Rice would be Muller’s first opportunity for establishing himself as an independent investigator. At Rice, Muller taught a course in general biology and studied Drosophila melanogaster flies. It is at Rice where Muller would study lethal fly mutants with abnormal wings. Muller found that the deadly mutation was recessive. In contrast, the so-called beaded wing mutation was dominant and mapped to the fruit fly’s third chromosome.

Based on his analysis of winged mutants, Muller proposed a mechanism for the origin of mutations in a plant called Oenothera larmarckiana, the evening primrose. Hugo de Vries had previously suggested a so-called discontinuous evolution model, which involved converting old species character mutations into new traits. Instead, Muller had proposed that the plant’s modifications were the result of chromosomal crossovers, rather than by changing individual genes, as suggested by de Vries.

Muller further hypothesized that the so-called lethal genes were present in chromosomal pairs, a condition he called “balanced lethals.” These lethals were thought by Muller to prevent a homozygous formation between chromosome alleles, thus maintaining a heterozygous state. However, if a rare crossing over event would occur between the balanced lethal genes, then the chromosomes became homozygous, thus expressing the previously silent recessive genes. Therefore, Muller’s contribution to the field was that the plant “mutations” were due to recombination events rather than point mutations within the plant genes.

6) After Texas, what new adventures seemed to beckon for Muller?

Muller left Texas for Germany after the Great Depression partly due to his socialist views and his opinions about the U.S. society regressing. Inevitably, the rise in Nazism influenced Muller to seek a new laboratory to conduct his research. The Soviet Union provided Muller that haven in 1933. There, he was placed in a laboratory in the Institute of Genetics in Moscow. His position as a senior geneticist lasted for about four years. After that, Muller was forced to seek yet another haven due to Russia’s stance on heredity –they followed Lamarckian views of inheritance. Stalin opposed Morgan’s philosophy of genetics. Thus, those who agreed with Morgan’s theory were terminated or persecuted. Muller noticed that some of his laboratory colleagues were “missing” or sent to Siberia. Muller took this as a sign to relocate.

In 1937, Muller was in Spain for eight weeks, assisting the International Brigade in developing a blood transfusion method from recently killed soldiers. After that, Muller was off to the University of Edinburgh to study X-rays and other mutagens like UV and mustard gas.

The arrival of World War II resulted in Muller heading back to the United States. In 1945, Muller was invited to Indiana University in Bloomington to become a distinguished service professor of zoology. One year later, Muller won the Nobel Prize for his work on mutation-inducing X-rays. He continued his teaching duties and research there until his death. Muller died of congestive heart failure in Indianapolis, Indiana, on April 5, 1967.

7) His Nobel Prize was for “the discovery of the fact that mutations could be produced through X-ray irradiation.” We probably take for granted Muller’s discovery today—but why was this so significant then?

Wilhelm Roentgen had discovered x-rays in 1895. While their uses in medicine and industry had quickly become widespread, the X-rays’ detrimental effects were observed during the late 19th century with burns and cancer development. Later, it was discovered that X-rays fragmented chromosomes into pieces. Studies of toads in 1906 revealed that irradiated individuals produced sex cells that formed embryos with morphological abnormalities. Likewise, direct exposure of fertilized eggs with X-rays produced abnormal structures in their developing embryos. Yet, sperm cells that were subjected to irradiation still maintained their fertilizing functions. Another study revealed that X-rays had a more profound effect on cells undergoing division compared to non-dividing cells. These results implied that X-rays produced their damage at the cell nuclei level and their chromosomal contents. In time, it would be realized that radiation could be effectively used to kill cancerous tissue, which consisted of actively dividing cells.

For Muller’s research program, X-ray utilization would be exceptionally advantageous. From his studies of new mutants that he had generated using X-rays, he would further the field of genetics in fundamental ways. The mutational work facilitated advances in our knowledge of basic chromosome structure. He learned about gene function by deleting specific genes and measuring the outcomes of mutant fruit flies’ anatomical structures. Importantly, Muller’s work with mutants would provide new insights into the mechanisms involved in evolution.

Other investigators soon followed Muller’s X-ray technique to induce mutations and study their effects on the resulting mutant organisms. Plant and animal biologists soon began producing new mutants on their own. Microbial biologists would study mutant bacteria and bacteriophage viruses and further advances in genetics like gene structure, viral replication, and gene expression regulation. Studies of microbial mutants led to new advances in DNA replication mechanisms, RNA transcription, and protein translation. Gene mapping for various organisms became possible for many organisms, such as plants, animals, bacteria, and viruses.

Muller’s X-ray mutation induction work in 1927 would become relevant to human medicine. He noted X-rays’ propensity to produce mutations in the genetic material of living cells. Thus, humans serving as healthcare providers, like physicians and X-ray technicians, and their patients risked hazardous exposure and would suffer detrimental effects. However, Muller’s warnings went unheeded until 1945, with the atomic bomb’s invention and its dramatic impact on Hiroshima and Nagasaki’s victims.

In modern times, the study of mutants is an ongoing research activity for many life sciences, medicine, biomedicine, and molecular biology. Structure-function studies became possible to determine the biological function of any protein. First, one produces a mutation that destroys the molecule. Then, the effects on biochemistry, cell biology, and physiology are measured. This molecular biological approach is frequently used in the study of protein chemistry. New molecular structures and their inactivating mutations are generated in the cell as well as in computer simulations.

Induction of mutations, generated physically by Muller, can also be accomplished chemically, with mutagenic compounds. The changes in DNA base sequences, whether caused physically or chemically, can be faithfully made to produce their gene products in vivo (in an organism) or in silico (in a computer simulation). The mutated gene products can then be created and studied in molecular detail. There is no doubt that studies of mutants will continue for many years to come.

8) Berlin, Edinburgh, and Leningrad were all fortunate enough to have him with their students. Briefly—what did he accomplish in each country?

Starting in late 1932, Muller would tour Europe, a sojourn that would last eight years. Choosing to leave the U.S. for Europe was described as more of a push out than a pull abroad.

Muller’s tenure at Berlin was troublesome. Germany was in upheaval during the 1930s. Though Muller spent about one year in Germany, it was a tumultuous one due to Hitler’s policies and the Nazi Party. Muller was present during the persecution of people of Jewish descent and book burnings!

Muller arrived in Berlin, Germany in November of 1932, and lived in a guesthouse at the Kaiser Wilhelm Institute for Brain Research. His work consisted of editing his book, Out of the Night, which would eventually be published in 1935. In Berlin, Muller collaborated with Russian biologist Nikolaj Vladimirovich Timoféeff-Ressovsky. They studied radiation dosages and wavelengths on the mutational frequencies in fruit flies. Their work had implications for radioactive ionization and mutations within individual genes. Muller also studied the mechanisms of chromosome breakages due to physical events.

The precarious situation in Berlin grew more tenuous with the persecution of Professor Oscar Vogt and his family. Dr. Vogt had hired Muller and sponsored his visit to Germany. The Nazis invaded and damaged Prof. Vogt’s house and threatened him and his daughter Margaret for their refusal to make an oath to Hitler’s Nazi Party. The Nazi invaders also physically attacked the laboratory workers of the Institute, knocking some of them unconscious, an incident that Muller had personally witnessed. With genetics research in Germany in tatters and a return to Texas untenable, Muller chose to accept an offer in Leningrad, Russia.

Muller arrived in Leningrad at the Institute of Genetics in September of 1933. During Muller’s tenure there, he engaged in a lecture tour throughout the country. Muller spoke about the flaws of eugenics. He also attacked Lamarckism, which was still prevalent in the Soviet Union. He saved much of his ire for Morgan and his younger collaborators.

Meanwhile, in the Leningrad laboratory, Muller studied genetics from a cytological perspective. He analyzed fruit fly genes that were mapped to the extreme distal end of the X chromosome. Using his X-ray mutation technique on males, Muller focused on genes that governed body color and bristle structure. Next, Muller crossed the mutant males with normal females by mating them. He found that the ensuing generation exhibited chromosome rearrangements in the regions where the genes for the body color and bristle structures were housed.

Muller also found that specific genes were missing in the new generation of fruit flies. The missing genes were presumably the result of chromosome breakages. One gene deletion mutation, in particular, turned out to have a lethal consequence. The affected gene was denoted scute-19, and it had been mapped previously on the X chromosome.

Muller moved to Moscow in December of 1934. If Muller’s stint in Berlin was troublesome, his tenure in Moscow was turbulent. To begin with, he had trouble with adequate housing and squatters. Muller soon encountered difficulty with one of Russia’s most famous scientists, Trofim D. Lysenko, who wagered an entire country’s food crops based on a Lamarckian fallacy. The nationwide experiment of waiting for plant seeds to evolve based on the harsh cold environment was a spectacular failure.

In Muller’s Moscow laboratory, an interesting mutation was discovered. The mutant fly had a duplication of a gene region on the chromosome called “bar,”and he dubbed it “double bar.” The mutant eye phenotype was small and bar-shaped eyes. Interestingly, Calvin Bridges had just published the same mutation in fruit flies from his lab. Muller thought he had been “scooped.” Whatever the case, it was a disappointment for Muller and his group.

The political situation in the U.S.S.R. in the mid-1930s was becoming dire, with arrests and executions as mandated by Stalin. In 1936, Muller was asked by university officials to return to Austin and answer questions about past dealings with The Spark. Muller chose to resign his professorship at Texas instead. Yet, during this tenure in Russia, Muller had a prodigiously productive period of investigation. He had delved into fruit fly chromosome rearrangement, gene sizes, gene number, gene loci within chromosomes, chromosome breakage points, gene mutation, and physiological effects of temperature and age on radiation-induced genetic mutation. Despite these advances in genetics by Muller in Russia, his clash with Lysenko would instill Stalin’s ire after a public debate.

In November of 1937, Muller moved to the University of Edinburgh in Scotland, where he took a new position at the Institute of Animal Genetics. At Edinburgh, Muller used ultraviolet (UV) radiation to induce mutations in fruit flies. He and members of his new laboratory analyzed the various UV dosages needed for gene mutation. They found that UV light generated precise mutations in the genes rather than large changes in chromosome rearrangement. Muller also studied the various dosage rates for X-rays and mutation. Muller also had an interest in chemical means of generating mutations in the chromosomes of the fruit flies.

During Muller’s tenure in Edinburgh, he spent a summer at the Marine Biological Laboratory in Woods Hole, MA. He took the famous physiology course and wrote an article titled “The Remaking of Chromosomes.” The paper would become a classic in the literature of genetics. An enjoyable situation for Muller was that none of Sturtevant’s camp had been at Woods Hole that summer.

His Edinburgh work entailed a new proposal that an inversion mutation could involve two chromosome breakage events. He further speculated that inversions could have distinct phenotypic outcomes depending on whether one or both arms of chromosomes broke during the inversion process. Another significant finding at Edinburgh involved his work with a graduate student named S. P. Ray-Chaudhuri. They fine-tuned the radiation doses of radium to pregnant fruit flies in such a manner as to generate high numbers of mutations with small amounts. The new work was significant because radioactive materials could cause precise mutations within genes. It meant that laboratory workers needed to shield themselves from the effects of radioactive and X-ray exposures. Even minute traces of radioactive materials were now considered hazardous! There was pushback by the medical establishment. It would be years before Muller was taken seriously on the potential hazards of radiation on human beings.

9) In summary—what can we say were his most significant accomplishments?

Hermann Muller suffered from clashes with other investigators who were competitors at best and nemeses at worst. He felt that he had not been appropriately credited for many of his contributions. There were indeed many such enduring contributions by Dr. Muller to the field of fly genetics involving members of the Fly Room of Morgan’s at Columbia. For instance, Muller was a prominent figure who provided theoretical contributions involving searches for genetic markers in fruit fly chromosomes. He made contributions to early discussions involving genetic recombination in the manner of crossing over in Drosophila melanogaster. He contributed to the conversations of nondisjunction in female flies who had an additional Y chromosome. Muller participated in Fly Room discussions for the measurements of rates of gene deletions and translocations.

Muller contributed to the chromosome theory of inheritance in fruit flies. He had focused on the nature of the individual gene and the generation of mutations within these fly genes. Muller had analyzed gene mutation rates, the work of which was the main feature in new advances in molecular biology in the 1950s and 1960s. Interestingly, Muller’s studies of the gene were in line with later findings by molecular biologists. In Muller’s heyday of the 1920s through the early 1950s, it was unknown whether the gene was nucleic acid or protein in its chemical nature.

Muller is generally credited for his work on chromosome and gene structure in fruit flies. He had provided keynote evidence for the presence of so-called modifiers and “chief genes.” Today we understand these elements to have regulatory and cooperative roles in the expression of genes.

According to historians of genetics, it is likely that Muller’s most important scientific contribution relies heavily upon his discovery that X-rays induce mutations in the genetic material of the fruit flies. As mentioned above, studies of mutations and mutants are still relevant in modern times. Undoubtedly, studies of mutants will continue to occupy the minds of many disparate fields of the biological and medical sciences for the unforeseeable future.

Another remarkable discovery by Muller is represented by his work with mutations that conferred lethality. He had shown that such “lethals” involved broken chromosomes and genetic rearrangements. The lethal mutant work would shed light on the mechanism of chromosome separation during meiosis.

Astutely using his mutagenesis methodology with radiation, Muller was able to make significant strides with gene sizes, structures, and functions. He touched upon the linearity of the genes along the length of the fruit fly chromosomes. Muller had observed that when the linearized systems of genes were disrupted, gene functions were likewise disrupted.

In terms of evolution, Muller addressed the nature of his mutations in their effects on natural selection and adaptation. Muller had studied how gene mutation and rearrangements in his modifiers and “chief genes” served as barriers to certain crossovers, leading to new speciation within a population.

As mentioned above, Muller had played with varying dosages of radioactive substances and efficiency of generating mutations in the fruit flies’ genes. In so doing, Muller would set the stage for later discoveries of the regulation of gene activities.

Muller’s work also applied to humans. In particular, one area dealt with genetic load involving previous and new mutations from generation to generation. Muller had analyzed mutation rates and the outcomes of harmful genes upon allelic relationships. Muller had speculated that humans in prehistoric times had a balanced genetic load. The successive generations needed to maintain the genetic balance to have their lines survive. Humans with high genetic limitations would disappear from the evolutionary tree.

Muller was a tragic figure in his personal and scientific lives, especially in his choices of locations to pursue his genetics studies. He experienced depression, and he suffered a nervous breakdown and divorce. Muller found to his dismay that he was at odds with influential scientific and political figures.

In addition to his vast array of scientific accomplishments, complete with a Nobel Prize, Muller was a key figure in politics and social reform. In Texas, he fled the injustices inherent in its tolerance of overt racism, class structure, and the poor’s exploitation for financial gain. In Germany, Muller faced rampant racism, anti-Semitism, book burnings, persecution of the educated, especially his fellow scientist colleagues. In Russia, he had to deal with the popularity of a flawed and fundamentally debunked scientific field of Lamarckism, as well as disappearances of his students and colleagues and the terrorism of a Fascist police state.

Despite his disappointments with scientific credit, Herman J. Muller was highly celebrated. In 1927, Muller received the Newcomb Cleveland Prize, and in 1931, Muller was elected to the U.S. National Academy of Sciences. As mentioned earlier, Muller took the 1946 Nobel Prize in Physiology or Medicine. In 1955-1959 Muller served as president of the American Humanist Association and president of the American Society of Human Genetics. Muller received the Linnean Society of London’s Darwin–Wallace Medal (1958), and in 1963, Muller received the Humanist of the Year Award and became a Foreign Member of the Royal Society.

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