Muller was born in  New York City , the son of Frances (Lyons) and Hermann Joseph Muller Sr., an artisan who worked with metals. Muller was a third-generation American whose father's ancestors were originally Catholic and came to the United States from  Koblenz . [ 3 ]  His mother's family was of mixed  Jewish  (descended from  Spanish and Portuguese Jews ) and Anglican background, and had come from Britain. [ 3 ] [ 4 ]  Among his first cousins was  Alfred Kroeber  (Kroeber was  Ursula Le Guin 's father) and first cousins once removed was  Herbert J. Muller . [ 3 ]  As an adolescent, Muller attended a  Unitarian  church and considered himself a  pantheist ; in high school, he became an  atheist . [ 5 ]  He excelled in the public schools. At 16, he entered  Columbia College . From his first semester, he was interested in biology; he became an early convert of the  Mendelian - chromosome  theory of heredity—and the concept of genetic  mutations  and  natural selection  as the basis for  evolution . He formed a biology club and also became a proponent of  eugenics ; the connections between biology and society would be his perennial concern. Muller earned a  Bachelor of Arts  degree in 1910. [ 6 ]


Muller remained at Columbia (the pre-eminent American zoology program at the time, due to  E. B. Wilson  and his students) for graduate school. He became interested in the  Drosophila  genetics work of  Thomas Hunt Morgan 's fly lab after undergraduate bottle washers  Alfred Sturtevant  and  Calvin Bridges  joined his biology club. In 1911–1912, he studied metabolism at  Cornell University , but remained involved with Columbia. He followed the  drosophilists  as the first genetic maps emerged from Morgan's experiments, and joined Morgan's group in 1912 (after two years of informal participation). [ 7 ]


In the fly group, Muller's contributions were primarily theoretical—explanations for experimental results and ideas and predictions for new experiments. In the emerging collaborative culture of the drosophilists, however, credit was assigned based on results rather than ideas; Muller felt cheated when he was left out of major publications. [ 8 ]


In 1914,  Julian Huxley  offered Muller a position at the recently founded William Marsh Rice Institute, now  Rice University ; he hurried to complete his  Doctor of philosophy  degree and moved to Houston for the beginning of the 1915–1916 academic year (his degree was issued in 1916). At Rice, Muller taught biology and continued  Drosophila  lab work. In 1918, he proposed an explanation for the dramatic discontinuous alterations in  Oenothera lamarckiana  that were the basis of  Hugo de Vries 's
theory of  mutationism : "balanced lethals" allowed the accumulation of recessive mutations, and rare  crossing over  events resulted in the sudden expression of these hidden traits. In other words, de Vries's experiments were explainable by the Mendelian-chromosome theory. Muller's work was increasingly focused on  mutation rate  and  lethal mutations . In 1918, Morgan, short-handed because many of his students and assistants were drafted for the U.S. entry into  World War I , convinced Muller to return to Columbia to teach and to expand his experimental program. [ 9 ]


At Columbia, Muller and his collaborator and longtime friend  Edgar Altenburg  continued the investigation of lethal mutations. The primary method for detecting such mutations was to measure the sex ratios of the offspring of female flies. They predicted the ratio would vary from 1:1 due to recessive mutations on the X chromosome, which would be expressed only in males (which lacked the functional allele on a second X chromosome). Muller found a strong temperature dependence in mutation rate, leading him to believe that spontaneous mutation was the dominant mode (and to initially discount the role of external factors such as ionizing radiation or chemical agents). In 1920, Muller and Altenburg coauthored a seminal paper in  Genetics  on "modifier genes" that determine the size of mutant  Drosophila  wings. In 1919, Muller made the important discovery of a mutant (later found to be a  chromosomal inversion ) that appeared to suppress crossing over, which opened up new avenues in mutation-rate studies. However, his appointment at Columbia was not continued; he accepted an offer from the  University of Texas  and left Columbia after the summer of 1920. [ 10 ]


Muller taught at the University of Texas from 1920 until 1932. Soon after returning to Texas, he married mathematics professor  Jessie Marie Jacobs , whom he had courted previously. In his early years at Texas, Muller's  Drosophila  work was slow going; the data from his mutation rate studies were difficult to interpret. In 1923, he began using  radium  and  X-rays , [ 11 ]  but the relationship between radiation and mutation was difficult to measure because such radiation also sterilized the flies. In this period, he also became involved with eugenics and human genetics. He carried out a study of twins separated at birth that seemed to indicate a strong hereditary component of  I.Q.  Muller was critical of the new directions of the eugenics movement (such as anti-immigration), but was hopeful about the prospects for positive eugenics. [ 12 ] [ 13 ]   In 1932, at the  Third International Eugenics Congress , Muller gave a speech and stated, "eugenics might yet perfect the human race, but only in a society consciously organized for the common good". [ 14 ]


In 1926, a series of major breakthroughs began. In November, Muller carried out two experiments with varied doses of X-rays, the second of which used the crossing over suppressor stock ("ClB") he had found in 1919. A clear, quantitative connection between radiation and lethal mutations quickly emerged. Muller's discovery created a media sensation after he delivered a paper entitled "The Problem of Genetic Modification" at the Fifth International Congress of Genetics in  Berlin ; it would make him one of the better-known public intellectuals of the early 20th century. By 1928, others had replicated his dramatic results, expanding them to other  model organisms , such as  wasps  and  maize . In the following years, he began publicizing the likely dangers of radiation exposure in humans (such as physicians who frequently operate X-ray equipment or shoe sellers who radiated their customers' feet). [ 15 ]


His lab grew quickly, but it shrank again following the onset of the  Great Depression . Especially after the stock market crash, Muller was increasingly pessimistic about the prospects of  capitalism . Some of his visiting lab members were from the  USSR , and he helped edit and distribute an illegal leftist student newspaper,  The Spark . It was a difficult period for Muller both scientifically and personally; his marriage was falling apart, and he was increasingly dissatisfied with his life in Texas. Meanwhile, the waning of the eugenics movement, ironically hastened by his own work pointing to the previously ignored connections between environment and genetics, meant that his ideas on the future of human evolution had reduced impact in the public sphere. [ 16 ]  Muller's speech before the  Third International Eugenics Conference  in New York has been credited with marking the end of  Galtonism , and perhaps even  eugenics  itself, as a popular movement in the sciences.  H. Bentley Glass , a contemporary observer and Ph.D. student of Muller's, would say Muller's speech "just about finished the activity of the Eugenics Society". [ 17 ]  Muller told the assembled that eugenic ideals could no longer be achieved, because the capitalistic system produces the wrong motives of individual action, and he disdained the natures of the dominant class, and the type of society they were creating. [ 18 ]


In September 1932, Muller moved to Berlin to work with the Russian expatriate geneticist  Nikolay Timofeeff-Ressovsky ; a trip intended as a limited sabbatical stretched into an eight-year, five-country journey. In Berlin, he met two physicists who would later be significant to the biology community:  Niels Bohr  and  Max Delbrück . The  Nazi  movement was precipitating the rapid emigration of scientific talent from Germany, and Muller was particularly opposed to the politics of National Socialism. The FBI was investigating Muller because of his involvement with  The Spark , so he chose instead to go to the Soviet Union (an environment better suited to his political beliefs). In 1933, Muller and his wife reconciled, and their son  David E. Muller  and she moved with Hermann to  Leningrad . There, at the Institute of Genetics, he imported the basic equipment for a  Drosophila  lab—including the flies—and set up shop. The institute was moved to  Moscow  in 1934, and Muller and his wife were divorced in 1935. [ 19 ]


In the USSR, Muller supervised a large and productive lab, and organized work on medical genetics. Most of his work involved further explorations of genetics and radiation. There he completed his eugenics book,  Out of the Night , the main ideas of which dated to 1910. [ 20 ]  By 1936, however,  Joseph Stalin 's repressive policies and the rise of  Lysenkoism  was making the USSR an increasingly problematic place to live and work. Muller and many of the Russian genetics community did what they could to oppose  Trofim Lysenko  and his  Larmarckian  evolutionary theory, but Muller was soon forced to leave the Soviet Union after Stalin read a translation of his eugenics book and was "displeased by it, and...ordered an attack prepared against it." [ 21 ]  By this time, Muller had already asked for a leave of absence. News of the  Lysenko  trials had reached the United States, and his son David was being raised there, after his divorce. [ 22 ]  In the official declaration by the Institute, biological determinism was rejected: "The development of society is subject not to biological laws but to higher social laws. Attempts to spread to humanity the laws of the animal kingdom are an attempt to lower the human being to the level of beasts." [ 23 ]


Muller, with about 250 strains of  Drosophila , moved to  University of Edinburgh  in September 1937, after  brief stays in  Madrid  and  Paris . In 1938, with war on the horizon, he began looking for a permanent position back in the United States. He also began courting Dorothea "Thea" Kantorowicz, a German refugee; they were married in May 1939. The Seventh International Congress on Genetics was held in Edinburgh later that year; Muller wrote a "Geneticists' Manifesto" [ 24 ]  in response to the question: "How could the world's population be improved most effectively genetically?" He also engaged in a debate with the perennial genetics gadfly  Richard Goldschmidt  over the existence of the gene, for which  little direct physical evidence existed at the time. [ 25 ]


When Muller returned to the United States in 1940, he took an untenured research position at  Amherst College , in the department of  Otto C. Glaser . After the U.S. entry into  World War II , his position was extended indefinitely and expanded to include teaching. His  Drosophila  work in this period focused on measuring the rate of spontaneous (as opposed to radiation-induced) mutations. Muller's publication rate decreased greatly in this period, from a combination of lack of lab workers and experimentally challenging projects. However, he also worked as an adviser in the  Manhattan Project  (though he did not know that was what it was), as well as a study of the mutational effects of  radar . Muller's appointment was ended after the 1944–1945 academic year, and despite difficulties stemming from his socialist political activities, he found a position as professor of zoology at  Indiana University . [ 26 ]   Here, he lived in a  Dutch Colonial Revival  house in  Bloomington 's  Vinegar Hill  neighborhood. [ 27 ]


In 1946, Muller was awarded the  Nobel Prize in Physiology or Medicine , "for the discovery that mutations can be induced by X-rays". Genetics, and especially the physical and physiological nature of the gene, was becoming a central topic in biology, and X-ray mutagenesis was a key to many recent advances, among them  George Beadle  and  Edward Tatum 's work on  Neurospora  that established in 1941 the  one gene-one enzyme hypothesis . [ 28 ]  In Muller's Nobel Prize lecture, he argued that no threshold dose of radiation existed that did not produce  mutagenesis , which led to the adoption of the  linear no-threshold model  of radiation on cancer risks. [ 29 ]


The Nobel Prize, in the wake of the  atomic bombings of Hiroshima and Nagasaki , focused public attention on a subject Muller had been publicizing for two decades - the dangers of radiation. In 1952,  nuclear fallout  became a public issue; since  Operation Crossroads , more and more evidence had been leaking out about  radiation sickness  and death caused by  nuclear testing . Muller and many other scientists pursued an array of political activities to defuse the threat of  nuclear war . With the  Castle Bravo  fallout controversy in 1954, the issue became even more urgent. [ citation needed ]  In 1955, Muller was one of 11 prominent intellectuals to sign the  Russell–Einstein Manifesto , the upshot of which was the first  1957 Pugwash Conference on Science and World Affairs , which addressed the control of nuclear weapons. [ 30 ] [ 31 ]  He was a signatory (with many other scientists) of the 1958 petition to the United Nations, calling for an end to nuclear weapons testing, which was initiated by the Nobel Prize-winning chemist  Linus Pauling . [ 30 ]


Muller's opinions on the effect of radiation on mutagenesis were used by  Rachel Carson  in her book  Silent Spring , [ 32 ]  however, his opinions have been criticized by some scientists; geneticist  James F. Crow  called Muller's view "alarmist" and wrote that it created in the public "an irrational fear of low-level radiation relative to other risks". [ 33 ] [ 34 ]  It has been argued that Muller's opinion was not supported by studies on the  survivors of the atomic bombings , or by research on mice, [ 35 ]  and that he ignored another study that contradicted the  linear no-threshold model  he supported, thereby affecting the formulation of policy that favored this model. [ 29 ]


Muller was elected to the  American Academy of Arts and Sciences  in 1942 and the  American Philosophical Society  in 1947 [ 36 ] [ 37 ]  Muller was awarded the  Linnean Society of London 's  Darwin-Wallace Medal  in 1958 and the Kimber Genetics Award of the U.S. National Academy of Sciences, of which he was a member, in 1955. [ 38 ] [ 39 ]  He served as president of the American Humanist Association from 1956 to 1958. [ 40 ]  The  American Mathematical Society  selected him as its Gibbs Lecturer for 1958. [ 41 ]   He retired in 1964. [ 42 ]  The  Drosophila  basic units of inheritance, their  chromosomal arms , are named " Muller elements " in Muller's honor. [ 43 ]  he died in 1967.


H. J. Muller and science fiction writer  Ursula K. Le Guin  were  first cousins once removed ; his father (Hermann J. Muller Sr.) and her father's mother (Johanna Muller Kroeber) were siblings, the children of Nicholas Müller, who immigrated to the United States in 1848, and at that time dropped the umlaut from his name. Another cousin was  Herbert J. Muller , whose grandfather Otto was another son of Nicholas and a sibling of Hermann Sr. and Johanna. [ 44 ]


In a recent retrospective article about Muller's contribution,  James Haber [ 45 ]  wrote as follows:


Drosophila geneticist, Hermann Muller, envisioned the fundamental principles that such a molecule must have: to be auto-assembling and to be mutable but then again stable. He followed his prescient review of these properties with a remarkable prediction: learning about the hereditary material and its properties would not come from studying Drosophila, but from studying bacteria and their bacteriophages.


He was one of the signatories of the agreement to convene a convention for drafting a  world constitution . [ 46 ] [ 47 ]  As a result, for the first time in human history, a  World Constituent Assembly  convened to draft and adopt a  Constitution for the Federation of Earth . [ 48 ]


Muller had a daughter, Helen J. Muller, now a professor emerita at the  University of New Mexico , who has a daughter,  Mala Htun , also a professor at the University of New Mexico. His son,  David E. Muller , professor emeritus of mathematics and computer science at the  University of Illinois  and at  New Mexico State University , died in 2008 in  Las Cruces, New Mexico . David's mother was Jessie Jacobs Muller Offermann (1890–1954), Hermann's first wife. Helen's mother was Dorothea Kantorowicz Muller (1909–1986), Hermann's second wife, who came to the U.S. in 1940 as a German Jewish refugee. [ 3 ]  He had a brief affair with  Milly Bennett . [ 49 ]


The  Nirenberg and Leder experiment  was a scientific experiment performed in 1964 by  Marshall W. Nirenberg  and  Philip Leder . The experiment elucidated the triplet nature of the  genetic code  and allowed the remaining ambiguous codons in the  genetic code  to be deciphered.


In this experiment, using a  ribosome  binding  assay  called the  triplet binding assay , various combinations of  mRNA  were passed through a filter which contained ribosomes. Unique triplets promoted the binding of specific  tRNAs  to the ribosome. By associating the tRNA with its specific  amino acid , it was possible to determine the triplet mRNA sequence that coded for each amino acid.


Oswald Avery  discovered that the substance responsible for producing inheritable change in the disease-causing bacteria was neither a protein nor a lipid, rather deoxyribonucleic acid ( DNA ). He and his colleagues  Colin MacLeod  and  Maclyn McCarty  suggested that DNA was responsible for transferring genetic information. Later,  Erwin Chargaff  discovered that the makeup of DNA differs from one species to another. These experiments helped pave the way for the discovery of the structure of DNA. In 1953, with the help of  Maurice Wilkins  and  Rosalind Franklin ’s  X-ray crystallography ,  James Watson  and  Francis Crick  proposed DNA is structured as a  double helix . [ 1 ]


In the 1960s, one main DNA mystery scientists needed to figure out was in  translation  how many bases would be in each code word, or  codon . Scientists knew there were a total of four bases ( guanine ,  cytosine ,  adenine , and  thymine ). They also knew that were 20 known  amino acids .  George Gamow  suggested that the genetic code was made of three nucleotides per amino acid. He reasoned that because there are 20 amino acids and only four bases, the coding units could not be single (4 combinations) or pairs (only 16 combinations). Rather, he thought triplets (64 possible combinations) were the coding unit of the genetic code.  However, he proposed that the triplets were overlapping and  non-degenerate . [ 2 ]


Seymour Benzer  in the late 1950s had developed an assay using phage mutations which provided the first detailed linearly structured map of a genetic region.
Crick felt he could use mutagenesis and genetic recombination phage to further delineate the nature of the genetic code. [ 3 ]
In the  Crick, Brenner et al. experiment , using these phages, the triplet nature of the genetic code was confirmed. They used  frameshift mutations  and a process called  reversions , to add and delete  various numbers of nucleotides. [ 4 ]  When a nucleotide triplet was added to or deleted from the DNA sequence, the encoded protein was minimally affected. Thus, they concluded that the genetic code is a triplet code because it did not cause a frameshift in the reading frame. [ 5 ]   They correctly concluded that the code is degenerate, that triplets are not overlapping, and that each nucleotide sequence is read from a specific starting point.


The very first amino acid codon (UUU encoding phenylalanine) was deciphered by Nirenberg and his postdoc  Heinrich Matthaei  (see  Nirenberg and Matthaei experiment ) using long synthetic RNA. However, when similar RNAs are made containing more than one RNA base, the order of the bases was random.  For example, a long RNA could be made that had a ratio of C to U of 2:1, and so would contain codons CCU, CUC, UCC at high frequency. When translated by ribosomes, this would produce a protein containing the amino acids proline, leucine, and serine; but it was not possible to say which codon matched which amino acid. [ 7 ]


Instead, Nirenberg's group turned to very short synthetic RNAs. They found that the trinucleotide UUU (which is the codon for phenylalanine), was able to cause specific association of phenylalanine-charged tRNA with ribosomes. This association could be detected by passing the mixture through a nitrocellulose filter: the filter captures ribosomes but not free tRNA; however if tRNA was associated with the ribosome, it would also be captured (along with the radioactive phenylalanine attached to the tRNA). They similarly found that trinucleotides AAA or CCC caused ribosome association of lysine-tRNA or proline-tRNA, respectively.  [ 8 ]


So an experimental plan was clear: synthesize all 64 different trinucleotide combinations, and use the filter assay with tRNAs charged with all 20 amino acids, to see which amino acid associated with which trinucleotide. However, obtaining pure trinucleotides with mixed base sequences, for example GUU, was a daunting challenge. Leder's pioneering studies used trinucleotides made by breaking down long random poly-GU RNA with nuclease and purifying specific trinucleotides by  paper chromatography : [ 8 ]  he determined that GUU, UGU, and UUG encoded the amino acids valine, [ 9 ]  cysteine and leucine, [ 10 ]  respectively. Subsequently, Nirenberg's group constructed trinucleotides by using DNA polymerases coupled with nucleotides and RNA polymerases to create the long random poly-GU RNA as well as artificially replicate the purified trinucleotides. Once high enough concentrations of mRNA were produced, degradation and reformation of polymerase products was accomplished through enzymatic processes. For example, AGU could be made from AG and U with  polynucleotide phosphorylase ; UAG could be made from AG and U with  ribonuclease A  in a high concentration of methanol. [ 11 ]  Nirenberg's postdoc  Merton Bernfield  used these techniques to determine that UUU and UUC encode phenylalanine, UCU and UCC encode serine, and CCC and CCU encode proline, highlighting a pattern in the way the genetic code redundantly encodes amino acids. [ 12 ]  Many others in the Nirenberg lab and at NIH contributed to the full decipherment of the genetic code. [ 11 ]


By the Cold Spring Harbor Symposium of 1966, between  Nirenberg and Khorana the  genetic code  was almost completely decoded.  Nirenberg was awarded the 1968  Nobel Prize in Physiology or Medicine . He shared the award with  Har Gobind Khorana  of the  University of Wisconsin  and Robert W. Holley of the Salk Institute. Working independently, Khorana had mastered the synthesis of nucleic acids, and Holley had discovered the exact chemical structure of transfer-RNA.


The New York Times  said of Nirenberg's work that "the science of biology has reached a new frontier," leading to "a revolution far greater in its potential significance than the atomic or hydrogen bomb." Most of the scientific community saw these experiments as highly important and beneficial.  However, there were some who were concerned with the new era of  molecular genetics . For example,   Arne Tiselius , the 1948 Nobel Laureate in Chemistry, asserted that knowledge of the genetic code could "lead to methods of tampering with life, of creating new diseases, of controlling minds, of influencing heredity, even perhaps in certain desired directions." [ 13 ]


The  Nirenberg and Matthaei experiment  was a scientific experiment performed in May 1961 by  Marshall W. Nirenberg  and his post-doctoral fellow,  J. Heinrich Matthaei , at the  National Institutes of Health  (NIH). The experiment deciphered the first of the 64 triplet codons in the  genetic code  by using  nucleic acid   homopolymers  to translate specific  amino acids .


In the experiment, an extract was prepared from bacterial cells that could make  protein  without the presence of intact living  cells . An artificial form of  RNA  consisting entirely of  uracil -containing nucleotides ( polyuridylic acid  or poly-U) was added to the extract, causing it to form a protein composed entirely of the amino acid  phenylalanine . This experiment cracked the first  codon  of the  genetic code  and showed that RNA controlled the production of specific types of protein.


Discoveries by  Frederick Griffith  and improved on by  Oswald Avery  discovered that the substance responsible for producing inheritable change in the disease-causing bacteria ( Streptococcus pneumoniae)  was neither a protein nor a lipid, rather deoxyribonucleic acid ( DNA ). In 1944, he and his colleagues  Colin MacLeod  and  Maclyn McCarty  suggested that DNA was responsible for transferring genetic information. Later,  Erwin Chargaff (1950) discovered that the makeup of DNA differs from one species to another. These experiments helped pave the way for the discovery of the structure of DNA. In 1953, with the help of  Maurice Wilkins  and  Rosalind Franklin 's  X-ray crystallography ,  James Watson  and  Francis Crick  proposed DNA is structured as a  double helix . [ 1 ]


In the 1960s, one main DNA mystery scientists needed to figure out was the number of bases found in each code word, or  codon , during  transcription . Scientists knew there was a total of four bases ( guanine ,  cytosine ,  adenine , and  thymine ). They also knew that were 20 known  amino acids .  George Gamow  suggested that the genetic code was made of three nucleotides per amino acid. He reasoned that because there are 20 amino acids and only four bases, the coding units could not be single (4 combinations) or pairs (only 16 combinations). Rather, he thought triplets (64 possible combinations) were the coding unit of the genetic code. However, he proposed that the triplets were overlapping and  non-degenerate [ 2 ]  (later explained by Crick in his  Wobble concept ).


Seymour Benzer  in the late 1950s had developed an assay using phage mutations which provided the first detailed linearly structured map of a genetic region. Crick felt  he  could use mutagenesis and genetic recombination phage to further delineate the nature of the genetic code. [ 3 ]  In the  Crick, Brenner et al. experiment , using these phages, the triplet nature of the genetic code was confirmed. They used  frameshift mutations  and a process called  reversions , to add and delete various numbers of nucleotides. [ 4 ]  When a nucleotide triplet was added or deleted to the DNA sequence the encoded protein was minimally affected. Thus, they concluded that the genetic code is a triplet code because it did not cause a frameshift in the reading frame. [ 5 ]  They correctly concluded that the code is degenerate (multiple triplets can correspond to a single amino acid) and that each nucleotide sequence is read from a specific starting point. [ 6 ]


In order to decipher this biological mystery, Nirenberg and Matthaei needed a  cell-free system  that would build amino acids into proteins. Following the work of  Alfred Tissieres  and after a few failed attempts, they created a stable system by rupturing  E. coli  bacteria cells and releasing the contents of the cytoplasm. [ 7 ]  This allowed them to synthesize protein, but only when the correct kind of RNA was added, allowing Nirenberg and Matthaei to control the experiment. They created synthetic RNA molecules outside the bacterium and introduced this RNA to the  E. coli  system. The experiments used mixtures with all 20 amino acids. For each individual experiment, 19 amino acids were "cold" (nonradioactive), and one was "hot" (radioactively tagged with  14 C so they could detect the tagged amino acid later). They varied the "hot" amino acid in each round of the experiment, seeking to determine which amino acids would be incorporated into a protein following the addition of a particular type of synthetic RNA.


The key first experiments were done with poly-U (synthetic RNA composed only of uridine bases, provided by  Leon Heppel  and  Maxine Singer [ 8 ] ). At 3 am on May 27, 1961, Matthaei used phenylalanine as the "hot" amino acid. After an hour, the control tube (no poly-U) showed a background level of 70 counts, whereas the tube with poly-U added showed 38,000 counts per milligram of protein. [ 9 ] [ 8 ]  Subsequent experiments showed that the 19 "cold" amino acids were not necessary and that the protein product had the biochemical characteristics of polyphenylalanine, [ 8 ]   [ 10 ]  demonstrating that a chain of repeated uracil bases produced a protein chain made solely of the repeating amino acid phenylalanine. While the experiment did not determine the number of bases per codon, it was consistent with the triplet codon UUU coding for phenylalanine.


In analogous experiments with other synthetic RNAs, they found that poly-C directed synthesis of polyproline. Nirenberg recounts that the labs of  Severo Ochoa  and  James Watson  had earlier done similar experiments with poly-A, but failed to detect protein synthesis because polylysine (unlike most proteins) is soluble in  trichloroacetic acid . Further, using synthetic RNAs that randomly incorporated two bases at different ratios, they produced proteins containing more than one type of amino acid, from which they could deduce the triplet nature of the genetic code and narrow down the codon possibilities for other amino acids. [ 10 ]  Nirenberg's group eventually decoded all the amino acid codons by 1966, [ 6 ]  however this required additional ingenious experimental methods (see  Nirenberg and Leder experiment ).


In August 1961, at the International Congress of Biochemistry in Moscow, Nirenberg presented the poly-U experiments – first to a small group, but then at  Francis Crick 's urging, again to about a thousand attendees. The work was very enthusiastically received, and Nirenberg became famous overnight. [ 11 ] [ 10 ]  The paper describing the work was published the same month. [ 8 ]


The experiment ushered in a furious race to fully crack the genetic code. Nirenberg's main competition was the esteemed biochemist Severo Ochoa.  Dr. Ochoa and Dr. Arthur Kornberg shared the 1959 Nobel Prize in Physiology or Medicine for their previous "discovery of the mechanisms in the biological synthesis of ribonucleic acid and deoxyribonucleic acid."  However, many colleagues at the  National Institutes of Health (NIH)  supported Nirenberg, aware that it may lead to the first  Nobel prize  by an intramural NIH scientist.  DeWitt Stetten Jr. , the NIH director who first hired Nirenberg, called this period of collaboration "NIH's finest hour." [ 9 ]   [ 12 ] [ 13 ]


Indeed, "for their interpretation of the genetic code and its function in protein synthesis," Marshall W. Nirenberg, Robert W. Holley, and Har Gobind Khorana were awarded the 1968  Nobel Prize in Physiology or Medicine . [ 14 ]   Working independently, Dr. Holley (Cornell University) had discovered the exact chemical structure of transfer-RNA, and Dr. Khorana (University of Wisconsin in Madison) had mastered the synthesis of nucleic acids. [ 15 ]   Dr. Nirenberg showed - excluding nonsense codons - every combination of a triplet (i.e. a codon) composed of four different nitrogen-containing bases found in DNA and in RNA produces a specific amino acid. [ 15 ]


The New York Times  said of Nirenberg's discovery that "the science of biology has reached a new frontier," leading to "a revolution far greater in its potential significance than the atomic or hydrogen bomb." Most of the scientific community saw these experiments as highly important and beneficial. However, there were some who were concerned with the new area of  molecular genetics . For example,  Arne Tiselius , the 1948 Nobel Laureate in Chemistry, asserted that knowledge of the genetic code could "lead to methods of tampering with life, of creating new diseases, of controlling minds, of influencing heredity, even perhaps in certain desired directions." [ 16 ]


In addition to the Nobel Prize, Dr. Nirenberg has received the Molecular Biology Award of the National Academy of Sciences and the Biological Science Award of the Washington Academy of Sciences (1962), the Paul Lewis Award of the American Chemical Society (1963), the Department of Health, Education, and Welfare Medal, along with the Harrison Howe Award of the American Chemical Society of USA, in America (1864). [ 15 ]


Marshall Warren Nirenberg  (April 10, 1927 – January 15, 2010) [ 1 ]  was an American  biochemist  and  geneticist . [ 2 ]  He shared a  Nobel Prize in Physiology or Medicine  in 1968 with  Har Gobind Khorana  and  Robert W. Holley  for "breaking the  genetic code " and describing how it operates in  protein synthesis . In the same year, together with  Har Gobind Khorana , he was awarded the  Louisa Gross Horwitz Prize  from  Columbia University . His most famous discovery came when he coined the phrase “The mitochondria is the powerhouse of the cell.”


Nirenberg was born in New York City to a  Jewish  family, the son of Minerva (Bykowsky) and Harry Edward Nirenberg, a shirtmaker. [ 3 ] [ 4 ]  He developed  rheumatic fever  as a boy, so the family moved to  Orlando , Florida to take advantage of the  subtropical climate . He developed an early interest in  biology . In 1948 he received his  BS degree , and in 1952, a  master's degree  in  zoology  from the  University of Florida  at Gainesville where he was also a member of the  Pi Lambda Phi   Fraternity . [ 5 ]  His  dissertation  for the  Master's thesis  was an  ecological  and  taxonomic  study of  caddis flies  ( Trichoptera ).  He received his  PhD  in  biochemistry  from the  University of Michigan ,  Ann Arbor  in 1957, studying hexose uptake in tumor cells with his advisor James F. Hogg. [ 6 ]


He began his  postdoctoral  work at the  National Institutes of Health  (NIH) in 1957 as a fellow of the  American Cancer Society  in what was then called the  National Institute of Arthritis and Metabolic Diseases . In 1959 he became a research biochemist at the  NIH  and began to study the steps that relate  DNA ,  RNA  and  protein . Nirenberg's groundbreaking experiments advanced him to become the head of the Section of Biochemical Genetics in 1962 in the  National Heart Institute  (now the  National Heart, Lung, and Blood Institute ), where he remained a laboratory chief until his death. Fellow laboratory chiefs included  Ernst Freese  and  Daniel Carleton Gajdusek .  He was married in 1961 to  Perola Zaltzman , a  chemist  from the  University of Brazil, Rio de Janeiro , who also worked at  NIH  and died in 2001. Nirenberg married  Myrna Weissman ,  PhD , Professor of  Epidemiology  and  Psychiatry  at  Columbia University College of Physicians and Surgeons  in 2005. He had four stepchildren: Susan Weissman of  Evanston , Illinois, Judith Weissman of  New York , New York, Sharon Weissman of  New Haven , Connecticut, and Jonathan Weissman of  San Francisco , California.  He was also survived by his sister, Joan Nirenberg Geiger of Dallas, Texas, several nieces and a nephew.


Nirenberg was awarded the  National Medal of Science  in 1964 and the National Medal of Honor in 1968 by  President   Lyndon B. Johnson . [ 7 ]  In 1981, Nirenberg became a founding member of the  World Cultural Council . [ 8 ]  In 1986, Nirenberg's achievements and contributions to the field of biochemistry genetics was recognized at an event honoring  Maimonides  and  Menachem M. Schneerson , in the nation's capital, hosted by  Bob Dole  and  Joe Biden . [ 9 ]  He was elected to the  American Philosophical Society  in 2001.  He died on January 15, 2010, from  cancer  after several months of illness. [ 1 ]


By 1958, experiments and analysis such as the  Avery–MacLeod–McCarty experiment , the  Hershey–Chase experiment , the  Watson–Crick structure  and the  Meselson–Stahl experiment  had shown  DNA  to be the molecule of genetic information. It was not known, however, how DNA directed the expression of  proteins , or what role  RNA  had in these processes. Nirenberg teamed up with  Heinrich J. Matthaei  at the  National Institutes of Health  to answer these questions. They produced  RNA  composed solely of  uracil , a  nucleotide  that only occurs in RNA. They then added this synthetic poly-uracil RNA into a cell-free extract of  Escherichia coli  which contained the DNA, RNA,  ribosomes  and other cellular machinery for protein synthesis. They added  DNase , which breaks apart the DNA, so that no additional proteins would be produced other than that from their synthetic  RNA . They then added 1 radioactively labeled  amino acid , the building blocks of proteins, and 19 unlabeled amino acids to the extract, varying the labeled amino acid in each sample. Only in the extract containing the radioactively labeled  phenylalanine , was the resulting protein also  radioactive . This implied that the  genetic code  for phenylalanine on RNA consisted of a repetition of uracil bases. Indeed, as we know now, it is UUU (three uracil bases in a row). This was the first step in deciphering the  codons  of the genetic code and the first demonstration of  messenger RNA  (see  Nirenberg and Matthaei experiment ). [ 10 ] [ 11 ] [ 12 ] [ 13 ] [ 14 ] [ 15 ] [ 16 ]


In August 1961, at the International Congress of Biochemistry in Moscow, Nirenberg presented a paper to a small group of scientists, reporting the decoding of the first codon of the genetic code.  Matthew Meselson , who was in the audience, spontaneously hugged Nirenberg at the end of the talk and then told  Francis Crick  about Nirenberg's result. [ 17 ]  Crick invited Nirenberg to repeat his performance the next day in a talk to a much larger audience. [ 18 ] [ 19 ]  Speaking before the assembled congress of more than a thousand people, Nirenberg electrified the scientific community. [ 17 ]  He quickly received great scientific attention for these experiments. Within a few years, his research team had performed similar experiments and found that three-base repeats of  adenosine  (AAA) produced the amino acid  lysine , and  cytosine  repeats (CCC) produced  proline . The next breakthrough came when  Philip Leder , a postdoctoral researcher in Nirenberg's lab, developed a method for determining the genetic code on pieces of  tRNA  (see  Nirenberg and Leder experiment ). This greatly sped up the assignment of three-base codons to amino acids so that 50 codons were identified in this way. Khorana's experiments confirmed these results and completed the genetic code translation.


The period between 1961 and 1962 is often referred to as the "coding race" because of the competition between the labs of Nirenberg at NIH and Nobel laureate Severo Ochoa at New York University Medical School, who had a massive staff. Faced with the possibility of helping the first NIH scientist win a Nobel prize, many NIH scientists put aside their own work to help Nirenberg in deciphering the mRNA codons for amino acids. Dr.  DeWitt Stetten, Jr. , director of the National Institute of Arthritis and Metabolic Diseases, called this period of collaboration "NIH's finest hour". [ 20 ]


Nirenberg's later research focused on  neuroscience , neural development, and the  homeobox  genes.


Severo Ochoa de Albornoz  ( Spanish:   [seˈβeɾo   oˈtʃoa   ðe   alβoɾˈnoθ] ; 24 September 1905 – 1 November 1993) was a Spanish  physician  and  biochemist , and winner of the 1959  Nobel Prize in Physiology or Medicine  together with  Arthur Kornberg  for their discovery of "the mechanisms in the  biological synthesis  of  deoxyribonucleic acid  (DNA)". [ 2 ] [ 3 ] [ 4 ] [ 5 ]


Ochoa was born in  Luarca  ( Asturias ),  Spain . His father was Severo Manuel Ochoa (who he was named after), a lawyer and businessman, and his mother was Carmen de Albornoz. Ochoa was the nephew of  Álvaro de Albornoz  (President of the Second Spanish Republic in exile and former Foreign Minister), and a cousin of the poet and critic  Aurora de Albornoz . His father died when Ochoa was seven, and he and his mother moved to  Málaga , where he attended elementary school through high school.  His interest in biology was stimulated by the publications of the Spanish neurologist and Nobel laureate  Santiago Ramón y Cajal . In 1923, he went to the  University of Madrid  Medical School, where he hoped to work with Ramón y Cajal, but Ramón y Cajal retired. He studied with father  Pedro Arrupe , and  Juan Negrín  was his teacher: [ 4 ]


Negrin opened wide, fascinating vistas to my imagination, not only through his lectures and laboratory teaching, but through his advice, encouragement, and stimulation to read scientific monographs and textbooks in languages other than Spanish . [ 4 ]


Negrín encouraged Ochoa and another student, José Valdecasas, to isolate  creatinine  from urine. [ 4 ]  The two students succeeded and also developed a method to measure small levels of muscle creatinine. Ochoa spent the summer of 1927 at  University of Glasgow  working with  D. Noel Paton  on  creatine  metabolism and improving his English skills. He also refined the assay procedure further and upon returning to Spain he and Valdecasas submitted a paper describing the work to the  Journal of Biological Chemistry , where it was rapidly accepted, [ 6 ]  marking the beginning of Ochoa's biochemistry career. [ 7 ]


Ochoa completed his undergraduate medical degree in the summer of 1929 and decide to go abroad again to gain further research experience. His creatine and creatinine work led to an invitation to join  Otto Meyerhof 's laboratory at the  Kaiser Wilhelm Institute for Biology  in Berlin-Dahlem in 1929. At that time the institute was a "hot bed" of the rapidly evolving discipline of biochemistry, and thus Ochoa had the experience of meeting and interacting with scientists such as  Otto Heinrich Warburg ,  Carl Neuberg ,  Einar Lundsgaard , and  Fritz Lipmann  in addition to Meyerhof who had received the Nobel Prize in Physiology and Medicine less than a decade earlier.


In 1930 Ochoa returned to Madrid to complete research for his MD thesis, which he defended that year. In 1931, a newly minted MD, he married Carmen García Cobián. They did not have any children. He then began postdoctoral study at the  National Institute for Medical Research  in London, where he worked with  Henry Hallett Dale . His London research involved the enzyme  glyoxalase  and was an important departure in Ochoa's career in two respects. First, the work marked the beginning of Ochoa's lifelong interest in enzymes. Second, the project was at the cutting edge of the rapidly evolving study of  intermediary metabolism . [ 4 ]


In 1933 the Ochoas returned to Madrid where he began to study glycolysis in heart muscle. Within two years, he was offered the directorship of the Physiology Section in a newly created Institute for Medical Research at the  University of Madrid Medical School . Unfortunately the appointment was made just as the  Spanish Civil War  erupted. Ochoa decided that trying to perform research in such an environment would destroy forever his "chances of becoming a scientist." Thus, "after much thought, my wife and I decided to leave Spain." In September 1936 they began what he later called the "wander years" as they traveled from Spain to Germany, to England, and ultimately to the United States within a span of four years. [ 4 ] [ 8 ]


Ochoa left Spain and returned to Meyerhof's Kaiser Wilhelm Institute for Biology now relocated in Heidelberg, where Ochoa found a profoundly changed research focus. During his 1930 visit the laboratory work was "classical physiology," which Ochoa described as "one could see muscles twitching everywhere". [ 4 ]  By 1936 Meyerhof's laboratory had become one of the world's foremost biochemical facilities focused on processes such as  glycolysis  and  fermentation . Rather than studying muscles "twitch," the lab was now purifying and characterizing the enzymes involved in muscle action and those involved in yeast fermentation.


From then until 1938, he held many positions and worked with many people at many places. For example,  Otto Meyerhof  appointed him Guest Research Assistant at the  Kaiser Wilhelm Institute for Medical Research  in  Heidelberg  for one year. From 1938 until 1941 he was Demonstrator and Nuffield Research Assistant at the  University of Oxford .


Ochoa then went to the United States, where he again held many positions at several universities. Between 1940 and 1942, Ochoa worked for  Washington University's School of Medicine . [ 9 ] [ 10 ]  In 1942 he was appointed research associate in medicine at the  New York University School of Medicine  and there subsequently became assistant professor of biochemistry (1945), professor of pharmacology (1946), professor of biochemistry (1954), and chair of the department of biochemistry.


In 1956, he became an American citizen. [ 5 ]  He was elected to both the United States  National Academy of Sciences  and the  American Academy of Arts and Sciences  in 1957. In 1959, Ochoa and  Arthur Kornberg  were awarded the Nobel Prize for Physiology or Medicine "for their discovery of the mechanisms in the biological  synthesis  of  ribonucleic acid  and  deoxyribonucleic acid ". He was elected to the  American Philosophical Society  in 1961. [ 11 ]


Ochoa continued research on  protein synthesis  and replication of  RNA viruses  until 1985, when he returned to now democratic Spain where he was a science advisor. Ochoa was also a recipient of U.S.  National Medal of Science  in 1978.


Severo Ochoa died in  Madrid ,  Spain  on 1 November 1993. Carmen García Cobián had died in 1986.


Long after his death, Spanish actress  Sara Montiel  claimed that she and Severo Ochoa were involved in a romantic relationship in the 1950s, as stated in an interview in Spanish newspaper  El País : "The great love of my life was Severo Ochoa. But it was an impossible love. Clandestine. He was married, and besides, him doing research and me doing films wasn't a good match."
 [ 12 ]


A new research center in the Autonomous University of Madrid (UAM), that was planned in the 1970s, was finally open in 1975 (CBM) and named, after his dead, the Centro de Biología Molecular Severo Ochoa. [ 13 ]


In  Leganés , Madrid, a hospital bears his name, as does the  Madrid Metro  station serving it,  Hospital Severo Ochoa .


The  asteroid   117435 Severochoa  is also named in his honor.


In 2003 the Spanish General Post Office ( Correos ) issued a €0,76 postage stamp honoring Ochoa, as one of a pair featuring Spanish medical Nobel Prize winners [ 14 ]  alongside  Santiago Ramón y Cajal .


In June 2011, the United States Postal Service issued a stamp honoring him, [ 15 ]  as part of the  American Scientists  collection, along with  Melvin Calvin ,  Asa Gray , and  Maria Goeppert-Mayer . This was the third volume in the series.


The main road in to the tourist resort Benidorm is named Avenida Dr. Severo Ochoa [ 16 ]  in his honor.


The  one gene–one enzyme hypothesis  is the idea that  genes  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 .  The concept was proposed by  George Beadle  and  Edward Tatum  in an influential 1941 paper [ 1 ]  on genetic mutations in the mold  Neurospora crassa , and subsequently was dubbed the "one gene–one enzyme hypothesis" by their collaborator  Norman Horowitz . [ 2 ]   In 2004, Horowitz reminisced that "these experiments founded the science of what Beadle and Tatum called 'biochemical genetics.'  In actuality they proved to be the opening gun in what became molecular genetics and all the developments that have followed from that." [ 3 ]   The development of the one gene–one enzyme hypothesis is often considered the first significant result in what came to be called  molecular biology . [ 4 ]   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. [ 5 ]


Although some instances of  errors in metabolism  following  Mendelian inheritance  patterns were known earlier, beginning with the 1902 identification by  Archibald Garrod  of  alkaptonuria  as a Mendelian  recessive  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  and George Beadle, two geneticists working on the eye color pigments of  Drosophila melanogaster  fruit flies in the  Caltech  laboratory of  Thomas Hunt Morgan .  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. [ 6 ]


After moving to  Stanford University  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 , 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 , 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 , it grew quickly, and because of the production of  ascospores  during reproduction it was easy to isolate genetic mutants for analysis.  They produced mutations by exposing the fungus to  X-rays , and then identified strains that had metabolic defects by varying the growth medium. This work of Beadle and Tatum led almost at once to an important generalization.  This was that most mutants unable to grow on minimal medium but able to grow on “complete” medium each require addition of only one particular supplement for growth on minimal medium.  If the synthesis of a particular nutrient (such as an  amino acid  or  vitamin ) was disrupted by mutation, that mutant strain could be grown by adding the necessary nutrient to the medium.  This finding suggested that most mutations affected only a single metabolic pathway.  Further evidence obtained soon after the initial findings tended to show that generally only a single step in the pathway is blocked.  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. [ 7 ]   The obvious inference from these experiments was that each gene mutation affects the activity of a single enzyme.  This led directly to the one gene–one enzyme hypothesis, which, with certain qualifications and refinements, has remained essentially valid to the present day.  As recalled by Horowitz et al., [ 8 ]  the work of Beadle and Tatum also demonstrated that genes have an essential role in biosyntheses.  At the time of the experiments (1941), non-geneticists still generally believed that genes governed only trivial biological traits, such as eye color, and bristle arrangement in fruit flies, while basic biochemistry was determined in the cytoplasm by unknown processes.  Also, many respected geneticists thought that gene action was far too complicated to be resolved by any simple experiment.  Thus Beadle and Tatum brought about a fundamental revolution in our understanding of genetics, for which they were awarded a   Nobel Prize in Physiology or Medicine   in 1958.


The nutritional mutants of  Neurospora  also proved to have practical applications; in one of the early, if indirect, examples of  military funding of science  in the biological sciences, Beadle garnered additional research funding (from the  Rockefeller Foundation  and an association of manufacturers of military rations) to develop strains that could be used to  assay  the nutrient content of foodstuffs, to ensure adequate nutrition for troops in  World War II . [ 9 ]


In their first  Neurospora  paper, published in the November 15, 1941, edition of the  Proceedings of the 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. [ 1 ]   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  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". [ 2 ]


Although influential, the one gene–one enzyme hypothesis was not unchallenged.  Among others,  Max Delbrück  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  (which was known to have heritable variations and which followed the same pattern of  autocatalysis  as many enzymatic reactions) and the crystallization of that virus as an apparently pure protein.  At the start of the 1950s, the Neurospora findings were widely admired, but the prevailing view in 1951 was that the conclusion Beadle had drawn from them was a vast oversimplification. [ 8 ]   Beadle wrote in 1966, that after reading the 1951 Cold Spring Harbor Symposium on Genes and Mutations, he had the impression that supporters of the one gene–one enzyme hypothesis “could be counted on the fingers of one hand with a couple of fingers left over.” [ 10 ]   By the early 1950s, most biochemists and geneticists considered  DNA  the most likely candidate for physical basis of the gene, and the one gene–one enzyme hypothesis was reinterpreted accordingly. [ 11 ]


In attributing an instructional role to genes, Beadle and Tatum implicitly accorded genes an informational capability.  This insight provided the foundation for the concept of a genetic code.  However, it was not until the experiments were performed showing that DNA was the genetic material, that proteins consist of a defined linear sequence of amino acids, and that DNA structure contained a linear sequence of base pairs, was there a clear basis for solving the genetic code.


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  and others showed through  electrophoresis  and  2D chromatography  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. [ 12 ]   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." [ 13 ]


Presently, the one gene–one polypeptide perspective cannot account for the various spliced versions in many eukaryote organisms which use a  spliceosome  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 [ 14 ]


Historian  Jan Sapp  has studied the controversy in regard to German geneticist  Franz Moewus   who, as some leading geneticists of the 1940s and 50s argued, generated similar results before Beadle and Tatum's celebrated 1941 work. [ 15 ]  Working on the algae  Chlamydomonas , 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, as Sapp skillfully details, those results were challenged by others who found the data 'too good to be true' statistically, and the results could not be replicated.


George Emil Palade   ForMemRS   HonFRMS  ( Romanian pronunciation:   [ˈdʒe̯ordʒe   eˈmil   paˈlade]   ⓘ ; November 19, 1912 – October 7, 2008) was a  Romanian-American   cell biologist . Described as "the most influential cell biologist ever", [ 3 ]  in 1974 he was awarded the  Nobel Prize in Physiology or Medicine  along with  Albert Claude  and  Christian de Duve . The prize was granted for his innovations in  electron microscopy  and  cell fractionation  which together laid the foundations of modern molecular  cell biology , [ 3 ]  the most notable discovery being the  ribosomes  of the  endoplasmic reticulum  – which he first described in 1955. [ 4 ] [ 5 ] [ 6 ] [ 7 ] [ 8 ]


Palade also received the U.S.  National Medal of Science  in Biological Sciences for "pioneering discoveries of a host of fundamental, highly organized structures in living cells" in 1986, and was previously elected a Member of the U.S.  National Academy of Sciences  in 1961. In 1968 he was elected as an  Honorary Fellow of the Royal Microscopical Society  (HonFRMS) [ 9 ]  and in 1984 he became a  Foreign Member of the Royal Society (ForMemRS) . [ 1 ]


George Emil Palade was born on November 19, 1912, in  Iași , Romania; his father was a professor of philosophy at the  University of Iași  and his mother was a high school teacher. Palade received his  M.D.  in 1940 from the  Carol Davila School of Medicine  in  Bucharest .


Palade was a member of the faculty at  University of Bucharest  until 1946, when he went to the United States [ 10 ]  to do  postdoctoral research . While assisting  Robert Chambers  in the Biology Laboratory of  New York University , he met Professor  Albert Claude . [ 11 ]  He later joined Claude at the  Rockefeller Institute for Medical Research . [ 10 ]


In 1952, Palade became a  naturalized citizen  of the United States. He worked at the Rockefeller Institute (1958–1973), and was a professor at  Yale University  Medical School (1973–1990), and  University of California, San Diego  (1990–2008). At UCSD, Palade was Professor of Medicine in Residence (Emeritus) in the Department of Cellular & Molecular Medicine, as well as a Dean for Scientific Affairs (Emeritus), in the School of Medicine at  La Jolla , California. [ 12 ]


In 1970, he was awarded the  Louisa Gross Horwitz Prize  from  Columbia University , together with  Renato Dulbecco  (winner of the 1975  Nobel Prize  in Physiology or Medicine) " for discoveries concerning the functional organization of the cell that were seminal events in the development of modern cell biology ", [ 13 ]  related to his previous research carried out at the Rockefeller Institute for Medical Research. [ 14 ]  His Nobel lecture, delivered on December 12, 1974, was entitled:  "Intracellular Aspects of the Process of Protein Secretion" , [ 15 ]  published in 1992 by the Nobel Prize Foundation, [ 16 ] [ 17 ]  He was elected an Honorary  member of the Romanian Academy  in 1975. He received the Golden Plate Award of the  American Academy of Achievement  in 1975. [ 18 ]  In 1981, Palade became a founding member of the  World Cultural Council . [ 19 ]
In 1985, he became the founding editor of the  Annual Review of Cell and Developmental Biology . [ 20 ]
In 1988 he was also elected an Honorary Member of the  American-Romanian Academy of Arts and Sciences  (ARA).


Palade was the first Chairman of the Department of Cell Biology at Yale University. Presently, the Chair of Cell Biology at Yale is named the "George Palade Professorship".


At the Rockefeller Institute for Medical Research, Palade used  electron microscopy  to study the internal organization of such cell structures as  ribosomes ,  mitochondria ,  chloroplasts , the Golgi apparatus, and others. His most important discovery was made while using an experimental strategy known as a  pulse-chase analysis . In the experiment Palade and his colleagues were able to confirm an existing hypothesis that a secretory pathway exists and that the  Rough ER  and the  Golgi apparatus  function together. [ 4 ]


He focused on  Weibel-Palade bodies  (a storage organelle unique to the  endothelium , containing  von Willebrand factor  and various proteins) which he described together with the  Swiss  anatomist  Ewald R. Weibel . [ 21 ]


The following is a concise excerpt from Palade's Autobiography appearing in the Nobel Award documents [ 10 ]


In the 1960s, I continued the work on the secretory process using in parallel or in succession two different approaches. The first relied exclusively on cell fractionation, and was developed in collaboration with  Philip Siekevitz ,  Lewis Joel Greene ,  Colvin Redman ,  David Sabatini , and  Yutaka Tashiro ; it led to the characterization of the zymogen granules and to the discovery of the segregation of secretory products in the cisternal space of the endoplasmic reticulum. The second approach relied primarily on radioautography, and involved experiments on intact animals or pancreatic slices which were carried out in collaboration with Lucien Caro and especially James Jamieson. This series of investigations produced a good part of our current ideas on the synthesis and intracellular processing of proteins for export. A critical review of this line of research is presented in the Nobel Lecture. [ 15 ]


One notes also that the  Nobel Prize  in  Chemistry  was awarded in 2009 to  Venkatraman Ramakrishnan ,  Thomas A. Steitz , and  Ada E. Yonath  " for studies of the structure and function of the ribosome ", discovered by George Emil Palade. [ 22 ]


He married Irina Malaxa (born in 1919, the daughter of industrialist  Nicolae Malaxa ) on June 12, 1941. The couple had two children: Georgia (born in 1943) and Theodore (born in 1949). [ 23 ]  After his wife died in 1969, Palade married  Marilyn Farquhar , a cell biologist at the  University of California, San Diego . [ 24 ]


Pangenesis  was  Charles Darwin 's hypothetical mechanism for  heredity , in which he proposed that each part of the body continually emitted its own type of small organic particles called  gemmules  that aggregated in the  gonads , contributing heritable information to the  gametes . [ 1 ]  He presented this 'provisional hypothesis' in his 1868 work  The Variation of Animals and Plants Under Domestication , intending it to fill what he perceived as a major gap in evolutionary theory at the time. The etymology of the word comes from the  Greek  words  pan  (a prefix meaning "whole", "encompassing") and  genesis  ("birth") or  genos  ("origin"). Pangenesis mirrored ideas originally formulated by  Hippocrates  and other pre-Darwinian scientists, but using new concepts such as  cell theory , explaining cell development as beginning with gemmules which were specified to be necessary for the occurrence of new growths in an organism, both in initial development and regeneration. [ 2 ]  It also accounted for  regeneration  and the  Lamarckian  concept of the inheritance of acquired characteristics, as a body part altered by the environment would produce altered gemmules. This made Pangenesis popular among the neo-Lamarckian school of evolutionary thought. [ 3 ]  This hypothesis was made effectively obsolete after the 1900 rediscovery among  biologists  of  Gregor Mendel 's theory of the  particulate nature of inheritance .


Pangenesis was similar to ideas put forth by  Hippocrates ,  Democritus  and other pre-Darwinian scientists in proposing that the whole of parental organisms participate in heredity (thus the prefix  pan ). [ 4 ]  Darwin wrote that Hippocrates' pangenesis was "almost identical with mine—merely a change of terms—and an application of them to classes of facts necessarily unknown to the old philosopher." [ 5 ]


The historian of science  Conway Zirkle  wrote that:


The hypothesis of pangenesis is as old as the belief in the inheritance of acquired characters. It was endorsed by  Hippocrates ,  Democritus ,  Galen ,  Clement of Alexandria ,  Lactantius ,  St. Isidore of Seville ,  Bartholomeus Anglicus ,  St. Albert the Great ,  St. Thomas of Aquinas ,  Peter of Crescentius ,  Paracelsus ,  Jerome Cardan ,  Levinus Lemnius ,  Venette ,  John Ray ,  Buffon ,  Bonnet ,  Maupertuis ,  von Haller  and  Herbert Spencer . [ 4 ]


Zirkle demonstrated that the idea of inheritance of acquired characteristics had become fully accepted by the 16th century and remained immensely popular through to the time of Lamarck's work, at which point it began to draw more criticism due to lack of hard evidence. [ 4 ]  He also stated that pangenesis was the only scientific explanation ever offered for this concept, developing from Hippocrates' belief that "the semen was derived from the whole body." [ 4 ]  In the 13th century, pangenesis was commonly accepted on the principle that semen was a refined version of food unused by the body, which eventually translated to 15th and 16th century widespread use of pangenetic principles in medical literature, especially in gynecology. [ 4 ]  Later pre-Darwinian important applications of the idea included hypotheses about the origin of the differentiation of races. [ 4 ]


A theory put forth by  Pierre Louis Maupertuis  in 1745 called for particles from both parents governing the attributes of the child, although some historians have called his remarks on the subject cursory and vague. [ 6 ] [ 7 ]


In 1749, the French naturalist  Georges-Louis Leclerc, Comte de Buffon  developed a hypothetical system of heredity much like Darwin's pangenesis, wherein 'organic molecules' were transferred to offspring during reproduction and stored in the body during development. [ 7 ] [ 8 ]  Commenting on Buffon's views, Darwin stated, "If Buffon had assumed that his organic molecules had been formed by each separate unit throughout the body, his view and mine would have been very closely similar." [ 4 ]


In 1801,  Erasmus Darwin  advocated a hypothesis of pangenesis in the third edition of his book  Zoonomia . [ 9 ]  In 1809,  Jean-Baptiste Lamarck  in his  Philosophie Zoologique  put forth evidence for the idea that characteristics acquired during the lifetime of an organism, from either environmental or behavioural effects, may be passed on to the offspring. Charles Darwin first had significant contact with  Lamarckism  during his time at the  University of Edinburgh Medical School  in the late 1820s, both through  Robert Edmond Grant , whom he assisted in research, and in Erasmus's journals. [ 10 ]  Darwin's first known writings on the topic of Lamarckian ideas as they related to inheritance are found in a notebook he opened in 1837, also entitled  Zoonomia . [ 11 ]  Historian Jonathan Hodge states that the theory of pangenesis itself first appeared in Darwin's notebooks in 1841. [ 12 ]


In 1861, the Irish physician  Henry Freke  developed a variant of pangenesis in his book  Origin of Species by Means of Organic Affinity . [ 13 ]  Freke proposed that all life was developed from microscopic organic agents which he named  granules , which existed as 'distinct species of organizing matter' and would develop into different biological structures. [ 14 ]


Four years before the publication of  Variation , in his 1864 book  Principles of Biology ,  Herbert Spencer  proposed a theory of "physiological units" similar to Darwin's gemmules, which likewise were said to be related to specific body parts and responsible for the transmission of characteristics of those body parts to offspring. [ 5 ]  He supported the  Lamarckian  idea of transmission of acquired characteristics.


Darwin had debated whether to publish a theory of heredity for an extended period of time due to its highly speculative nature. He decided to include pangenesis in  Variation  after sending a 30-page manuscript to his close friend and supporter  Thomas Huxley  in May 1865, which was met by significant criticism from Huxley that made Darwin even more hesitant. [ 15 ]  However, Huxley eventually advised Darwin to publish, writing: "Somebody rummaging among your papers half a century hence will find Pangenesis & say 'See this wonderful anticipation of our modern Theories—and that stupid ass, Huxley, prevented his publishing them'" [ 16 ]  Darwin's initial version of pangenesis appeared in the first edition of  Variation  in 1868, and was later reworked for the publication of a second edition in 1875.


Darwin's pangenesis theory attempted to explain the process of  sexual reproduction , inheritance of traits, and complex  developmental  phenomena such as cellular  regeneration  in a unified mechanistic structure. [ 15 ] [ 17 ]  Longshan Liu wrote that in modern terms, pangenesis deals with issues of "dominance inheritance,  graft hybridization ,  reversion , xenia,  telegony , the inheritance of acquired characters, regeneration and many groups of facts pertaining to variation, inheritance and development." [ 18 ]  Mechanistically, Darwin proposed pangenesis to occur through the transfer of organic particles which he named 'gemmules.' Gemmules, which he also sometimes referred to as  plastitudes, [ 19 ]  pangenes, granules, [ 20 ]  or germs, were supposed to be shed by the organs of the body and carried in the bloodstream to the reproductive organs where they accumulated in the germ cells or gametes. [ 21 ]  Their accumulation was thought to occur by some sort of a 'mutual affinity.' [ 15 ]  Each gemmule was said to be specifically related to a certain body part- as described, they did not contain information about the entire organism. [ 20 ]  The different types were assumed to be dispersed through the whole body, and capable of self-replication given 'proper nutriment'. When passed on to offspring via the reproductive process, gemmules were thought to be responsible for developing into each part of an organism and expressing characteristics inherited from both parents. [ 20 ]  Darwin thought this to occur in a literal sense: he explained cell proliferation to progress as gemmules to bind to more developed cells of their same character and mature. In this sense, the uniqueness of each individual would be due to their unique mixture of their parents' gemmules, and therefore characters. [ 20 ]  Similarity to one parent over the other could be explained by a quantitative superiority of one parent's gemmules. [ 18 ]  Yongshen Lu points out that Darwin knew of cells' ability to multiply by self-division, so it is unclear how Darwin supposed the two proliferation mechanisms to relate to each other. [ 18 ]  He did clarify in a later statement that he had always supposed gemmules to only bind to and proliferate from developing cells, not mature ones. [ 22 ]  Darwin hypothesized that gemmules might be able to survive and multiply outside of the body in a letter to  J. D. Hooker  in 1870. [ 23 ]


Some gemmules were thought to remain dormant for generations, whereas others were routinely expressed by all offspring. Every child was built up from selective expression of the mixture of the parents and grandparents' gemmules coming from either side. Darwin likened this to gardening: a flowerbed could be sprinkled with seeds "most of which soon germinate, some lie for a period dormant, whilst others perish." [ 24 ]  He did not claim gemmules were in the blood, although his theory was often interpreted in this way. Responding to  Fleming Jenkin 's review of  On the Origin of Species , he argued that pangenesis would permit the preservation of some favourable variations in a population so that they wouldn't die out through blending. [ 25 ]


Darwin thought that environmental effects that caused altered characteristics would lead to altered gemmules for the affected body part. The altered gemmules would then have a chance of being transferred to offspring, since they were assumed to be produced throughout an organism's life. [ 2 ]  Thus, pangenesis theory allowed for the Lamarckian idea of transmission of characteristics acquired through use and disuse. Accidental gemmule development in incorrect parts of the body could explain deformations and the 'monstrosities' Darwin cited in  Variation . [ 2 ]


Hugo de Vries  characterized his own version of pangenesis theory in his 1889 book  Intracellular Pangenesis  with two propositions, of which he only accepted the first:


The historian of science  Janet Browne  points out that while  Spencer and  Carl von Nägeli  also put forth ideas for systems of inheritance involving gemmules, their version of gemmules differed from Darwin's in that it contained "a complete microscopic blueprint for an entire creature." [ 27 ]  Spencer published his theory of "physiological units" three years prior to Darwin's publication of  Variation . [ 4 ]  Browne adds that Darwin believed specifically in gemmules from each body part because they might explain how environmental effects could be passed on as characteristics to offspring. [ 27 ]


Interpretations and applications of pangenesis continued to appear frequently in medical literature up until  Weismann's  experiments and subsequent publication on germ-plasm theory in 1892. [ 4 ]  For instance, an address by Huxley spurred on substantial work by Dr. James Ross in linking ideas found in Darwin's pangenesis to the  germ theory of disease . [ 28 ]  Ross cites the work of both Darwin and Spencer as key to his application of pangenetic theory. [ 28 ]


Darwin's half-cousin  Francis Galton  conducted wide-ranging inquiries into heredity which led him to refute Charles Darwin's hypothetical theory of pangenesis. In consultation with Darwin, he set out to see if gemmules were transported in the blood. In a long series of experiments from 1869 to 1871, he transfused the blood between dissimilar breeds of rabbits, and examined the features of their offspring. He found no evidence of characters transmitted in the transfused blood. [ 29 ]


Galton  was troubled because he began the work in good faith, intending to prove Darwin right, and having praised pangenesis in  Hereditary Genius  in 1869. Cautiously, he criticized his cousin's theory, although qualifying his remarks by saying that Darwin's gemmules, which he called "pangenes", might be temporary inhabitants of the blood that his experiments had failed to pick up. [ 30 ]


Darwin challenged the validity of Galton's experiment, giving his reasons in an article published in  Nature  where he wrote: [ 31 ]


Now, in the chapter on Pangenesis in my  Variation of Animals and Plants under Domestication,  I have not said one word about the blood, or about any fluid proper to any circulating system. It is, indeed, obvious that the presence of gemmules in the blood can form no necessary part of my hypothesis; for I refer in illustration of it to the lowest animals, such as the Protozoa, which do not possess blood or any vessels; and I refer to plants in which the fluid, when present in the vessels, cannot be considered as true blood." He goes on to admit: "Nevertheless, when I first heard of Mr. Galton's experiments, I did not sufficiently reflect on the subject, and saw not the difficulty of believing in the presence of gemmules in the blood. [ 31 ]


After the circulation of Galton's results, the perception of pangenesis quickly changed to severe skepticism if not outright disbelief. [ 18 ]


August Weismann 's idea, set out in his 1892 book  Das Keimplasma: eine Theorie der Vererbung  (The Germ Plasm: a Theory of Inheritance), [ 32 ]  was that the hereditary material, which he called the  germ plasm , and the rest of the body (the  soma ) had a one-way relationship: the germ-plasm formed the body, but the body did not influence the germ-plasm, except indirectly in its participation in a population subject to natural selection. This distinction is commonly referred to as the  Weismann Barrier . If correct, this made Darwin's pangenesis wrong and Lamarckian inheritance impossible. His experiment on mice, cutting off their tails and showing that their offspring had normal tails across multiple generations, was proposed as a proof of the non-existence of Lamarckian inheritance, although Peter Gauthier has argued that  Weismann's experiment  showed only that injury did not affect the germ plasm and neglected to test the effect of Lamarckian use and disuse. [ 33 ]  Weismann argued strongly and dogmatically for Darwinism and against neo-Lamarckism, polarising opinions among other scientists. [ 3 ]  This increased anti-Darwinian feeling, contributing to  its eclipse . [ 34 ] [ 35 ]


Darwin's pangenesis theory was widely criticised, in part for its  Lamarckian  premise that parents could  pass on traits acquired  in their lifetime. [ 36 ]  Conversely, the neo-Lamarckians of the time seized upon pangenesis as evidence to support their case. [ 3 ]  Italian Botanist Federico Delpino's objection that gemmules' ability to self-divide is contrary to their supposedly innate nature gained considerable traction; however, Darwin was dismissive of this criticism, remarking that the particulate agents of smallpox and scarlet fever seem to have such characteristics. [ 22 ]  Lamarckism fell from favour after  August Weismann 's research in the 1880s indicated that changes from use (such as lifting weights to increase muscle mass) and disuse (such as being lazy and becoming weak) were not heritable. [ 37 ] [ 38 ]  However, some scientists continued to voice their support in spite of Galton's and Weismann's results: notably, in 1900 Karl Pearson wrote that pangenesis "is no more disproved by the statement that 'gemmules have not been found in the blood,' than the atomic theory is disproved by the fact that no atoms have been found in the air." [ 39 ]  Finally, the rediscovery of Mendel's Laws of Inheritance in 1900 led to pangenesis being fully set aside. [ 40 ]  Julian Huxley has observed that the later discovery of  chromosomes  and the research of  T. H. Morgan  also made pangenesis untenable. [ 41 ]


Some of Darwin's pangenesis principles do relate to heritable aspects of  phenotypic plasticity , although the status of gemmules as a distinct class of organic particles has been firmly rejected. However, starting in the 1950s, many research groups in revisiting Galton's experiments found that heritable characteristics could indeed arise in rabbits and chickens following DNA injection or blood transfusion. [ 42 ]  This type of research originated in the Soviet Union in the late 1940s in the work of Sopikov and others, and was later corroborated by researchers in Switzerland as it was being further developed by the Soviet scientists. [ 43 ] [ 18 ]  Notably, this work was supported in the USSR in part due to its conformation with the ideas of  Trofim Lysenko , who espoused a version of neo-Lamarckism as part of  Lysenkoism . [ 43 ]  Further research of this heritability of acquired characteristics developed into, in part, the modern field of  epigenetics . Darwin himself had noted that "the existence of free gemmules is a gratuitous assumption"; by some accounts in modern interpretation, gemmules may be considered a prescient mix of DNA, RNA, proteins, prions, and other mobile elements that are heritable in a non-Mendelian manner at the molecular level. [ 15 ] [ 44 ] [ 45 ]  Liu points out that Darwin's ideas about gemmules replicating outside of the body are predictive of  in vitro  gene replication used, for instance, in  PCR . [ 18 ]


Post-docs:


Linus Carl Pauling   FRS  ( / ˈ p ɔː l ɪ ŋ /   PAW -ling ; February 28, 1901 – August 19, 1994) [ 4 ]  was an American  chemist ,  biochemist ,  chemical engineer ,  peace activist , author, and educator. He published more than 1,200 papers and books, of which about 850 dealt with scientific topics. [ 5 ]   New Scientist  called him one of the 20 greatest scientists of all time. [ 6 ]  For his scientific work, Pauling was awarded the  Nobel Prize in Chemistry  in 1954. For his peace activism, he was awarded the  Nobel Peace Prize  in 1962. He is one of five people to have  won more than one Nobel Prize  (the others being  Marie Curie ,  John Bardeen ,  Frederick Sanger , and  Karl Barry Sharpless ). [ 7 ]  Of these, he is the only person to have been awarded two unshared Nobel Prizes, [ 8 ]  and one of two people to be awarded Nobel Prizes in different fields, the other being  Marie Curie . [ 7 ]


Pauling was one of the founders of the fields of  quantum chemistry  and  molecular biology . [ 9 ]  His contributions to the theory of the chemical bond include the concept of  orbital hybridisation  and the first accurate scale of  electronegativities  of the elements. Pauling also worked on the structures of biological molecules, and showed the importance of the  alpha helix  and  beta sheet  in  protein secondary structure . Pauling's approach combined methods and results from  X-ray crystallography ,  molecular model  building, and quantum chemistry. His discoveries inspired the work of  Rosalind Franklin ,  James Watson ,  Francis Crick , and  Maurice Wilkins  on the structure of  DNA , which in turn made it possible for geneticists to crack the DNA code of all organisms. [ 10 ]


In his later years, he promoted  nuclear disarmament , as well as  orthomolecular medicine ,  megavitamin therapy , [ 11 ]  and  dietary supplements , especially  ascorbic acid  (commonly known as Vitamin C). None of his ideas concerning the medical usefulness of large doses of vitamins have gained much acceptance in the mainstream scientific community. [ 6 ] [ 12 ]  He was married to the American human rights activist  Ava Helen Pauling .


Linus Carl Pauling was born on February 28, 1901, in  Portland, Oregon , [ 13 ] [ 14 ]  the firstborn child of Herman Henry William Pauling (1876–1910) and Lucy Isabelle "Belle" Darling (1881–1926). [ 15 ] : 22   He was named "Linus Carl", in honor of Lucy's father, Linus, and Herman's father, Carl. [ 16 ] : 8   His ancestry included German and English. [ 17 ] [ 18 ]


In 1902, after his sister Pauline was born, Pauling's parents decided to move out of Portland to find more affordable and spacious living quarters than their one-room apartment. [ 19 ] : 4   Lucy stayed with her husband's parents in Oswego until Herman brought the family to  Salem , where he worked briefly as a traveling salesman for the Skidmore Drug Company. Within a year of Lucile's birth in 1904, Herman Pauling moved his family to  Oswego, Oregon  where he opened his own drugstore. [ 19 ] : 4   He moved his family to  Condon, Oregon , in 1905. [ 19 ] : 5   By 1906, Herman Pauling was suffering from recurrent  abdominal pain . He died of a perforated  ulcer  on June 11, 1910, leaving Lucy to care for Linus, Lucile and Pauline. [ 16 ] : 9


Pauling attributes his interest in becoming a chemist to being amazed by experiments conducted by a friend,  Lloyd A. Jeffress , who had a small chemistry lab kit. [ 19 ] : 17   He later wrote: "I was simply entranced by chemical phenomena, by the reactions in which substances, often with strikingly different properties, appear; and I hoped to learn more and more about this aspect of the world." [ 20 ]


In high school, Pauling conducted chemistry experiments by scavenging equipment and material from an abandoned steel plant. With an older friend, Lloyd Simon, Pauling set up Palmon Laboratories in Simon's basement.  They approached local dairies offering to perform butterfat samplings at cheap prices but dairymen were wary of trusting two boys with the task, and the business ended in failure. [ 19 ] : 21


At age 15, the high school senior had enough credits to enter  Oregon State University  (OSU), known then as Oregon Agricultural College. [ 19 ] : 22   Lacking two American history courses required for his  high school diploma , Pauling asked the school principal if he could take the courses concurrently during the spring semester. Denied, he left  Washington High School  in June without a diploma. [ 15 ] : 48   The school awarded him an honorary diploma 45 years later, after he was awarded two Nobel Prizes. [ 7 ] [ 21 ] [ 22 ]


Pauling held a number of jobs to earn money for his future college expenses, including working part-time at a grocery store for  US$ 8 per week (equivalent to  US$ 220 in 2023). His mother arranged an interview with the owner of a number of manufacturing plants in Portland, Mr. Schwietzerhoff, who hired him as an apprentice machinist at a salary of  US$ 40 per month (equivalent to  US$ 1,120 in 2023). This was soon raised to  US$ 50 per month. [ 19 ] : 23   Pauling also set up a photography laboratory with two friends. [ 19 ] : 24   In September 1917, Pauling was finally admitted by Oregon State University. He immediately resigned from the machinist's job and informed his mother, who saw no point in a university education, of his plans. [ 19 ] : 25


In his first semester, Pauling registered for two courses in chemistry, two in mathematics, mechanical drawing, introduction to mining and use of explosives, modern English prose, gymnastics and military drill. [ 19 ] : 26   His roommate was childhood pal and lifelong best friend Lloyd Jeffress. [ 23 ]   He was active in campus life and founded the school's chapter of the  Delta Upsilon  fraternity. [ 24 ]  After his second year, he planned to take a job in Portland to help support his mother. The college offered him a position teaching  quantitative analysis , a course he had just finished taking himself. He worked forty hours a week in the laboratory and classroom and earned  US$ 100 a month (equivalent to  US$ 1,500 in 2023), enabling him to continue his studies. [ 19 ] : 29


In his last two years at school, Pauling became aware of the work of  Gilbert N. Lewis  and  Irving Langmuir  on the  electronic structure  of atoms and their  bonding  to form  molecules . [ 19 ] : 29   He decided to focus his research on how the  physical  and  chemical properties  of substances are related to the structure of the atoms of which they are composed, becoming one of the founders of the new science of quantum chemistry. [ citation needed ]


Engineering professor Samuel Graf (1887–1966) [ 25 ] [ 26 ]  selected Pauling to be his teaching assistant in a mechanics and materials course. [ 19 ] : 29  [ 27 ] [ 28 ]  During the winter of his senior year, Pauling taught a chemistry course for  home economics  majors. It was in one of these classes that Pauling met his future wife,  Ava Helen Miller . [ 19 ] : 31  [ 28 ] : 41  [ 29 ] [ 30 ]


In 1922, Pauling graduated with a degree in  chemical engineering . He went on to graduate school at the  California Institute of Technology  (Caltech) in  Pasadena, California , under the guidance of  Roscoe Dickinson  and  Richard Tolman . [ 1 ]  His graduate research involved the use of  X-ray diffraction  to determine the structure of  crystals . He published seven papers on the  crystal structure  of minerals while he was at Caltech. He received his PhD in  physical chemistry  and  mathematical physics , [ 3 ]   summa cum laude , in 1925. [ 31 ]


In 1926, Pauling was awarded a  Guggenheim Fellowship  to travel to Europe, to study under German physicist  Arnold Sommerfeld  in Munich, Danish physicist  Niels Bohr  in Copenhagen and Austrian physicist  Erwin Schrödinger  in  Zürich . All three were experts in the new field of  quantum mechanics  and other branches of physics. [ 2 ]  Pauling became interested in how quantum mechanics might be applied in his chosen field of interest, the  electronic structure  of atoms and molecules. In Zürich, Pauling was also exposed to one of the first quantum mechanical analyses of bonding in the  hydrogen  molecule, done by  Walter Heitler  and  Fritz London . [ 32 ]  Pauling devoted the two years of his European trip to this work and decided to make it the focus of his future research. He became one of the first scientists in the field of quantum chemistry and a pioneer in the application of quantum theory to the structure of molecules. [ 33 ]


In 1927, Pauling took a new position as an assistant professor at  Caltech  in  theoretical chemistry . [ 34 ]  He launched his faculty career with a very productive five years, continuing with his  X-ray  crystal studies and also performing quantum mechanical calculations on atoms and molecules. He published approximately fifty papers in those five years, and created the five rules now known as  Pauling's rules . [ 35 ] [ 36 ]  By 1929, he was promoted to associate professor, and by 1930, to full professor. [ 34 ]  In 1931, the  American Chemical Society  awarded Pauling the Langmuir Prize for the most significant work in pure science by a person 30 years of age or younger. [ 37 ]  The following year, Pauling published what he regarded as his most important paper, in which he first laid out the concept of  hybridization of atomic orbitals  and analyzed the  tetravalency  of the  carbon  atom. [ 38 ]


At Caltech, Pauling struck up a close friendship with  theoretical physicist   Robert Oppenheimer  at the  University of California, Berkeley , who spent part of his research and teaching schedule as a visitor at Caltech each year. [ 15 ] [ 39 ]  Pauling was also affiliated with Berkeley, serving as a visiting lecturer in physics and chemistry from 1929 to 1934. [ 40 ]  Oppenheimer even gave Pauling a stunning personal collection of minerals. [ 41 ]   The two men planned to mount a joint attack on the nature of the chemical bond: apparently Oppenheimer would supply the mathematics and Pauling would interpret the results. Their relationship soured when Oppenheimer tried to pursue Pauling's wife, Ava Helen. When Pauling was at work, Oppenheimer came to their home and blurted out an invitation to Ava Helen to join him on a tryst in Mexico. She flatly refused, and reported the incident to Pauling. He immediately cut off his relationship with Oppenheimer. [ 15 ] : 152  [ 39 ]


In the summer of 1930, Pauling made another European trip, during which he learned about gas-phase electron  diffraction  from  Herman Francis Mark . After returning, he built an  electron diffraction  instrument at Caltech with a student of his,  Lawrence Olin Brockway , and used it to study the  molecular structure  of a large number of chemical substances. [ 42 ]


Pauling introduced the concept of  electronegativity  in 1932. [ 43 ]  Using the various properties of molecules, such as the energy required to break bonds and the  dipole   moments  of molecules, he established a scale and an associated numerical value for most of the elements  —  the  Pauling Electronegativity Scale  —  which is useful in predicting the nature of bonds between atoms in molecules. [ 44 ]


In 1936, Pauling was promoted to chairman of the division of chemistry and chemical engineering at Caltech, and to the position of director of the Gates and Crellin Laboratories of Chemistry. He would hold both positions until 1958. [ 34 ]  Pauling also spent a year in 1948 at the  University of Oxford  as George Eastman Visiting Professor and Fellow of Balliol. [ 45 ]


In the late 1920s, Pauling began publishing papers on the nature of the  chemical bond . Between 1937 and 1938, he took a position as George Fischer Baker Non-Resident Lecturer in Chemistry at  Cornell University . While at Cornell, he delivered a series of nineteen lectures [ 46 ]  and completed the bulk of his famous textbook  The Nature of the Chemical Bond . [ 47 ] [ 36 ] : Preface   It is based primarily on his work in this area that he received the  Nobel Prize in Chemistry  in 1954 "for his research into the nature of the chemical bond and its application to the elucidation of the structure of complex substances". [ 7 ]  Pauling's book has been considered "chemistry's most influential book of this century and its effective bible". [ 48 ]  In the 30 years after its first edition was published in 1939, the book was cited more than 16,000 times. Even today, many modern scientific papers and articles in important journals cite this work, more than seventy years after the first publication. [ 49 ]


Part of Pauling's work on the nature of the chemical bond led to his introduction of the concept of  orbital hybridization . [ 50 ]  While it is normal to think of the electrons in an atom as being described by  orbitals  of types such as  s  and  p , it turns out that in describing the bonding in molecules, it is better to construct functions that partake of some of the properties of each. Thus the one 2s and three 2p orbitals in a carbon atom can be (mathematically) 'mixed' or combined to make four equivalent orbitals (called sp 3  hybrid orbitals), which would be the appropriate orbitals to describe carbon compounds such as  methane , or the 2s orbital may be combined with two of the 2p orbitals to make three equivalent orbitals (called sp 2  hybrid orbitals), with the remaining 2p orbital unhybridized, which would be the appropriate orbitals to describe certain  unsaturated  carbon compounds such as  ethylene . [ 36 ] : 111–120   Other hybridization schemes are also found in other types of molecules.
Another area which he explored was the relationship between  ionic bonding , where electrons are transferred between atoms, and  covalent bonding , where electrons are shared between atoms on an equal basis. Pauling showed that these were merely extremes, and that for most actual cases of bonding, the  quantum-mechanical   wave function  for a polar molecule AB is a  combination  of wave functions for covalent and ionic molecules. [ 36 ] : 66   Here Pauling's  electronegativity  concept is particularly useful; the electronegativity difference between a pair of atoms will be the surest predictor of the degree of ionicity of the bond. [ 51 ]


The third of the topics that Pauling attacked under the overall heading of "the nature of the chemical bond" was the accounting of the structure of  aromatic hydrocarbons , particularly the prototype,  benzene . [ 52 ]  The best description of benzene had been made by the German chemist  Friedrich Kekulé . He had treated it as a rapid interconversion between two structures, each with alternating single and  double bonds , but with the double bonds of one structure in the locations where the single bonds were in the other. Pauling showed that a proper description based on quantum mechanics was an intermediate structure which was a blend of each. The structure was a superposition of structures rather than a rapid interconversion between them. The name " resonance " was later applied to this phenomenon. [ 53 ]  In a sense, this phenomenon resembles those of hybridization and also polar bonding, both described above, because all three phenomena involve combining more than one electronic structure to achieve an intermediate result. [ citation needed ]


In 1929, Pauling published  five rules  which help to  predict  and explain  crystal structures  of  ionic compounds . [ 54 ] [ 36 ]
These rules concern (1) the ratio of cation radius to anion radius, (2) the electrostatic bond strength, (3) the sharing of polyhedron corners, edges and faces, (4) crystals containing different cations, and (5) the rule of parsimony. [ citation needed ]


In the mid-1930s, Pauling, strongly influenced by the biologically oriented funding priorities of the Rockefeller Foundation's  Warren Weaver , decided to strike out into new areas of interest. [ 55 ]  Although Pauling's early interest had focused almost exclusively on inorganic molecular structures, he had occasionally thought about molecules of biological importance, in part because of Caltech's growing strength in biology. Pauling interacted with such great biologists as  Thomas Hunt Morgan ,  Theodosius Dobzhanski ,  Calvin Bridges  and  Alfred Sturtevant . [ 56 ]  His early work in this area included studies of the structure of  hemoglobin  with his student  Charles D. Coryell . He demonstrated that the hemoglobin molecule changes structure when it gains or loses an  oxygen  molecule. [ 56 ]  As a result of this observation, he decided to conduct a more thorough study of  protein structure  in general. He returned to his earlier use of X-ray diffraction analysis. But protein structures were far less amenable to this technique than the crystalline minerals of his former work. The best X-ray pictures of proteins in the 1930s had been made by the British crystallographer  William Astbury , but when Pauling tried, in 1937, to account for Astbury's observations quantum mechanically, he could not. [ 57 ]


It took eleven years for Pauling to explain the problem: his  mathematical  analysis was correct, but Astbury's pictures were taken in such a way that the protein molecules were tilted from their expected positions. Pauling had formulated a model for the structure of hemoglobin in which atoms were arranged in a  helical  pattern, and applied this idea to proteins in general. [ citation needed ]