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132-477: The first important document of the RNA Tie Club was Francis Crick 's adaptor hypothesis in 1955. Experimental work on the hypothesis led to the discovery of transfer RNA , a molecule that carries the key to genetic code. Most of the theoretical groundwork and preliminary experiments on the genetic code were done by the club members within a decade. However, the specific code was discovered by Marshall Nirenberg ,

264-505: A stop codon . Mutations that disrupt the reading frame sequence by indels ( insertions or deletions ) of a non-multiple of 3 nucleotide bases are known as frameshift mutations . These mutations usually result in a completely different translation from the original, and likely cause a stop codon to be read, which truncates the protein. These mutations may impair the protein's function and are thus rare in in vivo protein-coding sequences. One reason inheritance of frameshift mutations

396-405: A biochemical or evolutionary model for its origin. If amino acids were randomly assigned to triplet codons, there would be 1.5 × 10 possible genetic codes. This number is found by calculating the number of ways that 21 items (20 amino acids plus one stop) can be placed in 64 bins, wherein each item is used at least once. However, the distribution of codon assignments in the genetic code

528-612: A black wool-knit tie with a green and yellow RNA helix emblazoned on it. The original design of the tie came from Orgel, with the final pattern re-imagined by Gamow. Gamow's tie pattern was delivered to a Los Angeles haberdasher on Colorado Avenue by Watson, with the shop tailor promising to make the ties for $ 4 each. Along with each tie, members of the club were to receive a golden tiepin with the three letter abbreviation of their club amino acid designation. Not all members may have received their pin. Gamow, however, wore his pin on several occasions, often causing confusion and questioning of why he

660-468: A chain-initiation codon or start codon . The start codon alone is not sufficient to begin the process. Nearby sequences such as the Shine-Dalgarno sequence in E. coli and initiation factors are also required to start translation. The most common start codon is AUG, which is read as methionine or as formylmethionine (in bacteria, mitochondria, and plastids). Alternative start codons depending on

792-561: A functional 65th ( in vivo ) codon. In 2015 N. Budisa , D. Söll and co-workers reported the full substitution of all 20,899 tryptophan residues (UGG codons) with unnatural thienopyrrole-alanine in the genetic code of the bacterium Escherichia coli . In 2016 the first stable semisynthetic organism was created. It was a (single cell) bacterium with two synthetic bases (called X and Y). The bases survived cell division. In 2017, researchers in South Korea reported that they had engineered

924-456: A helical structure was not the only possible shape for DNA—so they had a dilemma. In an effort to clarify this issue, Max Ferdinand Perutz later published what had been in the progress report, and suggested that nothing was in the report that Franklin herself had not said in her talk (attended by Watson) in late 1951. Perutz explained that the report was to a Medical Research Council (MRC) committee that had been created to "establish contact between

1056-548: A longer article on 12 June 1953). The university's undergraduate newspaper Varsity also ran its own short article on the discovery on Saturday 30 May 1953. Bragg's original announcement of the discovery at a Solvay conference on proteins in Belgium on 8 April 1953 went unreported by the British press. In a seven-page, handwritten letter to his son at a British boarding school on 19 March 1953 Crick explained his discovery, beginning

1188-439: A mouse with an extended genetic code that can produce proteins with unnatural amino acids. In May 2019, researchers reported the creation of a new "Syn61" strain of the bacterium Escherichia coli . This strain has a fully synthetic genome that is refactored (all overlaps expanded), recoded (removing the use of three out of 64 codons completely), and further modified to remove the now unnecessary tRNAs and release factors. It

1320-618: A non-member, who received Nobel Prize in Physiology or Medicine in 1968 for the discovery. In 1953, English biophysicist Francis Crick and American biologist James Watson , working together at the Cavendish Laboratory of the University of Cambridge, deduced the structure of DNA , the principal genetic material of organisms, thought to link genetic information in DNA to proteins. By 1954, it

1452-447: A nucleotide code consisting of three letters (triplets) would be enough to define all 20 amino acids. This concept is the basis of " codons ", and set an upper and lower limit on their size. Gamow had simply estimated that the number of bases and their complementary pairs in a DNA strand could create 20 cavities for amino acids, meaning that 20 different amino acids could be involved in protein synthesis. He named this DNA–protein interaction

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1584-479: A pupil at Mill Hill. Crick studied at University College London (UCL), a constituent college of the University of London and earned a Bachelor of Science degree awarded by the University of London in 1937. Crick began a PhD at UCL, but was interrupted by World War II . He later became a PhD student and Honorary Fellow of Gonville and Caius College, Cambridge , and mainly worked at the Cavendish Laboratory and

1716-520: A scientist until the bitter end" according to Christof Koch . Crick was the first son of Harry Crick and Annie Elizabeth Crick (née Wilkins). He was born on 8 June 1916 and raised in Weston Favell , then a small village near the English town of Northampton , in which Crick's father and uncle ran the family's boot and shoe factory. His grandfather, Walter Drawbridge Crick , an amateur naturalist , wrote

1848-457: A second attempt to do so. They asked for, and received, permission to do so from both William Lawrence Bragg and Wilkins. To construct their model of DNA, Watson and Crick made use of information from unpublished X-ray diffraction images of Franklin's (shown at meetings and freely shared by Wilkins), including preliminary accounts of Franklin's results/photographs of the X-ray images that were included in

1980-522: A similar approach to FACIL with a larger Pfam database. Despite the NCBI already providing 27 translation tables, the authors were able to find new 5 genetic code variations (corroborated by tRNA mutations) and correct several misattributions. Codetta was later used to analyze genetic code change in ciliates . The genetic code is a key part of the history of life , according to one version of which self-replicating RNA molecules preceded life as we know it. This

2112-463: A small audience in Moscow at a 1961 conference. Crick's reaction was to invite Nirenberg to deliver his talk to a larger audience. Watson and Crick's use of DNA X-ray diffraction data collected by Franklin and Wilkins has generated an enduring controversy. It arose from the fact that some of Franklin's unpublished data were used without her knowledge or consent by Watson and Crick in their construction of

2244-645: A small house on the south side of Abington Avenue; he had a shed at the bottom of his little garden where he taught Crick to blow glass, do chemical experiments and to make photographic prints. When he was eight or nine he transferred to the most junior form of the Northampton Grammar School , on the Billing Road. This was about 1.25 mi (2 km) from his home so he could walk there and back, by Park Avenue South and Abington Park Crescent, but he more often went by bus or, later, by bicycle. The teaching in

2376-485: A survey of local foraminifera (single-celled protists with shells), corresponded with Charles Darwin , and had two gastropods (snails or slugs) named after him. At an early age, Francis was attracted to science and what he could learn about it from books. As a child, he was taken to church by his parents. But by about age 12, he said he did not want to go any more as he preferred a scientific search for answers over religious belief. Walter Crick, his uncle, lived in

2508-545: A synthetic DNA. In addition to synthetic DNA there are also attempts to construct synthetic codons , synthetic endonucleases , synthetic proteins and synthetic zinc fingers . Using synthetic DNA, instead of there being 4 codons, if there are n new bases there could be as many as n codons. Research is currently being done to see if codons can be expanded to more than 3 bases. These new codons can code for new amino acids. These synthetic molecules can be used not only in medicine, but in creation of new materials. The discovery

2640-460: A three-nucleotide codon in a nucleic acid sequence specifies a single amino acid. The vast majority of genes are encoded with a single scheme (see the RNA codon table ). That scheme is often referred to as the canonical or standard genetic code, or simply the genetic code, though variant codes (such as in mitochondria ) exist. Efforts to understand how proteins are encoded began after DNA's structure

2772-545: A type-written paper titled "On Degenerate Templates and the Adaptor Hypothesis: A Note for the RNA Tie Club" to the members of the club in January 1955, which "totally changed the way we thought about protein synthesis", as Watson recalled. The hypothesis states that the triplet code was not passed on to amino acids as Gamow thought, but carried by a different molecule, an adaptor, that interacts with amino acids. The adaptor

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2904-417: A while they were forbidden to make further efforts to find a molecular model of DNA. Of great importance to the model building effort of Watson and Crick was Rosalind Franklin's understanding of basic chemistry, which indicated that the hydrophilic phosphate -containing backbones of the nucleotide chains of DNA should be positioned so as to interact with water molecules on the outside of the molecule while

3036-531: A written progress report for the King's College laboratory of Sir John Randall from late 1952. It is a matter of debate whether Watson and Crick should have had access to Franklin's results without her knowledge or permission, and before she had a chance to formally publish the results of her detailed analysis of her X-ray diffraction data which were included in the progress report. However, Watson and Crick found fault in her steadfast assertion that, according to her data,

3168-436: Is CCG, whereas in humans this is the least used proline codon. In some proteins, non-standard amino acids are substituted for standard stop codons, depending on associated signal sequences in the messenger RNA. For example, UGA can code for selenocysteine and UAG can code for pyrrolysine . Selenocysteine came to be seen as the 21st amino acid, and pyrrolysine as the 22nd. Both selenocysteine and pyrrolysine may be present in

3300-455: Is accomplished by the ribosome , which links proteinogenic amino acids in an order specified by messenger RNA (mRNA), using transfer RNA (tRNA) molecules to carry amino acids and to read the mRNA three nucleotides at a time. The genetic code is highly similar among all organisms and can be expressed in a simple table with 64 entries. The codons specify which amino acid will be added next during protein biosynthesis . With some exceptions,

3432-511: Is called clonal interference and causes competition among the mutations. Degeneracy is the redundancy of the genetic code. This term was given by Bernfield and Nirenberg. The genetic code has redundancy but no ambiguity (see the codon tables below for the full correlation). For example, although codons GAA and GAG both specify glutamic acid (redundancy), neither specifies another amino acid (no ambiguity). The codons encoding one amino acid may differ in any of their three positions. For example,

3564-440: Is fully viable and grows 1.6× slower than its wild-type counterpart "MDS42". A reading frame is defined by the initial triplet of nucleotides from which translation starts. It sets the frame for a run of successive, non-overlapping codons, which is known as an " open reading frame " (ORF). For example, the string 5'-AAATGAACG-3' (see figure), if read from the first position, contains the codons AAA, TGA, and ACG ; if read from

3696-519: Is irreversible. During the remainder of his career, he held the post of J.W. Kieckhefer Distinguished Research Professor at the Salk Institute for Biological Studies in La Jolla, California . His later research centred on theoretical neurobiology and attempts to advance the scientific study of human consciousness. He remained in this post until his death; "he was editing a manuscript on his death bed,

3828-422: Is nonrandom. In particular, the genetic code clusters certain amino acid assignments. Amino acids that share the same biosynthetic pathway tend to have the same first base in their codons. This could be an evolutionary relic of an early, simpler genetic code with fewer amino acids that later evolved to code a larger set of amino acids. It could also reflect steric and chemical properties that had another effect on

3960-434: Is rare is that, if the protein being translated is essential for growth under the selective pressures the organism faces, absence of a functional protein may cause death before the organism becomes viable. Frameshift mutations may result in severe genetic diseases such as Tay–Sachs disease . Although most mutations that change protein sequences are harmful or neutral, some mutations have benefits. These mutations may enable

4092-479: Is relevant both to peptide bonds in proteins and the structure of nucleotides in DNA. In 1951 and 1952, together with William Cochran and Vladimir Vand, Crick assisted in the development of a mathematical theory of X-ray diffraction by a helical molecule. This theoretical result matched well with X-ray data for proteins that contain sequences of amino acids in the alpha helix conformation. Helical diffraction theory turned out to also be useful for understanding

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4224-408: Is so well-structured for hydropathicity that a mathematical analysis ( Singular Value Decomposition ) of 12 variables (4 nucleotides x 3 positions) yields a remarkable correlation (C = 0.95) for predicting the hydropathicity of the encoded amino acid directly from the triplet nucleotide sequence, without translation. Note in the table, below, eight amino acids are not affected at all by mutations at

4356-534: Is the RNA world hypothesis . Under this hypothesis, any model for the emergence of the genetic code is intimately related to a model of the transfer from ribozymes (RNA enzymes) to proteins as the principal enzymes in cells. In line with the RNA world hypothesis, transfer RNA molecules appear to have evolved before modern aminoacyl-tRNA synthetases , so the latter cannot be part of the explanation of its patterns. A hypothetical randomly evolved genetic code further motivates

4488-607: Is the same for all organisms: three-base codons, tRNA , ribosomes, single direction reading and translating single codons into single amino acids. The most extreme variations occur in certain ciliates where the meaning of stop codons depends on their position within mRNA. When close to the 3' end they act as terminators while in internal positions they either code for amino acids as in Condylostoma magnum or trigger ribosomal frameshifting as in Euplotes . The origins and variation of

4620-488: Is universal (the same in all organisms) or nearly so". The first variation was discovered in 1979, by researchers studying human mitochondrial genes . Many slight variants were discovered thereafter, including various alternative mitochondrial codes. These minor variants for example involve translation of the codon UGA as tryptophan in Mycoplasma species, and translation of CUG as a serine rather than leucine in yeasts of

4752-400: Is what made Crick confident that DNA was a double helix with antiparallel chains, but there were other chains of reasoning and sources of information that also led to these conclusions. As a result of leaving King's College for Birkbeck College , Franklin was asked by John Randall to give up her work on DNA. When it became clear to Wilkins and the supervisors of Watson and Crick that Franklin

4884-567: The Medical Research Council (MRC) Laboratory of Molecular Biology in Cambridge. He was also an Honorary Fellow of Churchill College, Cambridge , and of University College, London. Crick began a PhD research project on measuring the viscosity of water at high temperatures (which he later described as "the dullest problem imaginable" ) in the laboratory of physicist Edward Neville da Costa Andrade at University College London, but with

5016-553: The New York University Tandon School of Engineering . During World War II, he worked for the Admiralty Research Laboratory , from which many notable scientists emerged, including David Bates , Robert Boyd , Thomas Gaskell , George Deacon , John Gunn , Harrie Massey , and Nevill Mott ; he worked on the design of magnetic and acoustic mines and was instrumental in designing a new mine that

5148-452: The Nobel Prize in Physiology or Medicine in 1962 with Wilkins. When Watson came to Cambridge, Crick was a 35-year-old graduate student (due to his work during WWII) and Watson was only 23, but had already obtained a PhD. They shared an interest in the fundamental problem of learning how genetic information might be stored in molecular form. Watson and Crick talked endlessly about DNA and

5280-766: The United States government and he did not visit the UK until later, at which point he met none of the DNA researchers in England. At any rate he was preoccupied with proteins at the time, not DNA. Watson and Crick were not officially working on DNA. Crick was writing his PhD thesis; Watson also had other work such as trying to obtain crystals of myoglobin for X-ray diffraction experiments. In 1952, Watson performed X-ray diffraction on tobacco mosaic virus and found results indicating that it had helical structure. Having failed once, Watson and Crick were now somewhat reluctant to try again and for

5412-519: The helical structure of the DNA molecule . Crick and Watson's paper in Nature in 1953 laid the groundwork for understanding DNA structure and functions. Together with Maurice Wilkins, they were jointly awarded the 1962 Nobel Prize in Physiology or Medicine "for their discoveries concerning the molecular structure of nucleic acids and its significance for information transfer in living material". Crick

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5544-414: The hydrophobic bases should be packed into the core. Franklin shared this chemical knowledge with Watson and Crick when she pointed out to them that their first model (from 1951, with the phosphates inside) was obviously wrong. Crick described what he saw as the failure of Wilkins and Franklin to cooperate and work towards finding a molecular model of DNA as a major reason why he and Watson eventually made

5676-494: The " adaptor hypothesis " (a name given by Brenner) suggesting that some molecule ferried the amino acids around, and put them in the correct order corresponding to the nucleic acid sequence. The hypothesis contradicted Gamow's direct DNA template hypothesis, positing that DNA could not synthesise proteins directly, but instead requires other molecules, adaptors to convert the DNA sequences to amino acid sequences. He also suggested that there were such 20 separate adaptor molecules. This

5808-472: The "CTG clade" (such as Candida albicans ). Because viruses must use the same genetic code as their hosts, modifications to the standard genetic code could interfere with viral protein synthesis or functioning. However, viruses such as totiviruses have adapted to the host's genetic code modification. In bacteria and archaea , GUG and UUG are common start codons. In rare cases, certain proteins may use alternative start codons. Surprisingly, variations in

5940-470: The "color names" theme. In a broad academic audience, the concept of the evolution of the genetic code from the original and ambiguous genetic code to a well-defined ("frozen") code with the repertoire of 20 (+2) canonical amino acids is widely accepted. However, there are different opinions, concepts, approaches and ideas, which is the best way to change it experimentally. Even models are proposed that predict "entry points" for synthetic amino acid invasion of

6072-404: The "diamond code." Although Gamow's premise that DNA directly synthesized proteins was proven wrong, the triplet code became the foundation of genetic code. Sydney Brenner proposed the concept of the codon, the idea that three non-overlapping nucleotides could code for one amino acid. His proof involved statistics and experimental evidence from amino acid protein sequences. Francis Crick proposed

6204-525: The "elaborate chemical mechanisms that natural selection had evolved over billions of years." He described this transition as, "almost as if one had to be born again". According to Crick, the experience of learning physics had taught him something important—hubris—and the conviction that since physics was already a success, great advances should also be possible in other sciences such as biology. Crick felt that this attitude encouraged him to be more daring than typical biologists who tended to concern themselves with

6336-419: The "proofreading" ability of DNA polymerases . Missense mutations and nonsense mutations are examples of point mutations that can cause genetic diseases such as sickle-cell disease and thalassemia respectively. Clinically important missense mutations generally change the properties of the coded amino acid residue among basic, acidic, polar or non-polar states, whereas nonsense mutations result in

6468-453: The 'holes' of deoxyribonucleic acid molecules, and thus unite into the corresponding peptide chains. In May 1954, Watson visited Gamow, who was on sabbatical at the University of California, Berkeley . While discussing Gamow's hypothesis, he suggested that they form a 20-member club to work out the genetic code. Gamow instantly came up with the RNA Tie Club to "solve the riddle of the RNA structure and to understand how it built proteins", adding

6600-433: The 1940s, some evidence had been found pointing to another macromolecule, DNA, the other major component of chromosomes , as a candidate genetic molecule. In the 1944 Avery-MacLeod-McCarty experiment , Oswald Avery and his collaborators showed that a heritable phenotypic difference could be caused in bacteria by providing them with a particular DNA molecule. However, other evidence was interpreted as suggesting that DNA

6732-487: The 20 standard amino acids used by living cells to build proteins, which would allow a maximum of 4 = 64 amino acids. He named this DNA–protein interaction (the original genetic code) as the "diamond code". In 1954, Gamow created an informal scientific organisation the RNA Tie Club , as suggested by Watson, for scientists of different persuasions who were interested in how proteins were synthesised from genes. However,

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6864-661: The DNA double helix structure was made possible by their willingness to combine theory, modelling and experimental results (albeit mostly done by others) to achieve their goal. The DNA double helix structure proposed by Watson and Crick was based upon "Watson-Crick" bonds between the four bases most frequently found in DNA (A, C, T, G) and RNA (A, C, U, G). However, later research showed that triple-stranded, quadruple-stranded and other more complex DNA molecular structures required Hoogsteen base pairing . The entire field of synthetic biology began with work by researchers such as Erik T Kool, in which bases other than A, C, T and G are used in

6996-488: The Watson and Crick model was not the first "bases in" model to be proposed. Furberg's results had also provided the correct orientation of the DNA sugars with respect to the bases. During their model building, Crick and Watson learned that an antiparallel orientation of the two nucleotide chain backbones worked best to orient the base pairs in the centre of a double helix. Crick's access to Franklin's progress report of late 1952

7128-422: The amino acid lysine , and the codon CCC specified the amino acid proline . Using various copolymers most of the remaining codons were then determined. Subsequent work by Har Gobind Khorana identified the rest of the genetic code. Shortly thereafter, Robert W. Holley determined the structure of transfer RNA (tRNA), the adapter molecule that facilitates the process of translating RNA into protein. This work

7260-470: The amino acid phenylalanine . They thereby deduced that the codon UUU specified the amino acid phenylalanine. This was followed by experiments in Severo Ochoa 's laboratory that demonstrated that the poly- adenine RNA sequence (AAAAA...) coded for the polypeptide poly- lysine and that the poly- cytosine RNA sequence (CCCCC...) coded for the polypeptide poly- proline . Therefore, the codon AAA specified

7392-409: The amino acid leucine is specified by Y U R or CU N (UUA, UUG, CUU, CUC, CUA, or CUG) codons (difference in the first or third position indicated using IUPAC notation ), while the amino acid serine is specified by UC N or AG Y (UCA, UCG, UCC, UCU, AGU, or AGC) codons (difference in the first, second, or third position). A practical consequence of redundancy is that errors in the third position of

7524-490: The annals of molecular biology." Watson recalled, "The most famous of these [unpublished] notes, by Francis, in time would totally change the way we thought about protein synthesis. Six members of the RNA Tie Club became Nobel laureates: Richard Feynman, Melvin Calvin, James Watson, Max Delbruck, Francis Crick and Sydney Brenner. However, the ultimate goal of understanding and deciphering the code linking nucleic acids and amino acids

7656-590: The binding of specific tRNAs to the ribosome. Leder and Nirenberg were able to determine the sequences of 54 out of 64 codons in their experiments. Khorana, Holley and Nirenberg received the Nobel Prize (1968) for their work. The three stop codons were named by discoverers Richard Epstein and Charles Steinberg. "Amber" was named after their friend Harris Bernstein, whose last name means "amber" in German. The other two stop codons were named "ochre" and "opal" in order to keep

7788-421: The club could have only 20 permanent members to represent each of the 20 amino acids; and four additional honorary members to represent the four nucleotides of DNA. The first scientific contribution of the club, later recorded as "one of the most important unpublished articles in the history of science" and "the most famous unpublished paper in the annals of molecular biology", was made by Crick. Crick presented

7920-486: The codon during its evolution. Amino acids with similar physical properties also tend to have similar codons, reducing the problems caused by point mutations and mistranslations. Given the non-random genetic triplet coding scheme, a tenable hypothesis for the origin of genetic code could address multiple aspects of the codon table, such as absence of codons for D-amino acids, secondary codon patterns for some amino acids, confinement of synonymous positions to third position,

8052-404: The conclusion that X-ray diffraction data for DNA indicated that the molecule had a helical structure—but Franklin vehemently disputed this conclusion. Stimulated by their discussions with Wilkins and what Watson learned by attending a talk given by Franklin about her work on DNA, Crick and Watson produced and showed off an erroneous first model of DNA. Their hurry to produce a model of DNA structure

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8184-479: The data from King's College, was to guess how the nucleotide bases pack into the core of the DNA double helix. Another key to finding the correct structure of DNA was the so-called Chargaff ratios , experimentally determined ratios of the nucleotide subunits of DNA: the amount of guanine is equal to cytosine and the amount of adenine is equal to thymine . A visit by Erwin Chargaff to England, in 1952, reinforced

8316-409: The daunting problems of biology and not the past successes of physics . For the better part of two years, Crick worked on the physical properties of cytoplasm at Cambridge's Strangeways Research Laboratory , headed by Honor Bridget Fell , with a Medical Research Council studentship, until he joined Max Perutz and John Kendrew at the Cavendish Laboratory . The Cavendish Laboratory at Cambridge

8448-626: The different groups of people working for the Council". Randall's and Perutz's laboratories were both funded by the MRC. It is also not clear how important Franklin's unpublished results from the progress report actually were for the model-building done by Watson and Crick. After the first crude X-ray diffraction images of DNA were collected in the 1930s, William Astbury had talked about stacks of nucleotides spaced at 3.4 angström (0.34 nanometre) intervals in DNA. A citation to Astbury's earlier X-ray diffraction work

8580-866: The discovery of the double helix model of DNA, Crick's interests quickly turned to the biological implications of the structure. In 1953, Watson and Crick published another article in Nature which stated: "it therefore seems likely that the precise sequence of the bases is the code that carries the genetical information". In 1956, Crick and Watson speculated on the structure of small viruses. They suggested that spherical viruses such as Tomato bushy stunt virus had icosahedral symmetry and were made from 60 identical subunits. After his short time in New York, Crick returned to Cambridge where he worked until 1976, at which time he moved to California. Crick engaged in several X-ray diffraction collaborations such as one with Alexander Rich on

8712-402: The double helix model of DNA. Of the four DNA researchers, only Franklin had a degree in chemistry; Wilkins and Crick had backgrounds in physics, Watson in biology. Codons The genetic code is the set of rules used by living cells to translate information encoded within genetic material ( DNA or RNA sequences of nucleotide triplets, or codons ) into proteins . Translation

8844-653: The first people in April 1953 to see the model of the structure of DNA , constructed by Crick and Watson; at the time they were working at Oxford University 's Chemistry Department. All were impressed by the new DNA model, especially Brenner who subsequently worked with Crick at Cambridge in the Cavendish Laboratory and the new Laboratory of Molecular Biology . According to the late Dr. Beryl Oughton, later Rimmer, they all travelled together in two cars once Dorothy Hodgkin announced to them that they were off to Cambridge to see

8976-499: The first position of certain codons, but not upon changes in the second position of any codon. Such charge reversal may have dramatic consequences for the structure or function of a protein. This aspect may have been largely underestimated by previous studies. The frequency of codons, also known as codon usage bias , can vary from species to species with functional implications for the control of translation . The codon varies by organism; for example, most common proline codon in E. coli

9108-541: The first scheme for protein synthesis from DNA. In early 1954, he spent several days at Woods Hole on Cape Cod with Crick, Watson and Sydney Brenner , discussing genetics. Based on the Watson-Crick model , he proposed a "direct DNA template hypothesis" stating that proteins are synthesised directly from the double-stranded grooves of DNA. The four bases of DNA were assumed to synthesise 20 different amino acids as triplets with overlapping nucleotide sequences. He published

9240-438: The genetic code, including the mechanisms behind the evolvability of the genetic code, have been widely studied, and some studies have been done experimentally evolving the genetic code of some organisms. Variant genetic codes used by an organism can be inferred by identifying highly conserved genes encoded in that genome, and comparing its codon usage to the amino acids in homologous proteins of other organisms. For example,

9372-494: The genetic code. Since 2001, 40 non-natural amino acids have been added into proteins by creating a unique codon (recoding) and a corresponding transfer-RNA:aminoacyl – tRNA-synthetase pair to encode it with diverse physicochemical and biological properties in order to be used as a tool to exploring protein structure and function or to create novel or enhanced proteins. H. Murakami and M. Sisido extended some codons to have four and five bases. Steven A. Benner constructed

9504-414: The heavyweight champ." Soon after Crick's death, there have been allegations about him having used LSD when he came to the idea of the helix structure of the DNA. While he almost certainly did use LSD, it is unlikely that he did so as early as 1953. In 1954, at the age of 37, Crick completed his PhD thesis: " X-Ray Diffraction: Polypeptides and Proteins " and received his degree. Crick then worked in

9636-541: The higher forms was satisfactory, but not as stimulating. After the age of 14, he was educated at Mill Hill School in London (on a scholarship), where he studied mathematics, physics , and chemistry with his best friend John Shilston. He shared the Walter Knox Prize for Chemistry on Mill Hill School's Foundation Day, Friday, 7 July 1933. He declared that his success was founded on the quality of teaching he received whilst

9768-400: The hypothesis in the 13 February 1954 issue of Nature , explaining: It seems to me that such translation procedure can be easily established by considering the ' key-and-lock ' relation between various amino-acids, and the rhomb-shaped 'holes' formed by various nucleotides in the deoxyribonucleic acid chain... One can speculate that free amino-acids from the surrounding medium get caught into

9900-430: The idea that it might be possible to guess a good molecular model of its structure. A key piece of experimentally-derived information came from X-ray diffraction images that had been obtained by Wilkins, Franklin, and Gosling. In November 1951, Wilkins came to Cambridge and shared his data with Watson and Crick. Alexander Stokes (another expert in helical diffraction theory) and Wilkins (both at King's College) had reached

10032-538: The interpretation of the genetic code exist also in human nuclear-encoded genes: In 2016, researchers studying the translation of malate dehydrogenase found that in about 4% of the mRNAs encoding this enzyme the stop codon is naturally used to encode the amino acids tryptophan and arginine. This type of recoding is induced by a high-readthrough stop codon context and it is referred to as functional translational readthrough . Despite these differences, all known naturally occurring codes are very similar. The coding mechanism

10164-464: The key features of the protein synthesis process: The adaptor molecules were eventually shown to be tRNAs and the catalytic "ribonucleic-protein complexes" became known as ribosomes . An important step was the realisation by Crick and Brenner on 15 April 1960 during a conversation with François Jacob that messenger RNA was not the same thing as ribosomal RNA . Later that summer, Brenner, Jacob, and Matthew Meselson conducted an experiment which

10296-722: The laboratory of David Harker at Brooklyn Polytechnic Institute , where he continued to develop his skills in the analysis of X-ray diffraction data for proteins, working primarily on ribonuclease and the mechanisms of protein synthesis . David Harker, the American X-ray crystallographer, was described as "the John Wayne of crystallography" by Vittorio Luzzati, a crystallographer at the Centre for Molecular Genetics in Gif-sur-Yvette near Paris, who had worked with Rosalind Franklin. After

10428-407: The letter "My Dear Michael, Jim Watson and I have probably made a most important discovery". The letter was put up for auction at Christie's New York on 10 April 2013 with an estimate of $ 1 to $ 2 million, eventually selling for $ 6,059,750, the largest amount ever paid for a letter at auction. Sydney Brenner , Jack Dunitz , Dorothy Hodgkin , Leslie Orgel , and Beryl M Oughton, were some of

10560-475: The model of the structure of DNA. Orgel also later worked with Crick at the Salk Institute for Biological Studies . Crick was often described as very talkative, with Watson – in The Double Helix – implying lack of modesty. His personality combined with his scientific accomplishments produced many opportunities for Crick to stimulate reactions from others, both inside and outside the scientific world, which

10692-497: The molecular structure of large molecules like proteins and DNA, but there were serious technical problems then preventing X-ray crystallography from being applicable to such large molecules. Crick taught himself the mathematical theory of X-ray crystallography. During the period of Crick's study of X-ray diffraction , researchers in the Cambridge lab were attempting to determine the most stable helical conformation of amino acid chains in proteins (the alpha helix ). Linus Pauling

10824-730: The morning of 28 July 2004 at the University of California, San Diego (UCSD) Thornton Hospital in La Jolla; he was cremated and his ashes were scattered into the Pacific Ocean. A public memorial was held on 27 September 2004 at the Salk Institute , La Jolla, near San Diego, California; guest speakers included James Watson , Sydney Brenner , Alex Rich , Seymour Benzer , Aaron Klug , Christof Koch , Pat Churchland , Vilayanur Ramachandran , Tomaso Poggio , Leslie Orgel , Terry Sejnowski , his son Michael Crick, and his younger daughter Jacqueline Nichols. A private memorial for family and colleagues

10956-401: The motto "do or die; or don't try." The club thus consisted of 20 eminent scientists, each of whom corresponded to an amino acid, plus four honorary members (S. Brenner, VAL. F. Lipmann, A. Szent-Gyorgyi , and another individual), one for each nucleotide . Each member received a woolen necktie having an embroidered helix, hence the name "RNA Tie Club". Members of the RNA Tie Club received

11088-580: The mutant organism to withstand particular environmental stresses better than wild type organisms, or reproduce more quickly. In these cases a mutation will tend to become more common in a population through natural selection . Viruses that use RNA as their genetic material have rapid mutation rates, which can be an advantage, since these viruses thereby evolve rapidly, and thus evade the immune system defensive responses. In large populations of asexually reproducing organisms, for example, E. coli , multiple beneficial mutations may co-occur. This phenomenon

11220-477: The next day; Victor K. McElheny , in researching his biography, "Watson and DNA: Making a Scientific Revolution", found a clipping of a six-paragraph New York Times article written from London and dated 16 May 1953 with the headline "Form of 'Life Unit' in Cell Is Scanned". The article ran in an early edition and was then pulled to make space for news deemed more important. ( The New York Times subsequently ran

11352-516: The organising principle of what became known as molecular biology. Crick had by this time become a highly influential theoretical molecular biologist. Proof that the genetic code is a degenerate triplet code finally came from genetics experiments, some of which were performed by Crick. The details of the code came mostly from work by Marshall Nirenberg and others who synthesized synthetic RNA molecules and used them as templates for in vitro protein synthesis. Nirenberg first announced his results to

11484-423: The organism (although Crick had stated that viruses were an exception). This is known as the "frozen accident" argument for the universality of the genetic code. However, in his seminal paper on the origins of the genetic code in 1968, Francis Crick still stated that the universality of the genetic code in all organisms was an unproven assumption, and was probably not true in some instances. He predicted that "The code

11616-419: The organism include "GUG" or "UUG"; these codons normally represent valine and leucine , respectively, but as start codons they are translated as methionine or formylmethionine. The three stop codons have names: UAG is amber , UGA is opal (sometimes also called umber ), and UAA is ochre . Stop codons are also called "termination" or "nonsense" codons. They signal release of the nascent polypeptide from

11748-628: The outbreak of World War II (in particular, an incident during the Battle of Britain when a bomb fell through the roof of the laboratory and destroyed his experimental apparatus), Crick was deflected from a possible career in physics. During his second year as a PhD student, however, he was awarded the Carey Foster Research Prize, a great honour. He did postdoctoral work at the Brooklyn Collegiate and Polytechnic Institute , now part of

11880-400: The predominant tautomers of the pyrimidine (C and T) bases would be the amine and keto configurations of cytosine and thymine, rather than the imino and enol forms that Crick and Watson had assumed. They consulted Jerry Donohue who confirmed the most likely structures of the nucleotide bases. The base pairs are held together by hydrogen bonds , the same non-covalent interaction that stabilise

12012-424: The program FACIL infers a genetic code by searching which amino acids in homologous protein domains are most often aligned to every codon. The resulting amino acid (or stop codon) probabilities for each codon are displayed in a genetic code logo. As of January 2022, the most complete survey of genetic codes is done by Shulgina and Eddy, who screened 250,000 prokaryotic genomes using their Codetta tool. This tool uses

12144-459: The protein α-helix. The correct structures were essential for the positioning of the hydrogen bonds. These insights led Watson to deduce the true biological relationships of the A:T and C:G pairs. After the discovery of the hydrogen bonded A:T and C:G pairs, Watson and Crick soon had their anti-parallel, double helical model of DNA, with the hydrogen bonds at the core of the helix providing a way to "unzip"

12276-477: The ribosome because no cognate tRNA has anticodons complementary to these stop signals, allowing a release factor to bind to the ribosome instead. During the process of DNA replication , errors occasionally occur in the polymerization of the second strand. These errors, mutations , can affect an organism's phenotype , especially if they occur within the protein coding sequence of a gene. Error rates are typically 1 error in every 10–100 million bases—due to

12408-401: The salience of this important fact for Watson and Crick. The significance of these ratios for the structure of DNA were not recognised until Watson, persisting in building structural models, realised that A:T and C:G pairs are structurally similar. In particular, the length of each base pair is the same. Chargaff had also pointed out to Watson that, in the aqueous, saline environment of the cell,

12540-421: The same organism. Although the genetic code is normally fixed in an organism, the achaeal prokaryote Acetohalobium arabaticum can expand its genetic code from 20 to 21 amino acids (by including pyrrolysine) under different conditions of growth. There was originally a simple and widely accepted argument that the genetic code should be universal: namely, that any variation in the genetic code would be lethal to

12672-399: The second position, it contains the codons AAT and GAA ; and if read from the third position, it contains the codons ATG and AAC. Every sequence can, thus, be read in its 5' → 3' direction in three reading frames , each producing a possibly distinct amino acid sequence: in the given example, Lys (K)-Trp (W)-Thr (T), Asn (N)-Glu (E), or Met (M)-Asn (N), respectively (when translating with

12804-402: The structural stability needed to hold genetic information in cells. It only remained as an exercise of experimental biology to discover exactly which molecule was the genetic molecule. In Crick's view, Charles Darwin's theory of evolution by natural selection , Gregor Mendel 's genetics and knowledge of the molecular basis of genetics, when combined, revealed the secret of life. Crick had

12936-426: The structure of collagen . However, Crick was quickly drifting away from continued work related to his expertise in the interpretation of X-ray diffraction patterns of proteins. George Gamow established a group of scientists interested in the role of RNA as an intermediary between DNA as the genetic storage molecule in the nucleus of cells and the synthesis of proteins in the cytoplasm (the RNA Tie Club ). It

13068-511: The structure of DNA. Late in 1951, Crick started working with James Watson at Cavendish Laboratory at the University of Cambridge , England. Using " Photo 51 " (the X-ray diffraction results of Rosalind Franklin and her graduate student Raymond Gosling of King's College London, given to them by Gosling and Franklin's colleague Wilkins), Watson and Crick together developed a model for a helical structure of DNA, which they published in 1953. For this and subsequent work they were jointly awarded

13200-451: The third position of the codon, whereas in the figure above, a mutation at the second position is likely to cause a radical change in the physicochemical properties of the encoded amino acid. Nevertheless, changes in the first position of the codons are more important than changes in the second position on a global scale. The reason may be that charge reversal (from a positive to a negative charge or vice versa) can only occur upon mutations in

13332-485: The transition from the non-living to the living, and how the brain makes a conscious mind. He realised that his background made him more qualified for research on the first topic and the field of biophysics . It was at this time of Crick's transition from physics to biology that he was influenced by both Linus Pauling and Erwin Schrödinger . It was clear in theory that covalent bonds in biological molecules could provide

13464-448: The triplet codon cause only a silent mutation or an error that would not affect the protein because the hydrophilicity or hydrophobicity is maintained by equivalent substitution of amino acids; for example, a codon of NUN (where N = any nucleotide) tends to code for hydrophobic amino acids. NCN yields amino acid residues that are small in size and moderate in hydropathicity ; NAN encodes average size hydrophilic residues. The genetic code

13596-411: The triplets were used, "magically" producing just the 20 needed combinations. Experimental results were needed; theory alone could not decide the nature of the code. Crick also used the term " central dogma " to summarise an idea that implies that genetic information flow between macromolecules would be essentially one-way: Some critics thought that by using the word "dogma", Crick was implying that this

13728-423: The two complementary strands for easy replication : the last key requirement for a likely model of the genetic molecule. As important as Crick's contributions to the discovery of the double helical DNA model were, he stated that without the chance to collaborate with Watson, he would not have found the structure by himself. Crick did tentatively attempt to perform some experiments on nucleotide base pairing, but he

13860-410: The vertebrate mitochondrial code). When DNA is double-stranded, six possible reading frames are defined, three in the forward orientation on one strand and three reverse on the opposite strand. Protein-coding frames are defined by a start codon , usually the first AUG (ATG) codon in the RNA (DNA) sequence. In eukaryotes , ORFs in exons are often interrupted by introns . Translation starts with

13992-450: The very optimistic view that life would very soon be created in a test tube. However, some people (such as fellow researcher and colleague Esther Lederberg ) thought that Crick was unduly optimistic. It was clear that some macromolecule such as a protein was likely to be the genetic molecule. However, it was well known that proteins are structural and functional macromolecules, some of which carry out enzymatic reactions of cells. In

14124-414: The wetter B form). Wilkins shared this information about the B form of DNA with Crick and Watson. Crick did not see Franklin's B form X-ray images ( Photo 51 ) until after the DNA double helix model was published. One of the few references cited by Watson and Crick when they published their model of DNA was to a published article that included Sven Furberg's DNA model that had the bases on the inside. Thus,

14256-498: Was a corresponding set of small "adaptor molecules" that would hydrogen bond to short sequences of a nucleic acid, and also link to one of the amino acids. He also explored the many theoretical possibilities by which short nucleic acid sequences might code for the 20 amino acids. During the mid-to-late 1950s Crick was very much intellectually engaged in sorting out the mystery of how proteins are synthesised. By 1958, Crick's thinking had matured and he could list in an orderly way all of

14388-404: Was a rule that could not be questioned, but all he really meant was that it was a compelling idea without much solid evidence to support it. In his thinking about the biological processes linking DNA genes to proteins, Crick made explicit the distinction between the materials involved, the energy required, and the information flow. Crick was focused on this third component (information) and it became

14520-465: Was achieved by Marshall Nirenberg , who was not a member of the RNA Tie Club, and received the Nobel Prize in Physiology or Medicine in 1968 with Holley and Har Gobind Khorana . Francis Crick Francis Harry Compton Crick OM FRS (8 June 1916 – 28 July 2004) was an English molecular biologist , biophysicist , and neuroscientist . He, James Watson , Rosalind Franklin , and Maurice Wilkins played crucial roles in deciphering

14652-429: Was an important theoretical molecular biologist and played a crucial role in research related to revealing the helical structure of DNA. He is widely known for the use of the term " central dogma " to summarise the idea that once information is transferred from nucleic acids (DNA or RNA) to proteins, it cannot flow back to nucleic acids. In other words, the final step in the flow of information from nucleic acids to proteins

14784-467: Was based upon Ochoa's earlier studies, yielding the latter the Nobel Prize in Physiology or Medicine in 1959 for work on the enzymology of RNA synthesis. Extending this work, Nirenberg and Philip Leder revealed the code's triplet nature and deciphered its codons. In these experiments, various combinations of mRNA were passed through a filter that contained ribosomes , the components of cells that translate RNA into protein. Unique triplets promoted

14916-422: Was becoming understood that the genetic information pathway involved DNA , RNA and proteins. However, the structure and nature of RNA were still a mystery (specific RNA molecules were not known until 1960), especially how RNA is involved in protein synthesis. Watson called this problem "the mystery of life" in his letter to Crick. Soviet-American physicist George Gamow at George Washington University suggested

15048-510: Was clear to Crick that there had to be a code by which a short sequence of nucleotides would specify a particular amino acid in a newly synthesised protein. In 1956, Crick wrote an informal paper about the genetic coding problem for the small group of scientists in Gamow's RNA group. In this article, Crick reviewed the evidence supporting the idea that there was a common set of about 20 amino acids used to synthesise proteins. Crick proposed that there

15180-486: Was discovered in 1953. The key discoverers, English biophysicist Francis Crick and American biologist James Watson , working together at the Cavendish Laboratory of the University of Cambridge, hypothesied that information flows from DNA and that there is a link between DNA and proteins. Soviet-American physicist George Gamow was the first to give a workable scheme for protein synthesis from DNA. He postulated that sets of three bases (triplets) must be employed to encode

15312-521: Was driven in part by the knowledge that they were competing against Linus Pauling. Given Pauling's recent success in discovering the Alpha helix, they feared that Pauling might also be the first to determine the structure of DNA. Many have speculated about what might have happened had Pauling been able to travel to Britain as planned in May 1952. As it was, his political activities caused his travel to be restricted by

15444-418: Was effective against German minesweepers . In 1947, aged 31, Crick began studying biology and became part of an important migration of physical scientists into biology research. This migration was made possible by the newly won influence of physicists such as Sir John Randall , who had helped win the war with inventions such as radar . Crick had to adjust from the "elegance and deep simplicity" of physics to

15576-480: Was going to the new job, and that Linus Pauling was working on the structure of DNA, they were willing to share Franklin's data with Watson and Crick, in the hope that they could find a good model of DNA before Pauling was able. Franklin's X-ray diffraction data for DNA and her systematic analysis of DNA's structural features were useful to Watson and Crick in guiding them towards a correct molecular model. The key problem for Watson and Crick, which could not be resolved by

15708-606: Was held on 3 August 2004. Crick's Nobel Prize medal and diploma from the Nobel committee was sold at auction in June 2013 for $ 2,270,000. It was bought by Jack Wang, the CEO of Chinese medical company Biomobie. 20% of the sale price of the medal was donated to the Francis Crick Institute in London. Crick was interested in two fundamental unsolved problems of biology: how molecules make

15840-400: Was later confirmed by Robert Holley and the adaptor molecules were named transfer RNAs (tRNAs). The typed paper distributed to the members of the RNA Tie Club in January 1955 as "On Degenerate Templates and the Adaptor Hypothesis: A Note for the RNA Tie Club" is described as "one of the most important unpublished articles in the history of science", and "the most famous unpublished paper in

15972-432: Was later identified as tRNA. The Crick, Brenner, Barnett and Watts-Tobin experiment first demonstrated that codons consist of three DNA bases. Marshall Nirenberg and J. Heinrich Matthaei were the first to reveal the nature of a codon in 1961. They used a cell-free system to translate a poly- uracil RNA sequence (i.e., UUUUU...) and discovered that the polypeptide that they had synthesized consisted of only

16104-537: Was made on 28 February 1953; the first Watson/Crick paper appeared in Nature on 25 April 1953. Sir Lawrence Bragg, the director of the Cavendish Laboratory , where Watson and Crick worked, gave a talk at Guy's Hospital Medical School in London on Thursday 14 May 1953 which resulted in an article by Ritchie Calder in the News Chronicle of London, on Friday 15 May 1953, entitled "Why You Are You. Nearer Secret of Life." The news reached readers of The New York Times

16236-433: Was more of a theoretical biologist than an experimental biologist. There was another near-discovery of the base pairing rules in early 1952. Crick had started to think about interactions between the bases. He asked John Griffith to try to calculate attractive interactions between the DNA bases from chemical principles and quantum mechanics . Griffith's best guess was that A:T and G:C were attractive pairs. At that time, Crick

16368-428: Was not aware of Chargaff's rules and he made little of Griffith's calculations, although it did start him thinking about complementary replication. Identification of the correct base-pairing rules (A-T, G-C) was achieved by Watson "playing" with cardboard cut-out models of the nucleotide bases, much in the manner that Linus Pauling had discovered the protein alpha helix a few years earlier. The Watson and Crick discovery of

16500-487: Was one of only eight references in Franklin's first paper on DNA. Analysis of Astbury's published DNA results and the better X-ray diffraction images collected by Wilkins and Franklin revealed the helical nature of DNA. It was possible to predict the number of bases stacked within a single turn of the DNA helix (10 per turn; a full turn of the helix is 27 angströms [2.7 nm] in the compact A form, 34 angströms [3.4 nm] in

16632-508: Was structurally uninteresting and possibly just a molecular scaffold for the apparently more interesting protein molecules. Crick was in the right place, in the right frame of mind, at the right time (1949), to join Max Perutz's project at the University of Cambridge , and he began to work on the X-ray crystallography of proteins. X-ray crystallography theoretically offered the opportunity to reveal

16764-533: Was the centre of his intellectual and professional life. Crick spoke rapidly, and rather loudly, and had an infectious and reverberating laugh, and a lively sense of humour. One colleague from the Salk Institute described him as "a brainstorming intellectual powerhouse with a mischievous smile. ... Francis was never mean-spirited, just incisive. He detected microscopic flaws in logic. In a room full of smart scientists, Francis continually re-earned his position as

16896-473: Was the first to identify the 3.6 amino acids per helix turn ratio of the alpha helix. Crick was witness to the kinds of errors that his co-workers made in their failed attempts to make a correct molecular model of the alpha helix; these turned out to be important lessons that could be applied, in the future, to the helical structure of DNA. For example, he learned the importance of the structural rigidity that double bonds confer on molecular structures which

17028-545: Was the first to prove the existence of messenger RNA. None of this, however, answered the fundamental theoretical question of the exact nature of the genetic code. In his 1958 article, Crick speculated, as had others, that a triplet of nucleotides could code for an amino acid. Such a code might be "degenerate", with 4×4×4=64 possible triplets of the four nucleotide subunits while there were only 20 amino acids. Some amino acids might have multiple triplet codes. Crick also explored other codes in which, for various reasons, only some of

17160-649: Was under the direction of Randall. (Randall had refused Crick's application to work at King's College.) Francis Crick and Maurice Wilkins of King's College were personal friends, which influenced subsequent scientific events as much as the close friendship between Crick and James Watson . Crick and Wilkins first met at King's College and not, as erroneously recorded by two authors, at the Admiralty during World War II. Crick married twice and fathered three children; his brother Anthony (born in 1918) predeceased him in 1966. Spouses: Children: Crick died of colon cancer on

17292-486: Was under the general direction of Sir Lawrence Bragg , who had won the Nobel Prize in 1915 at the age of 25. Bragg was influential in the effort to beat a leading American chemist, Linus Pauling , to the discovery of DNA 's structure (after having been pipped at the post by Pauling's success in determining the alpha helix structure of proteins). At the same time Bragg's Cavendish Laboratory was also effectively competing with King's College London , whose Biophysics department

17424-494: Was wearing the "wrong initials". The RNA Tie Club never had a formal meeting of all its members. Members visited each other to discuss the scientific developments, usually involving cigars and alcohol. This allowed bonding and close friendships to develop among this scientific elite, and it turned out to be a breeding ground for creative ideas. The members mailed letters and preprints of articles to each other suggesting new concepts and ideas. Using mathematics, Gamow postulated that

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