When was the theory of RNA announced?
Nirenberg and Matthaei experiment
In August 1961, at the International Congress of Biochemistry in Moscow, Nirenberg presented his paper. The experimentation with synthetic RNA in a cell-free system was a key technical innovation. In 1961, when they announced their methods for decoding the relationship of mRNA to amino acids, there was still a lot of experimentation required before the entire code was deciphered. The scientists had to determine which bases made up each codon, then determine the sequence of bases in the codons. This proved to be a tremendous amount of work.
History of RNA biology
When first studied in the early 1900s, the chemical and biological differences between RNA and DNA were not apparent, and they were named after the materials from which they were isolated; RNA was initially known as "yeast nucleic acid" and DNA was "thymus nucleic acid". Using diagnostic chemical tests, carbohydrate chemists showed that the two nucleic acids contained different sugars, whereupon the common name for RNA became "ribose nucleic acid". Other early biochemical studies showed that RNA was readily broken down at high pH, while DNA was stable (although denatured) in alkali. Nucleoside composition analysis showed first that RNA contained similar nucleobases to DNA, with uracil instead of thymine, and that RNA contained a number of minor nucleobase components, e.g. small amounts of pseudouridine and dimethylguanine.
Piaget's theory of cognitive development
However, by the time of Piaget's death in 1980, this notion had lost favor. One main problem was over the protein which, it was assumed, such RNA would necessarily produce, and that did not fit in with observation. It was determined that only about 3% of RNA does code for protein. Hence, most of the remaining 97% (the "ncRNA") could theoretically be available to serve as Piagetian schemas (or other regulatory roles in the 2000s under investigation). The issue has not yet been resolved experimentally, but its theoretical aspects were reviewed in 2008 — then developed further from the viewpoints of biophysics and epistemology. Meanwhile, this RNA-based approach also unexpectedly offered explanations for other several biological issues unresolved, thus providing some measure of corroboration.
RNA
The sequence of the 77 nucleotides of a yeast tRNA was found by Robert W. Holley in 1965, winning Holley the 1968 Nobel Prize in Medicine (shared with Har Gobind Khorana and Marshall Nirenberg).
RNA world
One of the challenges in studying abiogenesis is that the system of reproduction and metabolism utilized by all extant life involves three distinct types of interdependent macromolecules (DNA, RNA, and protein). This suggests that life could not have arisen in its current form, which has led researchers to hypothesize mechanisms whereby the current system might have arisen from a simpler precursor system. The concept of RNA as a primordial molecule can be found in papers by Francis Crick and Leslie Orgel, as well as in Carl Woese's 1967 book "The Genetic Code". In 1962, the molecular biologist Alexander Rich posited much the same idea in an article he contributed to a volume issued in honor of Nobel-laureate physiologist Albert Szent-Györgyi. Hans Kuhn in 1972 laid out a possible process by which the modern genetic system might have arisen from a nucleotide-based precursor, and this led Harold White in 1976 to observe that many of the cofactors essential for enzymatic function are either nucleotides or could have been derived from nucleotides. He proposed that these nucleotide cofactors represent "fossils of nucleic acid enzymes". The phrase "RNA World" was first used by Nobel laureate Walter Gilbert in 1986, in a commentary on how recent observations of the catalytic properties of various forms of RNA fit with this hypothesis.
Neutral network (evolution)
In later years, a new paradigm emerged, that placed RNA as a precursor molecule to DNA. A primordial molecule principle was put forth as early as 1968 by Crick, and lead to what is now known as The RNA World Hypothesis. DNA is found, predominantly, as fully base paired double helices, while biological RNA is single stranded and often exhibits complex base-pairing interactions. These are due to its increased ability to form hydrogen bonds, a fact which stems from the existence of the extra hydroxyl group in the ribose sugar.
RNA
In 1967, Carl Woese hypothesized that RNA might be catalytic and suggested that the earliest forms of life (self-replicating molecules) could have relied on RNA both to carry genetic information and to catalyze biochemical reactions—an RNA world.
Chuan He
In 2010, He proposed that RNA modifications could be reversible and may have regulatory roles analogous to well-known reversible DNA and protein modifications. He and colleagues subsequently discovered the first RNA demethylase that oxidatively reverses N6-methyladenosine (mA) methylation in mammalian messenger RNA (mRNA) in 2011. The existence of mA in mRNA was discovered in 1974 in both eukaryotic and viral mRNAs; however, the biological significance and functional role were not known before He’s work. This methylation is the most abundant internal modification in mammalian mRNA. In 2012, two independent studies reported transcriptome-wide mapping of mA in mammalian cells and tissues, revealing a unique distribution pattern. He and co-workers identified and characterized the direct reader proteins for mA, which impact the stability and the translation efficiency of mA-modified mRNA, elucidating functional roles of mRNA methylation. He’s group also purified the methyltransferase complex that mediates this methylation.
Jerard Hurwitz
Hurwitz joined the microbiology department at Washington University in 1956 and began investigating the incorporation of ribonucleotides into RNA. Two years later, he moved back to New York and became an Assistant Professor of Microbiology at the New York University (NYU) School of Medicine, where he continued to study RNA synthesis.
Non-coding RNA
Ribosomal RNA was next to be discovered, followed by URNA in the early 1980s. Since then, the discovery of new non-coding RNAs has continued with snoRNAs, Xist, CRISPR and many more. Recent notable additions include riboswitches and miRNA; the discovery of the RNAi mechanism associated with the latter earned Craig C. Mello and Andrew Fire the 2006 Nobel Prize in Physiology or Medicine.
Laboratory of Molecular Biology
During the next decade, molecular biology the world over flourished, the outline bones of the 1950s now having flesh put on them. The detailed 3-D atomic structures of a series of proteins, and how they function, were deduced. These included myoglobin, hemoglobin and chymotrypsin, the last by David Blow. The genetic code, from evidence around the world, was assembled by Crick. Punctuation signals in the messenger RNA — where to start translating the RNA into a protein sequence, and where to stop — were discovered by postdoctoral fellow Joan A. Steitz. Crick suggested how the tRNA molecules — his original adaptors — read the messenger in his wobble hypothesis. Sanger devised new methods for sequencing RNA molecules and then later for DNA molecules (for which he received a second Nobel prize in chemistry in 1980). Much later, this line was extended to include determining the sequence of whole genomes, in which John Sulston played a key role. How tRNA precursor molecules are processed to give a functional tRNA was elucidated by John Smith and Sid Altman, and this later led to the discovery of ribozymes. The atomic structure of the first tRNA molecule was solved and zinc fingers discovered by Klug (who received the Nobel prize for chemistry in 1982). The structure of the ATP synthase was solved by John E. Walker and Andrew Leslie, for which Walker shared the Nobel prize for chemistry in 1997. The structure of the ribosome was solved by Venkatraman Ramakrishnan, for which he shared the Nobel prize for chemistry in 2009.
NASBA (molecular biology)
NASBA was developed by J Compton in 1991, who defined it as "a primer-dependent technology that can be used for the continuous amplification of nucleic acids in a single mixture at one temperature". Immediately after the invention of NASBA it was used for the rapid diagnosis and quantification of HIV-1 in patient sera. Although RNA can also be amplified by PCR using a reverse transcriptase (in order to synthesize a complementary DNA strand as a template), NASBA's main advantage is that it works at isothermic conditions – usually at a constant temperature of 41 °C. NASBA can be used in medical diagnostics as an alternative to PCR that is quicker and more sensitive in some circumstances.
History of RNA biology
The discovery of catalytic RNA (ribozymes) showed that RNA could both encode genetic information (like DNA) and catalyze specific biochemical reactions (like protein enzymes). This realization led to the RNA World Hypothesis, a proposal that RNA may have played a critical role in prebiotic evolution at a time before the molecules with more specialized functions (DNA and proteins) came to dominate biological information coding and catalysis. Although it is not possible for us to know the course of prebiotic evolution with any certainty, the presence of functional RNA molecules with common ancestry in all modern-day life forms is a strong argument that RNA was widely present at the time of the last common ancestor.
History of molecular biology
Working in the 19th century, biochemists initially isolated DNA and RNA (mixed together) from cell nuclei. They were relatively quick to appreciate the polymeric nature of their "nucleic acid" isolates, but realized only later that nucleotides were of two types—one containing ribose and the other deoxyribose. It was this subsequent discovery that led to the identification and naming of DNA as a substance distinct from RNA.
RNA-induced silencing complex
The biochemical identification of RISC was conducted by Gregory Hannon and his colleagues at the Cold Spring Harbor Laboratory. This was only a couple of years after the discovery of RNA interference in 1998 by Andrew Fire and Craig Mello, who shared the 2006 Nobel Prize in Physiology or Medicine.
Germ theory of disease
John Snow was a skeptic of the then-dominant miasma theory. Even though the germ theory of disease pioneered by Girolamo Fracastoro had not yet achieved full development or widespread currency, Snow demonstrated a clear understanding of germ theory in his writings. He first published his theory in an 1849 essay "On the Mode of Communication of Cholera," in which he correctly suggested that the fecal-oral route was the mode of communication, and that the disease replicated itself in the lower intestines. He even proposed in his 1855 edition of the work, that the structure of cholera was that of a cell.
History of molecular biology
In addition to the advances being made in global structure determination via crystallography, the early 1990s also saw the implementation of NMR as a powerful technique in RNA structural biology. Coincident with the large-scale ribozyme structures being solved crystallographically, a number of structures of small RNAs and RNAs complexed with drugs and peptides were solved using NMR. In addition, NMR was now being used to investigate and supplement crystal structures, as exemplified by the determination of an isolated tetraloop-receptor motif structure published in 1997. Investigations such as this enabled a more precise characterization of the base pairing and base stacking interactions which stabilized the global folds of large RNA molecules. The importance of understanding RNA tertiary structural motifs was prophetically well described by Michel and Costa in their publication identifying the tetraloop motif: "..it should not come as a surprise if self-folding RNA molecules were to make intensive use of only a relatively small set of tertiary motifs. Identifying these motifs would greatly aid modeling enterprises, which will remain essential as long as the crystallization of large RNAs remains a difficult task".
Epitranscriptome
The most widely described RNA modification in mammalian viruses is mA, which was first identified in Influenza virus mRNAs, in 1976. The epitranscriptomic analysis of viral transcripts has revealed that mA levels in viral and cellular transcripts are similar. Nevertheless, in some viruses such as adenovirus-2, mA levels are higher in viral mRNAs. As with cellular RNAs, mA is predominantly added in the nucleus by METTL3, with the assistance of several cofactors such as METTL14, WTAP, KIAA1429 and RBM15/RMB15B.
Nathan Rosen
At the beginning of the 20th century science was progressing quickly and the inner workings of the atom were just beginning to be discovered. In 1900, Max Planck proposed the quantum theory, the idea that all energy moves in discrete amounts called quanta. In 1905, Albert Einstein published his theory of special relativity, which would be instrumental in the progression of physics and the understanding of the universe. Around 1927, Niels Bohr and Werner Heisenberg, collaborating with many other physicists, developed the Copenhagen interpretation of quantum theory, determining the probabilities of the movement of particles. These breakthroughs provided the model for the structure and workings of the atom and drove the revolution that would sweep up Nathan Rosen.
SnRNP
SnRNPs were discovered by Michael R. Lerner and Joan A. Steitz.
Thomas R. Cech and Sidney Altman also played a role in the discovery, winning the Nobel Prize for Chemistry in 1989 for their independent discoveries that RNA can act as a catalyst in cell development.
Ribonucleotide
It wasn’t until the discovery of nucleotides in 1919 by Phoebus Levene, a Russian-Lithuanian biochemist that re-opened the gates of the DNA discovery. Levene first identified the carbohydrate component present in yeast RNA was in fact ribose. However, it was not until his discovery that the carbohydrate component in thymus nucleic acid was also a sugar but lacked one oxygen atom, termed deoxyribose, that his discovery was widely appreciated by the scientific community. Eventually, Levene was able to identify the correct order of which the components of RNA and DNA are put together, a phosphate-sugar-base unit, in which he later called a nucleotide. Although the order of nucleotide components were well understood by Levene, the structure of nucleotide arrangement in space and its genetic code still remained a mystery during the early years of his career.
RNA
During the early 1970s, retroviruses and reverse transcriptase were discovered, showing for the first time that enzymes could copy RNA into DNA (the opposite of the usual route for transmission of genetic information). For this work, David Baltimore, Renato Dulbecco and Howard Temin were awarded a Nobel Prize in 1975.
In 1976, Walter Fiers and his team determined the first complete nucleotide sequence of an RNA virus genome, that of bacteriophage MS2.
Jerard Hurwitz
In 1955, Marianne Grunberg-Manago and Severo Ochoa had reported the isolation of an enzyme that catalyzed the synthesis of RNA. This enzyme was at first hoped to be responsible for the synthesis of RNA in cells, and Ochoa's discovery was honored with a Nobel prize in 1959. However, it was later realized that Ochoa's enzyme did not use DNA to synthesize RNA but instead formed arbitrary sequences, and later this enzyme was found to degrade RNA in cells. Undeterred by Ochoa's findings, Hurwitz searched for a cellular RNA polymerase on his own and in 1960 he reported the isolation of RNA polymerase activity from Escherichia coli extracts. Remarkably, several other research groups reported similar discoveries at roughly the same time (Samuel B. Weiss, Audrey Stevens, and James Bonner). Hurwitz continued his research on RNA synthesis, and in 1962 Hurwitz, John J. Furth, and Monika Anders reported the purification of RNA polymerase.
RNA
The earliest known regulators of gene expression were proteins known as repressors and activators, regulators with specific short binding sites within enhancer regions near the genes to be regulated.  More recently, RNAs have been found to regulate genes as well.  There are several kinds of RNA-dependent processes in eukaryotes regulating the expression of genes at various points, such as RNAi repressing genes post-transcriptionally, long non-coding RNAs shutting down blocks of chromatin epigenetically, and enhancer RNAs inducing increased gene expression. In addition to these mechanisms in eukaryotes, both bacteria and archaea have been found to use regulatory RNAs extensively. Bacterial small RNA and the CRISPR system are examples of such prokaryotic regulatory RNA systems. Fire and Mello were awarded the 2006 Nobel Prize in Physiology or Medicine for discovering microRNAs (miRNAs), specific short RNA molecules that can base-pair with mRNAs.
CRISPR interference
The CRISPR interference (CRISPRi) technique was first reported by Lei S. Qi and researchers at the University of California at San Francisco in early 2013. The technology uses a catalytically dead Cas9 (usually denoted as dCas9) protein that lacks endonuclease activity to regulate genes in an RNA-guided manner. Targeting specificity is determined by complementary base-pairing of a single guide RNA (sgRNA) to the genomic loci. sgRNA is a chimeric noncoding RNA that can be subdivided into three regions: a 20 nt base-pairing sequence, a 42 nt dCas9-binding hairpin and a 40 nt terminator (bacteria,
Unicellular organism
Primitive protocells were the precursors to today's unicellular organisms. Although the origin of life is largely still a mystery, in the currently prevailing theory, known as the RNA world hypothesis, early RNA molecules would have been the basis for catalyzing organic chemical reactions and self-replication. The RNA world hypothesis assumes that RNA molecules could form in abiotic conditions, which would require nucleic acids and ribose to be present. Theoretical and experimental findings show that nucleic acids and sugars could have been synthesized in early prebiotic conditions.
Adaptor hypothesis
The adaptor hypothesis is part of a scheme to explain how information encoded in DNA is used to specify the amino acid sequence of proteins. It was formulated by Francis Crick in the mid-1950s, together with the central dogma of molecular biology and the sequence hypothesis. It first appeared in an informal publication of the RNA Tie Club in 1955 and was formally published in an article “On Protein Synthesis” in 1958.The adaptor hypothesis was framed to explain how information could be extracted from a nucleic acid and used to put together a string of amino acids in a specific sequence, that sequence being determined by the nucleotide sequence of the nucleic acid (DNA or RNA) template. Crick proposed that each amino acid is first attached to its own specific “adaptor” piece of nucleic acid (in an enzyme-catalysed reaction). The order of assembly of the amino acids is then determined by a specific recognition between the adaptor and the nucleic acid which is serving as the informational template. In this way the amino acids could be lined up by the template in a specific order. Coupling between adjacent amino acids would then lead to the synthesis of a polypeptide whose sequence is determined by the template nucleic acid.Crick’s thinking behind this proposal was based on a general consideration of the chemical properties of the two classes of molecule — nucleic acids and proteins. The amino acids are characterised by having a variety of side chains which vary from being hydrophilic to hydrophobic: their individual characters reside in the very different properties these side chains have. By contrast, a nucleic acid is composed of a string of nucleotides whose sequence presents a geometrically defined surface for hydrogen bonding. This makes nucleic acids good at recognising each other, but poor at distinguishing the varied side chains of amino acids. It was this apparent lack of any possibility of specific recognition of amino acid side chains by a nucleotide sequence which led Crick to conclude that amino acids would first become attached to a small nucleic acid — the adaptor — and that this, by base-pairing with the template (presumably as occurs between DNA strands in the double helix), would carry the amino acids to be lined up on the template.That such adaptors do exist was discovered by Mahlon Hoagland and Paul Zamecnik in 1958. These “soluble RNAs” are now called transfer RNAs and mediate the translation of messenger RNAs on ribosomes according to the rules contained in the genetic code. Crick imagined that his adaptors would be small, perhaps 5-10 nucleotides long. In fact, they are much larger, having a more complex role to play in protein synthesis, and are closer to 100 nucleotides in length.
History of molecular biology
In the mid-1960s, the role of tRNA in protein synthesis was being intensively studied. At this point, ribosomes had been implicated in protein synthesis, and it had been shown that an mRNA strand was necessary for the formation of these structures. In a 1964 publication, Warner and Rich showed that ribosomes active in protein synthesis contained tRNA molecules bound at the A and P sites, and discussed the notion that these molecules aided in the peptidyl transferase reaction. However, despite considerable biochemical characterization, the structural basis of tRNA function remained a mystery. In 1965, Holley "et al." purified and sequenced the first tRNA molecule, initially proposing that it adopted a cloverleaf structure, based largely on the ability of certain regions of the molecule to form stem loop structures. The isolation of tRNA proved to be the first major windfall in RNA structural biology. Following Robert W. Holley's publication, numerous investigators began work on isolation tRNA for crystallographic study, developing improved methods for isolating the molecule as they worked. By 1968 several groups had produced tRNA crystals, but these proved to be of limited quality and did not yield data at the resolutions necessary to determine structure. In 1971, Kim "et al." achieved another breakthrough, producing crystals of yeast tRNA that diffracted to 2-3 Ångström resolutions by using spermine, a naturally occurring polyamine, which bound to and stabilized the tRNA. Despite having suitable crystals, however, the structure of tRNA was not immediately solved at high resolution; rather it took pioneering work in the use of heavy metal derivatives and a good deal more time to produce a high-quality density map of the entire molecule. In 1973, Kim "et al." produced a 4 Ångström map of the tRNA molecule in which they could unambiguously trace the entire backbone. This solution would be followed by many more, as various investigators worked to refine the structure and thereby more thoroughly elucidate the details of base pairing and stacking interactions, and validate the published architecture of the molecule.
Richard A. Jorgensen
His and Carolyn Napoli's observations of pigment gene "cosuppression" in Petunia flowers are examples of post transcriptional gene silencing that predated the discovery of RNA interference (RNAi) and contributed to the current understanding of the commonality of RNA-mediated gene silencing in eukaryotes. Their initial observations were made while working at the U.S. biotech company DNA Plant Technology and form part of the basis of a number of U.S. patents on gene regulation and crop manipulation. The significance of the discovery of cosuppression was described by NOVA scienceNOW in 2005. Jorgensen's primary focus on the problem of cosuppression in petunia has been on the epigenetic aspects of the phenomenon and the relationship between cosuppression (RNAi) and epigenetics. Together with William Lucas at UC Davis and others he proposed the existence of an RNA Information Superhighway in plants by which information is transmitted throughout the plant via RNA molecules which influence gene expression and epigenetic state Jorgensen was awarded the 2007 Martin Gibbs Medal by the American Society of Plant Biologists "for his pioneering work leading to the discovery of RNA interference (RNAi)." He was elected an Inaugural Fellow of the American Society of Plant Biologists in 2007 and a Fellow of the American Association for the Advancement of Sciences (www.aaas.org).
Andrew Fire
In 2006, Fire and Craig Mello shared the Nobel Prize in Physiology or Medicine for work first published in 1998 in the journal "Nature". Fire and Mello, along with colleagues SiQun Xu, Mary Montgomery, Stephen Kostas, and Sam Driver, reported that tiny snippets of double-stranded RNA (dsRNA) effectively shut down specific genes, driving the destruction of messenger RNA (mRNA) with sequences matching the dsRNA. As a result, the mRNA cannot be translated into protein. Fire and Mello found that dsRNA was much more effective in gene silencing than the previously described method of RNA interference with single-stranded RNA. Because only small numbers of dsRNA molecules were required for the observed effect, Fire and Mello proposed that a catalytic process was involved. This hypothesis was confirmed by subsequent research.
Peter Ritchie Calder
Sir Lawrence Bragg's original announcement of the discovery of the structure of DNA was made at a Solvay conference on proteins in Belgium on 8 April 1953 but went unreported by the UK press. He then 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".
Plant virus
The purification (crystallization) of TMV was first performed by Wendell Stanley, who published his findings in 1935, although he did not determine that the RNA was the infectious material. However, he received the Nobel Prize in Chemistry in 1946. In the 1950s a discovery by two labs simultaneously proved that the purified RNA of the TMV was infectious which reinforced the argument. The RNA carries genetic information to code for the production of new infectious particles.
Vault RNA
Vault RNA was first identified as part of the vault ribonucleoprotein complex in 1986. Since the first discovery of non-coding RNA in the mid 60’s, there had been considerable interest in the field. The fruition of this interest was apparent in the 80’s during a string of non-coding RNA discoveries, such as Ribosomal RNA, snoRNA, Xist, and vault RNA.
Oncovirus
In the 1960s, the replication process of RNA virus was believed to be similar to other single-stranded RNA. Single-stranded RNA replication involves RNA-dependent RNA synthesis which meant that virus-coding enzymes would make partial double-stranded RNA. This belief was proven to be incorrect because there were no double-stranded RNA found in the retrovirus cell. In 1964, Howard Temin proposed a provirus hypothesis, but shortly after reverse transcription in the retrovirus genome was discovered.
Life
Therefore, a possibility, first suggested by Francis Crick, is that the first life was based on RNA, which has the DNA-like properties of information storage and the catalytic properties of some proteins. This is called the RNA world hypothesis, and it is supported by the observation that many of the most critical components of cells (those that evolve the slowest) are composed mostly or entirely of RNA. Also, many critical cofactors (ATP, Acetyl-CoA, NADH, etc.) are either nucleotides or substances clearly related to them. The catalytic properties of RNA had not yet been demonstrated when the hypothesis was first proposed, but they were confirmed by Thomas Cech in 1986.
Sequence analysis
Since the very first sequences of the insulin protein were characterized by Fred Sanger in 1951, biologists have been trying to use this knowledge to understand the function of molecules. He and his colleague’s discoveries contributed to the successful sequence the first DNA-based genome. The method used in this study, which is called “Sanger method” or Sanger sequencing, was a milestone in sequencing long strand molecule such as DNA. This method was eventually used in human genome project. According to Michael Levitt, sequence analysis was born in the period from 1969-1977. In 1969 the analysis of sequences of transfer RNAs were used to infer residue interactions from correlated changes in the nucleotide sequences, giving rise to a model of the tRNA secondary structure. In 1970, Saul B. Needleman and Christian D. Wunsch published the first computer algorithm for aligning two sequences. Over this time, developments in obtaining nucleotide sequence greatly improved, leading to the publication of the first complete genome of a bacteriophage in 1977. Robert Holley and his team in Cornell University was believed to be the first to sequence RNA molecule.
History of molecular biology
The resurgence of RNA structural biology in the mid-1990s has caused a veritable explosion in the field of nucleic acid structural research. Since the publication of the hammerhead and P structures, numerous major contributions to the field have been made. Some of the most noteworthy examples include the structures of the Group I and Group II introns, and the Ribosome solved by Nenad Ban and colleagues in the laboratory of Thomas Steitz. It should be noted that the first three structures were produced using "in vitro" transcription, and that NMR has played a role in investigating partial components of all four structures - testaments to the indispensability of both techniques for RNA research. Most recently, the 2009 Nobel Prize in Chemistry was awarded to Ada Yonath, Venkatraman Ramakrishnan and Thomas Steitz for their structural work on the ribosome, demonstrating the prominent role RNA structural biology has taken in modern molecular biology.
Thomas Cech
Cech's main research area is that of the process of transcription in the nucleus of cells. He studies how the genetic code of DNA is transcribed into RNA. In the 1970s, Cech had been studying the splicing of RNA in the unicellular organism "Tetrahymena thermophila" when he discovered that an unprocessed RNA molecule could splice itself. In 1982, Cech became the first to show that RNA molecules are not restricted to being passive carriers of genetic information – they can have catalytic functions and can participate in cellular reactions. RNA-processing reactions and protein synthesis on ribosomes in particular are catalysed by RNA. RNA enzymes are known as ribozymes and have provided a new tool for gene technology. They also have the potential to provide new therapeutic agents – for example, they have the ability to destroy and cleave invading, viral RNAs.
Nucleic acid tertiary structure
The earliest work in RNA structural biology coincided, more or less, with the work being done on DNA in the early 1950s. In their seminal 1953 paper, Watson and Crick suggested that van der Waals crowding by the 2`OH group of ribose would preclude RNA from adopting a double helical structure identical to the model they proposed - what we now know as B-form DNA. This provoked questions about the three dimensional structure of RNA: could this molecule form some type of helical structure, and if so, how?
DNA
In 1933, while studying virgin sea urchin eggs, Jean Brachet suggested that DNA is found in the cell nucleus and that RNA is present exclusively in the cytoplasm. At the time, "yeast nucleic acid" (RNA) was thought to occur only in plants, while "thymus nucleic acid" (DNA) only in animals. The latter was thought to be a tetramer, with the function of buffering cellular pH.
Carl Woese
Carl Richard Woese (; July 15, 1928 – December 30, 2012) was an American microbiologist and biophysicist. Woese is famous for defining the Archaea (a new domain of life) in 1977 by phylogenetic taxonomy of 16S ribosomal RNA, a technique pioneered by Woese which revolutionized the discipline of microbiology. He was also the originator of the RNA world hypothesis in 1967, although not by that name. He held the Stanley O. Ikenberry Chair and was professor of microbiology at the University of Illinois at Urbana–Champaign.
RNA world
Some of the difficulties of producing the precursors on earth are bypassed by another alternative or complementary theory for their origin, panspermia. It discusses the possibility that the earliest life on this planet was carried here from somewhere else in the galaxy, possibly on meteorites similar to the Murchison meteorite. This does not invalidate the concept of an RNA world, but posits that this world or its precursors originated not on Earth but rather another, probably older, planet.
RNA world
Apparently, Diener's hypothesis lay dormant until 2014, when Flores et al. published a review paper, in which Diener's evidence supporting his hypothesis was summarized. In the same year, a New York Times science writer published a popularized version of Diener's proposal, in which, however, he mistakenly credited Flores et al. with the hypothesis' original conception.
Woese's dogma
RNA existing as a primordial self replicating entity is an idea that faces criticism. The idea of rRNA in particular being sufficient on its own to explain the progression of modern life struggles due to the fact that it lacks certain key pieces of evidence. In particular RNA cannot be shown to be prebiotic, as there is no way for the nucleotides or nucleosides that compose it to be non-enzymatically replicated. Additionally, other criticisms exist, such as the fact that RNA is not stable enough to have arisen prebiotically, and that it is too complex to have arisen prebiotically. This has led to the development of other hypotheses, such as 'proteins first', which states that proteins arose prior to RNA, or coevolved with RNA. This has also led to the proposal of other primordial molecules that may have developed into RNA and DNA, such as peptide nucleic acids, which also show evidence of self replication. Despite the fact that criticisms might exist on the primordial or prebiotic nature of rRNA, these criticisms are not aimed at Woese's Dogma on the whole, as Woese's Dogma only claims that the evolution of rRNA was a necessary precursor to modern life, not that rRNA arose prebiotically.
Olke C. Uhlenbeck
Olke C. Uhlenbeck is a biochemist presently at Northwestern University.
He was elected to the United States National Academy of Sciences in 1993 and has published over 200 peer-reviewed articles.
His research group has led to many breakthroughs in RNA biochemistry, most notably the enzymatic synthesis of RNAs from synthetic DNA templates using T7 RNA polymerase.
Olke was a founding member of the RNA society.
Marshall Warren Nirenberg
By 1958, experiments and analysis such as the Avery–MacLeod–McCarty experiment, the Hershey–Chase experiment, the 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").
Robert W. Holley
Holley's research on RNA focused first on isolating transfer RNA (tRNA), and later on determining the sequence and structure of alanine tRNA, the molecule that incorporates the amino acid alanine into proteins. Holley's team of researchers determined the tRNA's structure by using two ribonucleases to split the tRNA molecule into pieces. Each enzyme split the molecule at location points for specific nucleotides. By a process of "puzzling out" the structure of the pieces split by the two different enzymes, then comparing the pieces from both enzyme splits, the team eventually determined the entire structure of the molecule.
Ribozyme
In the 1980s Thomas Cech, at the University of Colorado at Boulder, was studying the excision of introns in a ribosomal RNA gene in "Tetrahymena thermophila". While trying to purify the enzyme responsible for the splicing reaction, he found that the intron could be spliced out in the absence of any added cell extract. As much as they tried, Cech and his colleagues could not identify any protein associated with the splicing reaction. After much work, Cech proposed that the intron sequence portion of the RNA could break and reform phosphodiester bonds. At about the same time, Sidney Altman, a professor at Yale University, was studying the way tRNA molecules are processed in the cell when he and his colleagues isolated an enzyme called RNase-P, which is responsible for conversion of a precursor tRNA into the active tRNA. Much to their surprise, they found that RNase-P contained RNA in addition to protein and that RNA was an essential component of the active enzyme. This was such a foreign idea that they had difficulty publishing their findings. The following year, Altman demonstrated that RNA can act as a catalyst by showing that the RNase-P RNA subunit could catalyze the cleavage of precursor tRNA into active tRNA in the absence of any protein component.
R-loop
R-looping was first described in 1976. Independent R-looping studies from the laboratories of Richard J. Roberts and Phillip A. Sharp showed that protein coding adenovirus genes contained DNA sequences that were not present in the mature mRNA. Roberts and Sharp were awarded the Nobel Prize in 1993 for independently discovering introns. After their discovery in adenovirus, introns were found in a number of eukaryotic genes such as the eukaryotic ovalbumin gene (first by the O'Malley laboratory, then confirmed by other groups), hexon DNA, and extrachromosomal rRNA genes of "Tetrahymena thermophila".
History of RNA biology
In 1933, while studying virgin sea urchin eggs, Jean Brachet suggested that DNA is found in cell nucleus and that RNA is present exclusively in the cytoplasm. At the time, "yeast nucleic acid" (RNA) was thought to occur only in plants, while "thymus nucleic acid" (DNA) only in animals. The latter was thought to be a tetramer, with the function of buffering cellular pH. During the 1930s, Joachim Hämmerling conducted experiments with "Acetabularia" in which he began to distinguish the contributions of the nucleus and the cytoplasm substances (later discovered to be DNA and mRNA, respectively) to cell morphogenesis and development.
RNA world
Alexander Rich first proposed the concept of the RNA world in 1962, and Walter Gilbert coined the term in 1986. Alternative chemical paths to life have been proposed, and RNA-based life may not have been the first life to exist. Even so, the evidence for an RNA world is strong enough that the hypothesis has gained wide acceptance.
RNA activation
RNA activation (RNAa) is a small RNA-guided and Argonaute (Ago)-dependent gene regulation phenomenon in which promoter-targeted short double-stranded RNAs (dsRNAs) induce target gene expression at the transcriptional/epigenetic level. RNAa was first reported in a 2006 PNAS paper by Li "et al." who also coined the term "RNAa" as a contrast to RNA interference (RNAi) to describe such gene activation phenomenon. dsRNAs that trigger RNAa have been termed small activating RNA (saRNA). Since the initial discovery of RNAa in human cells, many other groups have made similar observations in different mammalian species including human, non-human primates, rat and mice, plant and C. elegans, suggesting that RNAa is an evolutionarily conserved mechanism of gene regulation.
Sequence hypothesis
The sequence hypothesis was first formally proposed in the review "On Protein Synthesis" by Francis Crick in 1958. It states that the sequence of bases in the genetic material (DNA or RNA) determines the sequence of amino acids for which that segment of nucleic acid codes, and this amino acid sequence determines the three-dimensional structure into which the protein folds. The three-dimensional structure of a protein is required for a protein to be functional. This hypothesis then lays the essential link between information stored and inherited in nucleic acids to the chemical processes which enable life to exist.
Eckard Wimmer
Using the nucleotide sequence of the genome deciphered in 1981, Wimmer followed up on the work published in 1991 by synthesizing chemically the genome in the form of double stranded DNA (“cDNA”), which was then transcribed enzymatically into genome RNA and “booted to life” in the cell free system. This work, published in 2002 by Cello, Paul and Wimmer, was the first test-tube synthesis of an organism in the absence of a natural template achieved outside living cells. The poliovirus synthesis caught global attention, high praise, ridicule and fierce condemnation. Several years later, Wimmer published an essay in EMBO Reports reflecting on hotly debated issues that this new kind of research generated (ethical matters, questions about the global eradication of poliovirus, concerns of “dual use research”). Apart from providing a ‘proof of principle,’ the experiment heralded the total synthesis of organisms with computers as parents, a strategy that allows investigating the structure and function of an organism’s biology to an extent hitherto impossible. Meanwhile, synthetic biology has led to a new kind of RNA virus genetics and has been used to develop rapid methods for computer-aided chemical synthesis of viral recoded genomes. This strategy allows for the generation of new vaccines in a very short time.
Affirmations (L. Ron Hubbard)
The "Affirmations" (also referred to as the "Admissions") are a work said to have been written by L. Ron Hubbard in the late 1940s, a few years before he established Dianetics (1950) or Scientology (1952). They consist of a series of statements by and addressed to Hubbard, relating to various physical, sexual, psychological and social issues that he was encountering in his life. After the Affirmations became public knowledge in 1984, the Church of Scientology disputed their authenticity, though in legal papers it has described the Affirmations as having been "written by" Hubbard and sought to retain ownership of them.
Rochester Numismatic Association
The RNA was formed in January 1912 by Dr. George P. French with 32 charter members. The first meeting attracted 15 coin collectors. Dr. French collected other curiosities besides coins. His curios included the clothes worn by General Tom Thumb, one of the world's smallest men, and Peter the Great.
MiR-324-5p
miR-324-5p first appeared in literature in a paper published by John Kim et. al. in early 2004 that identified 32 entirely new miRNAs from cultured rat cortical neurons using miRNA cloning and RNA analysis. The miRNA quickly gained traction in scientific literature, appearing in articles about the evolutionary conservation of microRNAs, HIV, cancer, and other topics within a few years. Today, the functions and roles of miR-324-5p are still not yet fully characterized.
RNA
At first, regulatory RNA was thought to be a eukaryotic phenomenon, a part of the explanation for why so much more transcription in higher organisms was seen than had been predicted. But as soon as researchers began to look for possible RNA regulators in bacteria, they turned up there as well. Currently, the ubiquitous nature of systems of RNA regulation of genes has been discussed as support for the RNA World theory. Bacterial small RNAs generally act via antisense pairing with mRNA to down-regulate its translation, either by affecting stability or affecting cis-binding ability. Riboswitches have also been discovered. They are cis-acting regulatory RNA sequences acting allosterically. They change shape when they bind metabolites so that they gain or lose the ability to bind chromatin to regulate expression of genes.
Leslie Orgel
In the late 1960s, Orgel proposed that life was based on RNA before it was based on DNA or proteins. His theory included genes based on RNA and RNA enzymes. This view would be developed and shaped into the now widely-accepted RNA world hypothesis.
RNA world
The properties of RNA make the idea of the RNA world hypothesis conceptually plausible, though its general acceptance as an explanation for the origin of life requires further evidence. RNA is known to form efficient catalysts and its similarity to DNA makes clear its ability to store information. Opinions differ, however, as to whether RNA constituted the first autonomous self-replicating system or was a derivative of a still-earlier system. One version of the hypothesis is that a different type of nucleic acid, termed "pre-RNA", was the first one to emerge as a self-reproducing molecule, to be replaced by RNA only later. On the other hand, the discovery in 2009 that activated pyrimidine ribonucleotides can be synthesized under plausible prebiotic conditions suggests that it is premature to dismiss the RNA-first scenarios. Suggestions for 'simple' "pre-RNA" nucleic acids have included peptide nucleic acid (PNA), threose nucleic acid (TNA) or glycol nucleic acid (GNA). Despite their structural simplicity and possession of properties comparable with RNA, the chemically plausible generation of "simpler" nucleic acids under prebiotic conditions has yet to be demonstrated.
Alexander Dounce
Also in 1952, Dounce wrote a review article in which he, as one of the first scientists to do so, proposed that DNA might serve as a template for the synthesis of RNA, which in turn serves as a template for the synthesis of proteins. This order of synthesis, which has later been termed the "central dogma of molecular biology" by Francis Crick, is textbook knowledge today. However, it was not until 1958, when Crick coined the term "central dogma" and described the concept in more detail, that it gained widespread acceptance.
RNA polymerase II
Early studies suggested a minimum of two RNAPs: one which synthesized rRNA in the nucleolus, and one which synthesized other RNA in the nucleoplasm, part of the nucleus but outside the nucleolus. In 1969, science experimentalists Robert Roeder and William Rutter definitively discovered an additional RNAP that was responsible for transcription of some kind of RNA in the nucleoplasm. The finding was obtained by the use of DEAE-Sephadex ion-exchange chromatography. The technique separated the enzymes by the order of the corresponding elutions, Ι,ΙΙ,ΙΙΙ, by increasing the concentration of ammonium sulfate. The enzymes were named according to the order of the elutions, RNAP I, RNAP II, RNAP IΙI. This discovery demonstrated that there was an additional enzyme present in the nucleoplasm, which allowed for the differentiation between RNAP II and RNAP III.
Jean Brachet
In 1933 Brachet was able to show that DNA was found in chromosomes and that RNA was present in the cytoplasm of all cells. His work with Torbjörn Caspersson showed that RNA plays an active role in protein synthesis. Brachet also carried out pioneering work in the field of cell differentiation. Brachet demonstrated that differentiation is preceded by the formation of new ribosomes and accompanied by the release from the nucleus of a wave of new messenger RNA.
Gene silencing
RNA interference (RNAi) is a natural process used by cells to regulate gene expression. It was discovered in 1998 by Andrew Fire and Craig Mello, who won the Nobel Prize for their discovery in 2006. The process to silence genes first begins with the entrance of a double-stranded RNA (dsRNA) molecule into the cell, which triggers the RNAi pathway. The double-stranded molecule is then cut into small double-stranded fragments by an enzyme called Dicer. These small fragments, which include small interfering RNAs (siRNA) and microRNA (miRNA), are approximately 21–23 nucleotides in length. The fragments integrate into a multi-subunit protein called the RNA-induced silencing complex, which contains Argonaute proteins that are essential components of the RNAi pathway. One strand of the molecule, called the "guide" strand, binds to RISC, while the other strand, known as the "passenger" strand is degraded. The guide or antisense strand of the fragment that remains bound to RISC directs the sequence-specific silencing of the target mRNA molecule. The genes can be silenced by siRNA molecules that cause the endonucleatic cleavage of the target mRNA molecules or by miRNA molecules that suppress translation of the mRNA molecule. With the cleavage or translational repression of the mRNA molecules, the genes that form them are essentially inactive. RNAi is thought to have evolved as a cellular defense mechanism against invaders, such as RNA viruses, or to combat the proliferation of transposons within a cell's DNA. Both RNA viruses and transposons can exist as double-stranded RNA and lead to the activation of RNAi. Currently, siRNAs are being widely used to suppress specific gene expression and to assess the function of genes. Companies utilizing this approach include Alnylam, Sanofi, Arrowhead, Discerna, and Persomics, among others.
Enhancer RNA
Enhancer RNAs (eRNAs) represent a class of relatively short non-coding RNA molecules (50-2000 nucleotides) transcribed from the DNA sequence of enhancer regions. They were first detected in 2010 through the use of genome-wide techniques such as RNA-seq and ChIP-seq. eRNAs can be subdivided into two main classes: 1D eRNAs and 2D eRNAs, which differ primarily in terms of their size, polyadenylation state, and transcriptional directionality. The expression of a given eRNA seems to correlate with the activity of its corresponding enhancer in a context-dependent fashion. Increasing evidence suggests that eRNAs actively play a role in transcriptional regulation in cis and in trans, and while their mechanisms of action remain unclear, a few models have been proposed.
Xuemei Chen
In 1999 Chen started work as an assistant professor at Rutgers University's Waksman Institute of Microbiology. In 2002 she was part of a team that discovered that MicroRNA existed in plants. This work led her to win the 2005 Board of Trustees' Research Fellowship for Scholarly Excellence concurrent with a promotion to associate professor; in 2005 she moved to University of California, Riverside (UCR) and was promoted to full professor in 2009. In 2011 she was named a fellow of the American Association for the Advancement of Science for "pioneering discoveries in the field of plant biology in small RNA metabolism and plant development." That year she was also named a Plant Biology Investigator (an award of ) by the Howard Hughes Medical Institute and the Gordon and Betty Moore Foundation. In 2013 Chen was elected to the National Academy of Sciences: the third member from UCR's Center for Plant Cell Biology and sixth from the University's College of Natural and Agricultural Sciences.
David D. Sabatini
Largely based on these findings, in 1971 Blobel and Sabatini proposed a speculative model that later came to be known as the "signal hypothesis". For a discussion of the genesis and evolution of the signal hypothesis see LaBonte, 2017 In the 1971 paper, Blobel and Sabatini proposed that “all mRNAs to be translated on bound ribosomes have a common feature, such as several codons near their 5’ end, not present in mRNAs which are to be translated on free ribosomes” and that “the resulting common sequence of amino acids near the N-termini of the nascent chains, or a modification of it, would then be recognized by a factor mediating the binding to the membrane." They proposed that "This binding factor could be a soluble protein, which recognizes both a site on the large ribosomal subunit and a site on the membrane.” A decade later, Walter and Blobel demonstrated the existence of a Signal Recognition Protein (SRP) that mediates the binding of the ribosome and the signal sequence within the nascent chain to the membrane. In 1982, a cognate receptor for the Signal Recognition Particle (SRP) was discovered and characterized in the ER membrane. ,
Antisense RNA
The idea of asRNAs as drug targets started in 1978 when Zamecnik and Stephenson found an antisense oligonucleotide to the viral RNA of Rous scarcoma virus that was capable of inhibiting viral replication and protein synthesis. Since then, much effort has been devoted to developing asRNAs as drug candidates. In 1998, the first asRNA drug, fomivirsen, was approved by FDA. Fomivirsen, a 21 base-pair oligonucleotide, was developed to treat cytomegalovirus retinitis in patients with AIDS. It works by targeting the transcribed mRNA of the virus and consequently inhibiting replication of cytomegalovirus. Despite fomivirsen was discontinued in 2004 due to the loss of the market, it served as a successful and inspiring example of using asRNAs as drug targets or drug candidates.
RNA world
A research project completed in March 2015 by the Sutherland group found that a network of reactions beginning with hydrogen cyanide and hydrogen sulfide, in streams of water irradiated by UV light, could produce the chemical components of proteins and lipids, alongside those of RNA. The researchers used the term "cyanosulfidic" to describe this network of reactions. In November 2017, a team at the Scripps Research Institute identified reactions involving the compound diamidophosphate which could have linked the chemical components into short peptide and lipid chains as well as short RNA-like chains of nucleotides.
Spot 42 RNA
Spot42 was first described in 1973 as an unstable RNA species of 109 nucleotides in "Escherichia coli". It was discovered by polyacrylamide gel electrophoresis and 2-D fingerprinting in an attempt to study the accumulation of small RNAs in "E. coli" during amino acid starvation. In these experiments the electrophoretic mobility of Spot42 was similar to that of 5S rRNA. In 1979 Spot42 was found to accumulate under growth in the presence of glucose (i.e., when adenosine 3′,5′-cyclic monophosphate (cAMP) is low). During growth with a non-glucose carbon source (i.e., when cAMP concentrations are high) the Spot42 concentrations were found to be significantly lower.
Severo Ochoa
In 1956, he became an American citizen. In 1959, Ochoa was awarded the Nobel Prize for Physiology or Medicine for his work on the synthesis of RNA.
Ochoa continued research on protein synthesis and replication of RNA viruses until 1985, when he returned to Spain and gave advice to Spanish science policy authorities. Ochoa was also a recipient of U.S. National Medal of Science in 1978.
RNA polymerase
RNAP was discovered independently by Charles Loe, Audrey Stevens, and Jerard Hurwitz in 1960. By this time, one half of the 1959 Nobel Prize in Medicine had been awarded to Severo Ochoa for the discovery of what was believed to be RNAP, but instead turned out to be polynucleotide phosphorylase.
DNA nanotechnology
The conceptual foundation for DNA nanotechnology was first laid out by Nadrian Seeman in the early 1980s. Seeman's original motivation was to create a three-dimensional DNA lattice for orienting other large molecules, which would simplify their crystallographic study by eliminating the difficult process of obtaining pure crystals. This idea had reportedly come to him in late 1980, after realizing the similarity between the woodcut "Depth" by M. C. Escher and an array of DNA six-arm junctions. Several natural branched DNA structures were known at the time, including the DNA replication fork and the mobile Holliday junction, but Seeman's insight was that immobile nucleic acid junctions could be created by properly designing the strand sequences to remove symmetry in the assembled molecule, and that these immobile junctions could in principle be combined into rigid crystalline lattices. The first theoretical paper proposing this scheme was published in 1982, and the first experimental demonstration of an immobile DNA junction was published the following year.
Discovery and development of nucleoside and nucleotide reverse-transcriptase inhibitors
Discovery and development of nucleoside and nucleotide reverse-transcriptase inhibitors (NRTIs and NtRTIs) began in the 1980s when the AIDS epidemic hit Western societies. NRTIs inhibit the reverse transcriptase (RT), an enzyme that controls the replication of the genetic material of the human immunodeficiency virus (HIV). The first NRTI was zidovudine, approved by the U.S. Food and Drug Administration (FDA) in 1987, which was the first step towards treatment of HIV. Six NRTI agents and one NtRTI have followed. The NRTIs and the NtRTI are analogues of endogenous 2´-deoxy-nucleoside and nucleotide. Drug-resistant viruses are an inevitable consequence of prolonged exposure of HIV-1 to anti-HIV drugs.
Germ theory of disease
The germ theory was proposed by Girolamo Fracastoro in 1546, and expanded upon by Marcus von Plenciz in 1762. Such views were held in disdain, however, and Galen's miasma theory remained dominant among scientists and doctors. The nature of this doctrine prevented them from understanding how diseases actually progressed, with predictable consequences. By the early nineteenth century, smallpox vaccination was commonplace in Europe, though doctors were unaware of how it worked or how to extend the principle to other diseases. Similar treatments had been prevalent in India from just before AD 1000. A transitional period began in the late 1850s with the work of Louis Pasteur. This work was later extended by Robert Koch in the 1880s. By the end of the 1880s the miasma theory was struggling to compete with the germ theory of disease. Eventually, a "golden era" of bacteriology ensued, during which the theory quickly led to the identification of the actual organisms that cause many diseases. Viruses were discovered in the 1890s.
RNA world
Patrick Forterre has been working on a novel hypothesis, called "three viruses, three domains": that viruses were instrumental in the transition from RNA to DNA and the evolution of Bacteria, Archaea, and Eukaryota. He believes the last universal common ancestor was RNA-based and evolved RNA viruses. Some of the viruses evolved into DNA viruses to protect their genes from attack. Through the process of viral infection into hosts the three domains of life evolved. Another interesting proposal is the idea that RNA synthesis might have been driven by temperature gradients, in the process of thermosynthesis.
Single nucleotides have been shown to catalyze organic reactions.
DNA sequencing
RNA sequencing was one of the earliest forms of nucleotide sequencing. The major landmark of RNA sequencing is the sequence of the first complete gene and the complete genome of Bacteriophage MS2, identified and published by Walter Fiers and his coworkers at the University of Ghent (Ghent, Belgium), in 1972 and 1976. Traditional RNA sequencing methods require the creation of a cDNA molecule which must be sequenced.
Gene silencing
Antisense oligonucleotides were discovered in 1978 by Paul Zamecnik and Mary Stephenson. Oligonucleotides, which are short nucleic acid fragments, bind to complementary target mRNA molecules when added to the cell. These molecules can be composed of single-stranded DNA or RNA and are generally 13–25 nucleotides long. The antisense oligonucleotides can affect gene expression in two ways: by using an RNase H-dependent mechanism or by using a steric blocking mechanism. RNase H-dependent oligonucleotides cause the target mRNA molecules to be degraded, while steric-blocker oligonucleotides prevent translation of the mRNA molecule. The majority of antisense drugs function through the RNase H-dependent mechanism, in which RNase H hydrolyzes the RNA strand of the DNA/RNA heteroduplex. This mechanism is thought to be more efficient, resulting in an approximately 80% to 95% decrease in the protein and mRNA expression.
University of Massachusetts Medical School
UMMS has emerged on the national scene as a research center. In 1998, UMMS researcher Craig Mello (an investigator at the Howard Hughes Medical Institute) and his colleague Andrew Fire (of Stanford University, then of the Carnegie Institution in Washington, D.C.) discovered RNA interference (RNAi). Mello and Fire demonstrated that small pieces of double-stranded RNA had interfered with the expression of a gene whose coding sequence of DNA was similar to that of the RNA they tested. Since the discovery of RNAi, researchers at UMMS and around the world have taken advantage of its technology to speed investigation into a variety of diseases. Mello and Fire received the 2006 Nobel Prize in Physiology or Medicine for their discoveries related to RNA interference.
Central dogma of molecular biology
A second version of the central dogma is popular but incorrect. This is the simplistic DNA → RNA → protein pathway published by James Watson in the first edition of "The Molecular Biology of the Gene" (1965). Watson's version differs from Crick's because Watson describes the two-step (DNA → RNA and RNA → protein) pathway as the central dogma. While the dogma, as originally stated by Crick, remains valid today, Watson's version does not.
Francis Crick
The discovery 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" 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 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.
Argonaute
RNA interference (RNAi) was first reported in 1995 by Guo and Kemphues, and similar pathways collectively referred to as RNA silencing were discovered in plants and fungi. The mechanism of RNA silencing began to be understood in 1998 with the experiments of Fire and colleagues demonstrating that double-stranded RNA triggered RNAi. RNA silencing pathways process long RNAs into small RNAs that direct the repression of transcription or translation of nucleic acid targets with sequence corresponding to the small RNAs. These single-stranded RNAs, referred to as guide strands, are incorporated into RNA silencing effector complexes such as the RNA-induced silencing complex (RISC). These RNA silencing effector complexes contain Argonaute family proteins.
Hypercycle (chemistry)
At the time of the hypercycle theory formulation, ribozymes were not known. After the breakthrough of discovering RNA's catalytic properties in 1982, it was realized that RNA had the ability to integrate protein and nucleotide-chain properties into one entity. Ribozymes potentially serving as templates and catalysers of replication can be considered components of quasispecies that can self-organize into a hypercycle without the need to invent a translation process. In 2001, a partial RNA polymerase ribozyme was designed via directed evolution. Nevertheless, it was able to catalyse only a polymerization of a chain having the size of about 14 nucleotides, even though it was 200 nucleotides long. The most up-to-date version of this polymerase was shown in 2013. While it has an ability to catalyse polymerization of longer sequences, even of its own length, it cannot replicate itself due to a lack of sequence generality and its inability to transverse secondary structures of long RNA templates. However, it was recently shown that those limitations could in principle be overcome by the assembly of active polymerase ribozymes from several short RNA strands. In 2014, a cross-chiral RNA polymerase ribozyme was demonstrated. It was hypothesized that it offers a new mode of recognition between an enzyme and substrates, which is based on the shape of the substrate, and allows avoiding the Watson-Crick pairing and, therefore, may provide greater sequence generality. Various other experiments have shown that, besides bearing polymerase properties, ribozymes could have developed other kinds of evolutionarily useful catalytic activity such as synthase, ligase, or aminoacylase activities. Ribozymal aminoacylators and ribozymes with the ability to form peptide bonds might have been crucial to inventing translation. An RNA ligase, in turn, could link various components of quasispecies into one chain, beginning the process of a genome integration. An RNA with a synthase or a synthetase activity could be critical for building compartments and providing building blocks for growing RNA and protein chains as well as other types of molecules. Many examples of this kind of ribozyme are currently known, including a peptidyl transferase ribozyme, a ligase, and a nucleotide synthetase. A transaminoacylator described in 2013 has five nucleotides, which is sufficient for a trans-amino acylation reaction and makes it the smallest ribozyme that has been discovered. It supports a peptidyl-RNA synthesis that could be a precursor for the contemporary process of linking amino acids to tRNA molecules. An RNA ligase's catalytic domain, consisting of 93 nucleotides, proved to be sufficient to catalyse a linking reaction between two RNA chains. Similarly, an acyltransferase ribozyme 82 nucleotides long was sufficient to perform an acyltransfer reaction. Altogether, the results concerning the RNA ligase's catalytic domain and the acyltransferase ribozyme are in agreement with the estimated upper limit of 100 nucleotides set by the error threshold problem. However, it was hypothesized that even if the putative first RNA-dependent RNA-polymerases are estimated to be longer—the smallest reported up-to-date RNA-dependent polymerase ribozyme is 165 nucleotides long—they did not have to arise in one step. It is more plausible that ligation of smaller RNA chains performed by the first RNA ligases resulted in a longer chain with the desired catalytically active polymerase domain.
RNA-based evolution
In accordance with the central dogma of molecular biology, RNA passes information between the DNA of a genome and the proteins expressed within an organism. Therefore, from an evolutionary standpoint, a mutation within the DNA bases results in an alteration of the RNA transcripts, which in turn leads to a direct difference in phenotype.
RNA is also believed to have been the genetic material of the first life on Earth. The role of RNA in the origin of life is best supported by the ease of forming RNA from basic chemical building blocks (such as amino acids, sugars, and hydroxyl acids) that were likely present 4 billion years ago. Molecules of RNA have also been shown to effectively self-replicate, catalyze basic reactions, and store heritable information. As life progressed and evolved over time only DNA, which is much more chemically stable than RNA, could support large genomes and eventually took over the role as the major carrier of genetic information.
RNA world
In 2018, researchers at Georgia Institute of Technology identified three molecular candidates for the bases that might have formed an earliest version of proto-RNA: barbituric acid, melamine, and 2,4,6-triaminopyrimidine. These three molecules are simpler versions of the four bases in current RNA, which could have been present in larger amounts and could still be forwards compatibile with them, but may have been discarded by evolution in exchange for more optimal base pairs.
History of molecular biology
Watson and Crick's model attracted great interest immediately upon its presentation. Arriving at their conclusion on February 21, 1953, Watson and Crick made their first announcement on February 28. In an influential presentation in 1957, Crick laid out the "central dogma of molecular biology", which foretold the relationship between DNA, RNA, and proteins, and articulated the "sequence hypothesis." A critical confirmation of the replication mechanism that was implied by the double-helical structure followed in 1958 in the form of the Meselson–Stahl experiment. Work by Crick and coworkers showed that the genetic code was based on non-overlapping triplets of bases, called codons, and Har Gobind Khorana and others deciphered the genetic code not long afterward (1966). These findings represent the birth of molecular biology.
RNA interference
The process of RNAi was referred to as "co-suppression" and "quelling" when observed prior to the knowledge of an RNA-related mechanism. The discovery of RNAi was preceded first by observations of transcriptional inhibition by antisense RNA expressed in transgenic plants, and more directly by reports of unexpected outcomes in experiments performed by plant scientists in the United States and the Netherlands in the early 1990s. In an attempt to alter flower colors in petunias, researchers introduced additional copies of a gene encoding chalcone synthase, a key enzyme for flower pigmentation into petunia plants of normally pink or violet flower color. The overexpressed gene was expected to result in darker flowers, but instead caused some flowers to have less visible purple pigment, sometimes in variegated patterns, indicating that the activity of chalcone synthase had been substantially decreased or became suppressed in a context-specific manner. This would later be explained as the result of the transgene being inserted adjacent to promoters in the opposite direction in various positions throughout the genomes of some transformants, thus leading to expression of antisense transcripts and gene silencing when these promoters are active. Another early observation of RNAi was came from a study of the fungus "Neurospora crassa", although it was not immediately recognized as related. Further investigation of the phenomenon in plants indicated that the downregulation was due to post-transcriptional inhibition of gene expression via an increased rate of mRNA degradation. This phenomenon was called "co-suppression of gene expression", but the molecular mechanism remained unknown.
Craig Venter
While an employee of the NIH, Venter learned how to identify mRNA and began to learn more about those expressed in the human brain. The short cDNA sequence fragments he was interested in are called expressed sequence tags, or ESTs. The NIH Office of Technology Transfer and Venter decided to take the ESTs discovered by others in an attempt to patent the genes identified based on studies of mRNA expression in the human brain. When Venter disclosed this strategy during a Congressional hearing, a firestorm of controversy erupted. The NIH later stopped the effort and abandoned the patent applications it had filed, following public outcry.
Marcello Siniscalco
Although he never pursued a career as a practicing doctor, it was his training in biology, and the tutelage of his mentor Professor during the late 1940s and early 1950s at the , that enabled Marcello to discover the nascent field of genetics. As a part of his doctorate in 1948, he completed a study on the relationship between nucleic acid metabolism and protein synthesis carried out in tiny crustaceans. This was one of the earliest known works attempting to understand the link between DNA and RNA (the central dogma of molecular biology), contributing to a school of academic thought which culminated in Watson and Crick’s Nobel-prize winning discovery a decade later. This was the beginning of a successful period during which Siniscalco pursued research based at the University of Naples, collaborating closely with a variety of other prominent Italian scientists of the time.
The Times Science Review
In 1953 both "The Times" and its new "Science Review" supplement failed to report on James D. Watson's and Francis Crick's discovery of the structure of DNA. The discovery was made on February 28, 1953, and was announced by Sir Lawrence Bragg, the director of the Cavendish Laboratory where Watson and Crick worked, at the Solvay conference on proteins in Belgium on 8 April 1953. Bragg's announcement went unreported on by the press. Watson and Crick's paper then appeared in "Nature" magazine on April 25, 1953.
Memory RNA
Memory RNA is a debunked form of RNA that was proposed by James V. McConnell and others in the 1960s as a means of explaining how long-term memories are stored in the brain. The concept behind it was that since RNA encoded information, and since living cells could produce and modify RNA in reaction to external events, it might also be used in neurons to record stimuli.
Interferomics
RNA Interference is one such cellular mechanism that falls in this category and is to-date the only known interferomic phenomenon. Drs Andrew Z. Fire and Craig C. Mello were awarded the Nobel Prize in Physiology or Medicine in the year of 2006 for their collective discovery of RNA interference.
RNA Biology
The journal launched a new section for descriptions of families of RNA molecules in December 2008 and requires contributing authors to also submit a draft article on the RNA family for publication in Wikipedia. The journal submits the draft article to peer review and then publish it in Wikipedia. This initiative is a collaboration between the journal and the consortium that produces the Rfam database of RNA families.
Rfam
Version 1.0 of Rfam was launched in 2003 and contained 25 ncRNA families and annotated about 50 000 ncRNA genes. In 2005, version 6.1 was released and contained 379 families annotating over 280 000 genes. In August 2012, version 11.0 contained 2208 RNA families, while the current version (13.0) annotates 2686 families.
African-American self-determination
Established in 1968, the RNA attracted a number of members, including Robert F. Williams, Betty Shabazz and Chokwe Lumumba. The organization persists to this day.
RNA interference
RNA interference (RNAi) is a biological process in which RNA molecules inhibit gene expression or translation, by neutralizing targeted mRNA molecules. Historically, RNAi was known by other names, including "co-suppression", "post-transcriptional gene silencing" (PTGS), and "quelling". The detailed study of each of these seemingly different processes, elucidated that the identity of these phenomena were all actually RNAi. Andrew Fire and Craig C. Mello shared the 2006 Nobel Prize in Physiology or Medicine for their work on RNA interference in the nematode worm "Caenorhabditis elegans", which they published in 1998. Since the discovery of RNAi and its regulatory potentials, it has become evident that RNAi has immense potential in suppression of desired genes. RNAi is now known as precise, efficient, stable and better than antisense technology for gene suppression. However, antisense RNA produced intracellularly by an expression vector may be developed and find utility as novel therapeutic agents.
RNA world
On August 8, 2011, a report, based on NASA studies with meteorites found on Earth, was published suggesting building blocks of RNA (adenine, guanine and related organic molecules) may have been formed extraterrestrially in outer space. In 2017, a numerical model suggests that the RNA world may have emerged in warm ponds on the early Earth, and that meteorites were a plausible and probable source of the RNA building blocks (ribose and nucleic acids) to these environments. On August 29, 2012, astronomers at Copenhagen University reported the detection of a specific sugar molecule, glycolaldehyde, in a distant star system. The molecule was found around the protostellar binary "IRAS 16293-2422", which is located 400 light years from Earth. Because glycolaldehyde is needed to form RNA, this finding suggests that complex organic molecules may form in stellar systems prior to the formation of planets, eventually arriving on young planets early in their formation.
RNA Tie Club
Francis Crick proposed the "adaptor hypothesis" suggesting that some molecule ferried the amino acids around, and put them in the correct order corresponding to the nucleic acid sequence. He also suggested that there were 20 separate adaptor molecules. This was later to be found true by Robert Holley and the adaptor molecules were named transfer RNAs.
RNA world
One of the problems with the RNA world hypothesis is to discover the pathway by which RNA became upgraded to the DNA system. Geoffrey Diemer and Ken Stedman, at Portland State University in Oregon, may have found a solution. While conducting a survey of viruses in a hot acidic lake in Lassen Volcanic National Park, California, they uncovered evidence that a simple DNA virus had acquired a gene from a completely unrelated RNA-based virus. Virologist Luis Villareal of the University of California Irvine also suggests that viruses capable of converting an RNA-based gene into DNA and then incorporating it into a more complex DNA-based genome might have been common in the Virus world during the RNA to DNA transition some 4 billion years ago. This finding bolsters the argument for the transfer of information from the RNA world to the emerging DNA world before the emergence of the last universal common ancestor. From the research, the diversity of this virus world is still with us.
Transfer-messenger RNA
Coding by tmRNA was discovered in 1995 when Simpson and coworkers overexpressed the mouse cytokine IL-6 in "E. coli" and found multiple truncated cytokine-derived peptides each tagged at the carboxyl termini with the same 11-amino acid residue extension (A)ANDENYALAA. With the exception of the N-terminal alanine, which comes from the 3' end of tmRNA itself, this tag sequence was traced to a short open reading frame in "E. coli" tmRNA. Recognizing that the tag peptide confers proteolysis, the "trans"-translation model for tmRNA action was proposed.
Transcription (biology)
A molecule that allows the genetic material to be realized as a protein was first hypothesized by François Jacob and Jacques Monod. Severo Ochoa won a Nobel Prize in Physiology or Medicine in 1959 for developing a process for synthesizing RNA "in vitro" with polynucleotide phosphorylase, which was useful for cracking the genetic code. RNA synthesis by RNA polymerase was established "in vitro" by several laboratories by 1965; however, the RNA synthesized by these enzymes had properties that suggested the existence of an additional factor needed to terminate transcription correctly.