Timeline of mRNA research

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This is a timeline of mRNA research. Today, mRNA is a widely recognized and potent tool for generating antigen-specific immunity in the field of vaccines and immunotherapy.[1]

Sample questions

The following are some interesting questions that can be answered by reading this timeline:

Big picture

Time period Development summary More details
1950s "For much of the 1950s, the suggestion that DNA was the hereditary material in all organisms was accepted as a ‘working hypothesis’ but nothing more"[2]
1961–1989 Early research ": It started in 1961, when Brenner and colleagues described the presence of an unstable intermediate molecule that copies the information encoded by the DNA and directs the synthesis of proteins: RNA." "The turning point came in 1961 (Cobb). That year a group of scientists managed to isolate mRNA and determine its key role in protein synthesis (Brenner, Jacob, Meselson; Gros, Hiatt, Gilbert, Kurland; Jacob, Monod)." "Scientists continued to investigate the properties of mRNA and its role in the synthesis of proteins throughout the 1960s."[3]
1990 onwards The rise: mRNA as a therapeutic agent "In the 1990s, mRNA vaccines for personalized cancer have been developed, relying on non-nucleoside modified mRNA. mRNA based therapies continue to be investigated as a method of treatment or therapy for both cancer as well as auto-immune, metabolic, and respiratory inflammatory diseases. Gene editing therapies such as CRISPR may also benefit from using mRNA to induce cells to make the desired Cas protein."[4][5]
2001–2020 Development "Since the 2010s, RNA vaccines and other RNA therapeutics have been considered to be "a new class of drugs.""[6]
2020 onwards Acceleration

Full timeline

Year Month and date Event type Details Location
1909 German physician Paul Ehrlich suggest that the immune system may suppress tumor development. Today this may be demonstrated through promising applications for synthetic mRNA is immunotherapy for cancer[1] Germany
1944 "The acceptance of the genetic role of DNA began in 1944 with the publication of Avery, McLeod and McCarty’s first paper on the identification of the ‘transforming principle’ in pneumococcal bacteria as DNA 10, 11."[2][7][8]
1947 "The first person to argue that DNA produces RNA which in turn leads to protein synthesis was André Boivin, in 1947."[2] France
1950 March 1 Jeener and Szafarz of the University of Brussels first hypothesize that RNA is synthesized in the cell nucleus and then transferred into the cytoplasm, where it was aggregating with other molecules.[9][10] "The first suggestion that small RNA molecules move from the nucleus to the cytoplasm and associate with ribosomes where they drive protein synthesis was made by Raymond Jeener, in 1950."[2] Belgium
1952 September 1 American biochemist Alexander Dounce, of Rochester Medical School, proposes a biochemical model of how protein synthesis occurs on an RNA molecule, not on DNA.[11] Although the model is wrong, Dounce hypothesises that “the specific arrangement of amino acid residues in a given peptide chain is derived from the specific arrangement of nucleotide residues in a corresponding specific nucleic acid molecule”.[2] United States
1952 "In 1952 and 1954, first Monod’s group [12] and then Arthur Pardee [13] showed that in mutant bacteria β-galactosidase synthesis required the presence of the RNA-specific nucleotide uracil, indicating that RNA synthesis was necessary for protein synthesis. Their conclusion — which was shared by Crick — was merely that this showed that at least some RNA in the cytoplasm showed turnover."[2]
1953 James Watson and Francis Crick propose the model of the DNA double helix. After this, a new question would arise in the scientific community: how is information encoded by the DNA and how is it translated?[5] The mRNA molecule would be originally discovered as a result of scientists' search to understand the molecular mechanism by which DNA directs the formation of proteins within a cell, a search that would begin as soon as DNA was cracked by Watson and Crick.[3] United Kingdom
1953 "Al Hershey’s group showed that shortly after infection with phage, bacteria produced a form of RNA that was both synthesised at a high level and also broken down rapidly. It was possible, however, that this was a pathological consequence of infection."[2][14]
1956 Elliot Volkin and Lazarus Astrachan at Oak Ridge National Laboratory discover a 'DNA-like RNA' substance that does not resemble previously found types of RNA. Volkin and Astrachan notice it after infecting Escherichia coli with Enterobacteria phage T2 and then exposing the culture to radioactive Phosphorus-32 for a few minutes. Importantly the substance would appear to help the bacteria's cell machinery switch from making its own proteins to those that were characteristic of the virus.[3][2] United States
1957 "The realisation that genes produce a messenger molecule first occurred in Paris, during a sabbatical visit by Arthur Pardee to the Institut Pasteur, which began in 1957"[15][2]
1958 RNA-rich microsomal particles are baptised "ribosomes", during informal discussions at a conference.[2]
1958 September 29 "Volkin and Astrachan found that while radioactive RNA appeared rapidly in bacteria after phage infection, if the isotope was added later, then more radioactivity was found in DNA than in RNA[16]. Their interpretation of these results again focused on how RNA might act as a precursor to the synthesis of DNA. Despite widespread interest in their results — Thomas Duke recalled that when they presented their findings at the 1956 FASEB meeting, the room was so packed he had to listen from the doorway [17], and in 1958 Volkin gave a talk at a conference session organized by Monod’s group [9] — the interpretation of their finding as ‘DNA-like RNA’ obscured its true significance."[2]
1960 The idea of mRNA is first conceived by Sydney Brenner and Francis Crick on 15 April 1960 at King's College, Cambridge, while François Jacob tells them about a recent experiment conducted by Arthur Pardee, himself, and Jacques Monod.[2] United Kingdom
1960 "Finally, in 1960, Nomura, Hall and Spiegelman refined Volkin and Astrachan’s approach and showed that after phage infection two forms of RNA were synthesised: one was found in the ribosomal fraction, the other in soluble RNA [18]. They interpreted the soluble RNA fraction as either a precursor of ribosomal RNA (or its breakdown product) or as being involved in “the amino acid accepting function of normal soluble RNA”, in other words something like Crick’s adaptor molecule."[2]
1960 December "At the beginning of December 1960, Sol Spiegelman and Benjamin Hall submitted an article to PNAS showing that in T2 phage, DNA and transitory RNA showed sequence complementarity and would hybridise"[2][19]
1961 Early year "Similar-sized RNA molecules, attached to ribosomes, had been described at the beginning of 1961 by Aronson and McCarthy "[20]
1961 March "In March 1961, Nirenberg and his post-doc, Heinrich Matthaei, submitted an article to the rapid-publication journal Biochemical and Biophysical Research Communications [21]. In this paper they described the output of their cell-free protein synthesis system, emphasising that what they termed ribosomal RNA and soluble RNA had to both be present for the experiment to work; soluble RNA on its own could not drive protein synthesis. An attempt to fractionate the ribosomal RNA suggested that the biological activity tracked to a fraction that sedimented about three times as fast as soluble RNA."[2]
1961 "On May 13, 1961, two articles appeared in Nature, authored by a total of nine people, including Sydney Brenner, François Jacob and Jim Watson, announcing the isolation of messenger RNA (mRNA)"[22][23] "A better appreciation of the role of RNA was gained in 1961 when three publications revolutionized the way gene function was perceived by establishing messenger RNA (mRNA) as an information carrier in a transitional stage towards the synthesis of protein (Brenner et al. 1961; Gros et al. 1961; Jacob and Monod 1961)"[9] "Discovery of mRNA: It started in 1961, when Brenner and colleagues described the presence of an unstable intermediate molecule that copies the information encoded by the DNA and directs the synthesis of proteins: RNA. The group around Brenner worked with virus-infected cells and analysed the gene expression. They concluded that the protein-encoding information is not present in stable ribosomal RNA. Instead, a transient RNA molecule acts as a transcript of the genetic code. This RNA was termed messenger RNA (mRNA). Ribosomes synthesise proteins according to the information dictated by mRNA (Brenner et al., 1961)."[5] "The turning point came in 1961 (Cobb). That year a group of scientists managed to isolate mRNA and determine its key role in protein synthesis (Brenner, Jacob, Meselson; Gros, Hiatt, Gilbert, Kurland; Jacob, Monod)." "13 May 1961 Experiment confirms existence of mRNA Brenner, Jacob, Meselson University of Cambridge, Pasteur Institute, California Institute of Technology"[3]
1961 R.V. Eck publishes a paper in Nature leaving the door open to the possibility that genes are made of proteins, not DNA.[24][2]
1963 Isaacs et al. demonstrate that viral nucleic acids can induce the production of interferon in infected chick, rabbit, and mouse cells. The production of interferon supports the fact that nucleic acid is considered foreign to the cell.[5]
1965 October 14 The Nobel Prize in Physiology or Medicine is awarded to François Jacob, André Lwoff and Jacques Monod from Pasteur Institute for the elucidation of the nature of mRNA.[3] France
1969 "In-vitro mRNA translation: In 1969, mRNA was translated in the lab for the first time. Lockard and Lingrel, who worked together at the University of Cincinnati, Ohio, provided the first evidence of in-vitro translation of mRNA. They used a mammalian (rabbit) cell-free system to demonstrate the translation of an mRNA transcript from another mammalian species (Lockard and Lingrel, 1969)."[5] "Raymond Lockard and Jerry Lingrel, two scientists based at the University of Cincinnati, Ohio. In 1969 they showed that it was possible to get mouse lymphocytes to start producing globin, a protein that helps transport oxygen, by introducing mRNA, isolated from a rabbit, using a cell-free system developed from immature red blood cells (Lockard, Lingrel)." "8 Oct 1969 mRNA isolated from a rabbit introduced into mouse lymphocytes shown to stimulate production of a protein Lockard, Lingrel University of Cincinnati"[3]
1973 Research Canadian physician Ralph M. Steinman and Zanvil A. Cohn at Rockefeller University discover dendritic cells, a type of immune cell found in the bloodstream that helps present antigens to the immune system to activate the T cell response to destroy it. Many of the mRNA cancer vaccines target dendritic cells.[25][3] United States
1973 "Shatkin was doing this work alongside Yasuhiro Furuichi, a Japanese researcher visiting his laboratory, who back in 1973 had observed, on the basis of work with the cytoplasmic polyhedrosis virus (CPV) of silkworms, that mRNA synthesis was activated by methylation of a specific nucleotide during the initial stage of transcription of the double-stranded RNA genome. Furuichi originally tried to publish his findings in Nature in 1973, but the editors replied they were too busy to publish it. The paper was subsequently published in Nucleic Acids Research in 1974"[3]
1974 "July 1974 mRNA synthesis reported to be activated by a specific nucleotide during the initial stage of transcription of the double-stranded RNA genome. Furuichi National Institute of Genetics"[3]
1975 Y. Furuichi and A. J. Shatkin at AGENE Research Institute in Kamakura, Japan, discover a unique 'cap' structure at the tip end of mRNA.[26][3]
1976 "1976 Unique 'cap' structure discovered at the tip end of mRNA Furuichi, Muthukrishnan, Tomasz, Shatkin Roche Institute of Molecular Biology"[3]
1978 Liposomes ere utilized for the delivery of mRNA to eukaryotic cells. By the end of the following decade, a cationic liposome mRNA delivery system, DOTMA, would be described and commercialized.[5]
1978 "31 Aug 1978 First proteins produced in mouse and human cells by delivering mRNA packaged in a liposome Dimitriadis, Ostro, Giacomoni, Lavelle, Paxton, Dray National Institute for Medical Research, University of Illinois"[3]
1978 "Over the next decade scientists began to wonder whether they could exploit the cellular messaging system provided by mRNA to allow patients' cells themselves to produce therapeutic proteins. This idea was given a boost in August 1978 by the work of Georges Dimitriadis at the National Institute for Medical Research in London and a team led by Marc Ostro at the University of Illinois. Independently they managed to produce rabbit globin respectively in mouse and human cells. They achieved this by delivering mRNA using a liposome."[3]
1983 "It was not until the mid-1980s that the first elements of the answer were identified when it was reported that the actin mRNA in ascidian oocytes and embryos was asymmetrically distrib�uted (Jeffery et al. 1983)"[9]
1984 "SP6 and T7 RNA polymerase: Moreover, in 1984, experimental work showed that any desired cDNA can be utilised for the synthesis of functional mRNAs and, consequently, the synthesis of proteins (Krieg and Melton, 1984). In light of this work, SP6 RNA polymerase was eventually commercialised. In addition to SP6 polymerase, researchers extracted and purified T7 RNA polymerase. In 1985, they also designed a T7 polymerase-promoter complex for the controlled expression of specific genes that is still used today (in upgraded form) (Tabor & Richardson, 1985). These pioneer experiments lead to an unstoppable series of practical work concerning mRNA delivery and commercialisation."[5]
1984 "1984 First cationic (positively charged) lipid synthesised, opening up new possibilities to deliver drugs and gene therapy Felgner Syntex Research"[3]
1984 " the work of Paul Krieg and Douglas Melton, two developmental biologists based at Harvard, who in 1984 showed it was possible to produce large amounts of biologically active mRNA in the laboratory using an RNA-synthesis enzyme extracted from the vaccinia virus and other tools (Krieg, Melton)."[3]
1984 September 25 Paul Krieg and Douglas Melton at Harvard University produce large amounts of biological active mRNA in the laboratory using RNA-synthesis vaccine.[3][27]
1985 "SP6 and T7 RNA polymerase: Moreover, in 1984, experimental work showed that any desired cDNA can be utilised for the synthesis of functional mRNAs and, consequently, the synthesis of proteins (Krieg and Melton, 1984). In light of this work, SP6 RNA polymerase was eventually commercialised. In addition to SP6 polymerase, researchers extracted and purified T7 RNA polymerase. In 1985, they also designed a T7 polymerase-promoter complex for the controlled expression of specific genes that is still used today (in upgraded form) (Tabor & Richardson, 1985). These pioneer experiments lead to an unstoppable series of practical work concerning mRNA delivery and commercialisation."[5]
1987 "In late 1987 Malone conducted an experiment which showed it was possible to get cells to start producing luciferase, a protein that helps produce light. He achieved this by injecting the cells with some mRNA he had prepared using Krieg and Melton's technique mixed with the cationic lipids supplied by Felgner (Malone, Felgner, Verma; Dolgin Sept 2021). "[3]
1987 "1987 mRNA encapsulated into liposome made with cationic lipids injected into mouse cells shown to produce proteins Malone, Felgner, Verna Salk Institute for Biological Sciences, Syntex"[3]
1987 "1987 Vical Corporation founded Felgner, Vical"[3]
1988 "Dr. Robert Malone discovered in-vitro and in-vivo RNA transfection and invented mRNA platform technology while he was at the Salk Institute in 1988. He is thus, the father of the modern mRNA vaccine technology, and he has spoken out against its recent misuse in the COVID-19 pandemic."[28]
1989 mRNA as a therapeutic is first put forward "after the development of a broadly applicable in vitro transfection technique."[29]
1989 "In 1989 Felgner and Wolff reported together with others that the lipofection method could successfully be used to deliver functional DNA into the skeletal muscle of live mice, which enabled the cells to start producing proteins that they could not otherwise make. Soon after this Felgner and his Vical colleagues unexpectedly found that naked DNA and naked mRNA directly injected into the muscle of an animal, without mixing it with cationic lipids, could also stimulate cells to start producing proteins they could not make otherwise (Wolff, Malone, Williams; Felgner, Rhodes)."[3]
1989 "Liposomes as mRNA delivery vehicle: In 1978, liposomes were utilised for the delivery of mRNA to eukaryotic cells (Dimitriadis, 1978). By the end of the following decade, a cationic liposome mRNA delivery system, DOTMA, was described and commercialised (Malone et al., 1989)."[5]
1990 "1 Jan 1990 Experiment shows mRNA can be used to get cells to produce protein that inhibits blood clot formation Kariko, Barnathan University of Pennsylvania"[3]
1990 "23 Mar 1990 Naked mRNA and naked DNA injected directly into the skeletal muscle of mice reported to produce proteins Wolff, Malone, Williams, Chong, Acsadi, Jani University of Wisconsin, Salk Institute for Biological Sciences, Vical"[3]
1990 "The use of mRNA as a genetic vector is theoretically attractive because mRNA does not integrate into the genome, is immediately available for translation to make protein, and provides a transient signal, a feature that is desirable for some applications. The demon�stration that mRNA could, in fact, function in this capacity came in 1990, not long after the initial attempts at DNA-based gene ther�apy, when Wolff et al. injected naked mRNA encoding chloram�phenicol acetyl transferase into the skeletal muscle of mice and observed specific protein expression [6]."[1] "The first report of the successful use of in vitro transcribed (IVT) mRNA in animals was published in 1990, when reporter gene mRNAs were injected into mice and protein production was detected"[30][31]
1990 "mRNA expression in-vivo: The foundation of the concept of mRNA as a therapeutic agent was laid by Wolff J. and colleagues in 1990. The team injected naked RNA into mice muscles to provide proof of principle for direct gene transfer in vivo (Wolff et al., 1990)."[5]
1991 "In 1991, mRNA was proposed as an active pharmaceutical ingredient for the treatment of cancer."[32]
1992 "1st use of mRNA as therapeutic molecule: In 1992, a team of scientists working at Scripps Research Institute used mRNA to transiently reverse diabetes insipidus in Brattleboro rats that do not produce the hormone vasopressin (Jirikowski et al., 1992)."[5]
1992 "21 Feb 1992 Diabetes reported to be temporarily relieved by injecting mRNA into rat brains Jirikowski, Sanna, Maciejewski-Lenoir, Bloom Scripps Research Institute"[3]
1992 "The use of mRNA as a genetic vector is theoretically attractive because mRNA does not integrate into the genome, is immediately available for translation to make protein, and provides a transient signal, a feature that is desirable for some applications. The demon�stration that mRNA could, in fact, function in this capacity came in 1990, not long after the initial attempts at DNA-based gene ther�apy, when Wolff et al. injected naked mRNA encoding chloram�phenicol acetyl transferase into the skeletal muscle of mice and observed specific protein expression [6]. This was followed in 1992 by a study in which injection of a naked, synthetic mRNA encoding arginine vasopressin into the hypothalami of Brattleboro rats cured the chronic diabetes insipidus suffered by this strain [7]."[1]
1992 "A subsequent study in 1992 demonstrated that administration of vasopressin-encoding mRNA in the hypothalamus could elicit a physiological response in rats"[30][33]
1993 April 20 Literature Joel G. Belasco and George Brawerman publish Control of Messenger RNA Stability.[34]
1993 July "July 1993 First evidence that mRNA could provide a means for vaccines Martinon, Krishnan, Lenzen, Magne, Gomard, Guillet INSERM"[3]
1993 Martinon et al. show that subcutaneous injection of liposome-encapsidated mRNA encoding the influenza virus nucleoprotein induces anti-influenza cytotoxic T lymphocytes.[1]
1994 "In 1994, Kozak postulated that structure in 5′ UTR of mRNAs could act as regulatory sequences to enhance translation by allowing proteins to bind and shift structure downstream"[35]
1995 "1st use of mRNA as vaccines: Even though the concept of mRNA vaccines sounds relatively advanced, it dates back to 1995, when Robert and his team designed the first mRNA vaccine that encoded cancer antigens (Conry et al., 1995)."[5]
1995 "1 Apr 1995 mRNA vaccine vector shown to stimulate immune response against human cancer antigen Conry, LoBuglio, Wright, Sumerel, Pike, Johanning, Benjamin, Lu, Curiel University of Alabama at Birmingham"[3]
1995 "Improving RNA delivery: In parallel, Pieter Cullis at the University of British Columbia was studying lipids. In 1995, Cullis and his team started working on the application of lipid nanoparticles (liposomes) for the delivery of large biological molecules such as RNA. Even though the system did not work consistently, their work advanced the research on using lipids as an effective and safe delivery system (Bailey & Cullis, 1997)."[5]
1996 "In 1996 Gilboa and his colleagues showed that it was possible to induce very strong immune responses against tumours in mice using dendritic cells modified with mRNA coding for surface receptors found on the tumours"[3]
1996 "August 1996 Dendritic cells modified with mRNA shown to elicit strong immune response against tumours in mice Boczkowski, Nair, Snyder, D, Gilboa Duke University"[3]
1997 Canadian American biologist Jack W. Szostak and Richard W. Roberts show that fusions between a synthetic mRNA and its encoded myc epitope could be enriched from a pool of random sequence mRNA-polypeptide fusions by immunoprecipitation.[36]
1997 "1st mRNA company: All this work in mRNA therapeutics laid the cornerstone of the first mRNA company ever founded: Merix Bioscience (1997). In 2004, the company changed its name to Argos Therapeutics as a sign of its evolution."[5]
1997 "Argos Therapeutics was founded in 1997 by Nobel Laureate Ralph Steinman, whose core technology platform, Arcelis® Accurate immunotherapy techniques that use mRNA isolated from a patient's tumor to gene-edit the patient's antigen delivery cells so that the antigen-presenting cells produce tumor-specific antibodies to activate the body's immune response to tumors and are suitable for the treatment of a variety of cancers and infectious diseases"[37]
1997 "In 1997, the biggest problem encountered by scientists in the process of research was that both natural RNA and artificially synthesized in vitro RNA would activate the response of human immune cells, causing RNA to be degraded before it could be translated into protein.In 1997, the biggest problem encountered by scientists in the process of research was that both natural RNA and artificially synthesized in vitro RNA would activate the response of human immune cells, causing RNA to be degraded before it could be translated into protein."[32]
1997 "In 2007, some scientists conducted research on the application of RNA on stem cells based on the previous method of modifying mRNA uridine, trying to reprogram somatic cells into embryonic stem cells."[32]
1997 "1997 Merix Bioscience founded as spin-out to develop mRNA for cancer vaccines Gilboa Duke University"[3]
1997 October MRNA Formation and Function.[38]
1998 "Bringing about post-transcriptional changes with RNA interference. Another class of naturally occurring RNA called small interfering RNA (siRNA) or micro RNA (miRNA) was discovered in 1998 (MK and Kostas, 1998). They are part of the post-transcriptional machinery in the cell. In principal, siRNA and miRNA target specific mRNAs to form double stranded RNA molecules that are quickly degraded (gene silencing). In this way, gene expression in a cell can be controlled at a post-transcriptional level. This approach is used to develop treatments for HIV, cancer and melanoma."[5]
2000 January "January 2000 Freshly synthesised naked RNA and protamine-protected RNA shown to be suitable tool for vaccination Hoerr, Obst, Ramemenseee, Jung University of Tübingen"[3]
2000 "2000 CureVac, a spin out company, set up to develop mRNA for vaccines Ingmar Hoerr CureVac"[3] "2000, CureVacCureVac AG was founded as the first company to successfully apply mRNA to the medical field."[37]
2000 October "October 2000 mRNA encoding for HIV reported to activate potent T cell immune response Drew Weissman, H Ni, D Scales, Dude, Capodici, McGibney, Abdool, SN Isaacs, Cannon, Kariko University of Pennsylvania"[3]
2004 March "March 2004 mRNA reported to activate series of Toll-like receptors, signalling receptors of the innate immune system Kariko, Houping Ni, Capodici, Lamphier, Drew Weissman University of Pennsylvania"[3]
2005 August "August 2005 mRNA rendered invisible to immune system by replacing its nucleoside uridine with pseudouridine Kariko, Buckstein, Houping Ni, Drew Weissman University of Pennsylvania"[3]
2005 "19 Oct 2005 Lipid nanoparticle system published for delivering drugs and gene therapy MacLachlan, Cullis Protiva Biotherapeutics, Inex Pharmaceuticals"[3]
2006 "2006 Spin-out company, RNARx, founded to commercialise modified mRNA for anaemia treatment Kariko, Drew Weissman"[3]
2006 March 26 "26 Mar 2006 Monkey studies show lipid nanoparticle system successfully delivered RNA to silence disease causing genes Zimmerman, ACH Lee, Akinc, Bramlage, Bumcrot, Fedorik, Harborth, James Heyes, Lloyd Jeffs, Matthias John, Adam Judge, Kieu Lam, Kevin McClintock, Nechev, Lorne Palmer, Racie, Ingo Rohl, Seiffert, Shannmugam, Sood, Soutschek, Toudjarska, Wheat, Yaworski, Z Protiva Biotherapeutics"[3]
2006 December 15 "15 Dec 2006 Method published to produce mRNA with increased stability and translational efficiency Holtkamp, Sebastian Kreiter, Abderraouf Selmi, Petra Simon, Koslowski, Christoph Huber, Tureci, Sahin Johannes-Gutenberg University"[3]
2008 "Following the first proposed delivery of self-amplifying RepRNA vaccines by synthetic, biodegradable particles in 2008 [14], complexing the RNA for delivery to DCs has shown applicability for polysaccharide, polyplex and lipoplex. "[39][40]
2008 "2008 Biopharmaceutical New Technologies (BioNTech) founded to develop mRNA as personalised cancer immunotherapies Sahin, Tureci, Huber BioNTech"[3] " BioNTechBioNTech AG was founded in 2008 to develop more accurate and personalized immunotherapy."[37]
2009 "In 2009, researchers conducted the first-ever trial on cancer immunotherapy using mRNA-based vaccines in human subjects with metastatic melanoma. The results of the trial showed an increase in the number of vaccine-directed T cells against melanoma (Weide et al., 2009)."[5]
2010 "Derrick Rossi, working at Harvard Medical School, built upon Shinya Yamanaka’s work of inducing pluripotency and used RNA to create embryonic stem cells from adult cells (Warren et al., 2010). This eventually led to the foundation of Moderna in 2010. "[5]
2010 "Regenerative medicine. mRNA has not only been a subject of interest for vaccine development, it has also influenced other fields including stem cell science and protein replacement therapies. Induced pluripotent stem cells (IPSCs) are a highly interesting addition to the tool-box of regenerative medicine, as IPSCs can differentiate into every other cell type in the body. The Japanese scientist Shinya Yamanaka transfected somatic cells by introducing several transcription factors and converted them to an embryonic stem cell state. That’s the dream of regenerative medicine. However, this process has the inherited danger of DNA integration into random sites of the genome and thereby potentially leading to adverse mutations, and unpredictable results. To counteract this issue, Yakubov et al. reprogrammed fibroblasts (a kind of skin cells) into IPSCs using mRNA transfection. This method completely avoids DNA integration and could be further developed to replace already available methods to generate IPSCs (Yakubov et al., 2010)."[5]
2010 November "November 2010 Moderna Therapeutics founded to commercialize modified mRNA vaccines and therapeutics Rossi, Kernneth Chien, Robert Langer Moderna"[5] "Moderna Therapeutics, founded in 2010 to develop mRNA therapies, is the last of the "mRNA Big Three" to be established, but is valued well ahead of the other two companies."[37]
2010 November 5 "5 Nov 2010 Modified mRNA reported to transform skin cells into pluripotent stem cells Luigi Warren, Philip Manos, Ahfeldt, Ahfeldt, Yuin-Han Loh, Hu Li, Frank Lau, Wataru Ebina, Pankaj Mandal, Zachary Smith, Meissner, George Daley, Brack, James Collins, Chad Cowan, Schlaeger, Rossi Harvard University"[5]
2011 "2011, CureVac established an extensive partnership with Sanofi Pasteur"[37]
2012 "Genetic engineering. In 2012, teams led by Jennifer Doudna and Emmanuelle Charpentier independently published papers showing how the power of CRISPR can be harnessed to edit the genome. In general, the system is composed of the Cas9 enzyme and a single stranded guide RNA (sgRNA) that are delivered to the cell via a plasmid or viral vector. It has been found that vectors are relatively stable and can persist in the cell. Off-target activity of the CRISPR/Cas system, however, is partly attributed to the sustained persistence of plasmid DNA encoding Cas9 in the cells."[5]
2013 "2013, CureVac teamed up with Johnson and Johnson's Janssen Pharmaceuticals to develop a mRNA flu vaccine."[37]
2013 "TheRNA Immunotherapies was founded in 2013 by a Belgian biotechnology company, founded by Professor Kris Thielemans, a renowned immunologist at the Free University of Brussels, in partnership with other partners to develop immunotherapy for cancer and infectious diseases based on its proprietary mRNA TriMix platform."[37]
2013 " in 2013, Moderna teamed up with AstraZeneca, which will give Moderna priority over targeting on oncology and cardiovascular disease."[37]
2013 October "October 2013 Modified mRNA shown to help improve heart function in mice Lior Zangi, Kathy Lui, von Gise, Qing Ma, Ebina,Ptaszek, Spater, Huansheng Xu, Tabebordbar,Gorbatov, Sena, Nahrendorf, David Briscoe,Ronald Li, Amy Wagers, Rossi, William Pu, Kenneth Chien Harvard University, Massachusetts General Hospital, Children's Hospital Boston, Mount Sinai School of Medicine, Karolinska Institute"[5]
2014 "Applications of mRNA technology. During the following years, various pre-clinical and clinical trials on mRNA-based vaccines against infectious diseases, hypersensitivities and cancer were completed (Sahin et al., 2014; Weissman, 2015)."[5]
2014 "2014, CureVac partnered with Blinger Ingehan (BI) to conduct a clinical trial of CureVac's therapeutic mRNA lung cancer vaccine."[37]
2014 "2011, CureVac established an extensive partnership with Sanofi Pasteur, and in 2014, the two sides decided to further strengthen their partnership in the field of mRNA vaccines, which Sanofi will develop a cureVac-based RNActive vaccine."[37]
2015 May 11 "On May 11, 2015, BioNTech entered into a partnership agreement with Lilly to develop new tumor immunotherapy treatments such as TCR for a total of more than $360 million"[37]
2015 "Applications of mRNA technology. During the following years, various pre-clinical and clinical trials on mRNA-based vaccines against infectious diseases, hypersensitivities and cancer were completed (Sahin et al., 2014; Weissman, 2015)."[5]
2015 "In 2015, Moderna and Mercerton partnered on an infectious disease mRNA vaccine, which will give Mercerton commercialization of five of Modena's candidate products"[37]
2015 "In 2015, Katalin Karikó and her colleague Drew Weissmann found the solution to prevent activation of the immune response against the injected mRNA. It has been found that mRNA activates the toll-like receptors (TLR) on immune cells. Karikó and Weissman modified the RNA by inserting a naturally occurring modified nucleoside: pseudouridine."[5]
2015 "Protein replacement therapies. Fundamentally, mRNA therapeutics can be considered as a transient form of gene therapy that bypasses the complications of “conventional” gene therapy where DNA is inserted in the genome, including insertional mutagenesis and toxicity associated with viral vectors. Currently, researchers are working on introducing mRNA-based protein replacement therapies for treating myocardial infarction (heart attack) (Weissman, 2015)."[5]
2016 May 29 Literature "Synthetic mRNA: Production, Introduction Into Cells, and Physiological Consequences"[41]
2016 "In 2016, BioNTech partnered with Bayer to develop a new generation of mRNA vaccines and drugs for animal health, and in September of the same year, BioNTech partnered with Roche's Genentech to develop an individualized mRNA tumor vaccine with a specific new etony."[37]
2016 "In 2016, for example, Merck expanded a collaboration with Moderna, first struck in 2015, to develop and commercialise personalised mRNA cancer vaccines."[3]
2016 November "Translate Bio, headquartered in Massachusetts, USA, was registered in November 2016 under the name RaNA Therapeutics"[37]
2017 " Significant progress has been made regarding the efficacy of antibody encoding mRNA against HIV and rabies (Pardi et al., 2017; Thran et al., 2017; Schlake et al., 2019)."[5]
2017 " Significant progress has been made regarding the efficacy of antibody encoding mRNA against HIV and rabies (Pardi et al., 2017; Thran et al., 2017; Schlake et al., 2019)."[5]
2017 " there are some limitations of mAbs application. They have a short serum half-life, especially bispecific antibodies. In addition, there are manufacturing issues, including reduced stability, and a tendency of mAbs to aggregate. Impurities can also accumulate during the production process. All these limitations can be addressed by direct application of mRNA encoding for mAbs (Stadler et al., 2017; Schlake et al., 2019)."[5]
2017 October "October 2017, CureVac partnered strategically with Lilly to develop and commercialize five cancer vaccine products for CureVac, and in November of the same year, CureVac partnered with CRISPR to develop Cas9 mRNA for in vivo gene editing."[37]
2017 November "October 2017, CureVac partnered strategically with Lilly to develop and commercialize five cancer vaccine products for CureVac, and in November of the same year, CureVac partnered with CRISPR to develop Cas9 mRNA for in vivo gene editing."[37]
2018 January 12 "12 Jan 2018 mRNA flagged up as promising new vaccine technology for combating infectious diseases Pardi, Michael Hogan, Frederick Porter, Drew Weismann University of Pennsylvania"[3]
2018 "Moderna Therapeutics, founded in 2010 to develop mRNA therapies, is the last of the "mRNA Big Three" to be established, but is valued well ahead of the other two companies. Nasdaq in 2018, setting a record for the largest biotech IPO in history, valued at about $7.6 billion."[37]
2018 July "In July 2018, BioNTech and Genevant announced that they would partner in the development of five mRNA treatment options for the treatment of rare diseases with high medical needs, and reached a series of exclusive licenses to apply Genevant's delivery technology to five oncology projects at BioNTech;"[37]
2018 "In-vitro transcription of mRNA: Nucleic acids have revolutionised the field of genetics and regenerative medicine. The in-vitro transcription of mRNA has addressed almost all the challenges associated with the use of mRNA as a therapeutic agent. In-vitro transcription is simple, rapid, and controlled. Most importantly, chemical modifications can be introduced to the mRNA strand in-vitro (Kwon et al., 2018)."[5]
2018 "Moreover, in 2018, FDA approved mRNA-based therapeutics against hereditary ATTR amyloidosis (DeWeerdt, 2019)."[5]
2018 "2018, CureVac and Arcturus have established a strategic partnership to jointly identify, develop and commercialize new mRNA therapies."[37]
2018 December "in December 2018, Institute for Clinical and Economic Review announced their intent to use a supplementary measure in addition to the QALY, entitled the equal value of life years gained (evLYG). The evLYG is intended to act as a supplement, rather than a replacement, for the QALY"
2019 " there are some limitations of mAbs application. They have a short serum half-life, especially bispecific antibodies. In addition, there are manufacturing issues, including reduced stability, and a tendency of mAbs to aggregate. Impurities can also accumulate during the production process. All these limitations can be addressed by direct application of mRNA encoding for mAbs (Stadler et al., 2017; Schlake et al., 2019)."[5]
2019 "2019, CureVac has a research partnership and licensing agreement with Genmab that combines CureVacmRNA technology and know-how with Genmab's proprietary antibody technology and expertise to focus on mRNA antibody product development."[37]
2019 " BioNTech announced in 2019 that it would extend its research collaboration with Sanofi for November 2015, with Sanofi investing 80 million euros in BioNTech to jointly develop and commercialize mRNA-based cancer immunological drugs for solid tumors."[37]
2019 " Significant progress has been made regarding the efficacy of antibody encoding mRNA against HIV and rabies (Pardi et al., 2017; Thran et al., 2017; Schlake et al., 2019)."[5]
2019 "mRNA encoding antibodies against toxins: Antibodies are administered in people exposed to venom (from snakes and spiders for instance) or toxins (diphtheria, botulinum). Untreated, it takes the body several days or even weeks to produce antibodies. However, in the case of venom or toxin, an immediate neutralising response is paramount. Antibodies that neutralise toxins are produced by using mammalian cell cultures; a very expensive and less accessible system. mRNA technology can facilitate the direct production of antibodies and the administration by intravenous, intradermal, subcutaneous, intramuscular or intranodal route allows for a fast response. mRNA-mediated neutralisation could be a fast acting alternative to the use of antibodies (Schlake et al., 2019)."[5]
2019 "Since the mRNA needs to be taken up and expressed by the immune cells immediately, much attention has been given to the type of mRNA vaccine used, administration route and delivery format (naked, carrier mediated, cell based). Lindsay and team, working at Georgia Tech and Emory University, tracked the movement of the mRNA vaccine in-vivo. They reported that the first strong signal of mRNA in the lymphoid node was observed after 4 hours as a result of intramuscular administration (Lindsay et al., 2019)."[5]
2019 December 6 Literature The Biology of mRNA: Structure and Function.[42]
2020 "2020, BioNTech and Pfizer have partnered to develop a new mRNA vaccine, which is currently in Phase I clinical trials in Germany and the United States, and the new crown mRNA vaccine approved by BioNTech has been approved for clinical trials in China."[37]
2020 July "July 2020, CureVac and GSK reached an 850 million euro strategic partnership on mRNA technology, which will be used to conduct research on infectious disease mRNA vaccines and monoclonal antibodies. in addition, CureVac has partnered with Auitas to obtain Acuitas' LNP technology."[37]
2020 December Pfizer–BioNTech and Moderna obtain authorization for their mRNA-based COVID-19 vaccines. "In 2020, the FDA approved the first mRNA-based vaccines against an infectious disease SARS-CoV-2. This was only made possible by decades of research on mRNA-based therapeutics."[5]
2020 December 11 "11 Dec 2020 FDA approved first mRNA vaccine for COVID-19 for emergency use BioNTech, Pfizer"[3]
2020 December 18 "18 Dec 2020 FDA approved second mRNA vaccine for COVID-19 Moderna"[3]
2021 "3. mRNA encoding antibodies against tumours: mAbs can identify and kill cancer cells directly or by activating immune cells to fight cancer. Additionally, some antibodies are specific to both T cells and cancer cells, known as bispecific antibodies. They bring T cells and cancer cells in close proximity and induce the T cells to kill the cancer cells. mRNA-based vaccines for colorectal cancer, prostate cancer, triple negative breast cancer, bladder cancer, pancreatic cancer, esophageal squamous carcinoma, gastric adenocarcinoma, melanoma, and non-small cell lung carcinoma are currently undergoing clinical trials (Miao et al., 2021). "[5]
2021 August 16 Literature "mRNA Medicine: Basics, Side Effects and Latest Research: New Cure for Covid, Cancer and Autoimmune Diseases?"[43]

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References

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