Difference between revisions of "Timeline of mRNA research"

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* Summary by decade
 
* https://www.theguardian.com/society/2024/apr/26/cancer-mrna-vaccine-melanoma-trial
 
* https://www.theguardian.com/society/2024/apr/26/cancer-mrna-vaccine-melanoma-trial
 
* https://www.mskcc.org/news/can-mrna-vaccines-fight-pancreatic-cancer-msk-clinical-researchers-are-trying-find-out
 
* https://www.mskcc.org/news/can-mrna-vaccines-fight-pancreatic-cancer-msk-clinical-researchers-are-trying-find-out

Revision as of 17:20, 22 July 2024

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
1961–1989 Early research In 1961, Sydney Brenner and colleagues make a significant discovery by identifying an unstable intermediate molecule called mRNA, which copies genetic information from DNA and guides protein synthesis. This marks a turning point in the understanding of mRNA's pivotal role in protein synthesis. In the same year, other scientists such as Cobb, Gros, Hiatt, Gilbert, Kurland, Jacob, and Monod also contribute to the investigation of mRNA's properties and its involvement in protein synthesis. Throughout the 1960s, scientists continue their research on mRNA to further unravel its functions and mechanisms in the synthesis of proteins.[2] In the 1970s, studies are conducted to explore the means of delivering mRNA into cells.[3]
1990 onwards The rise: mRNA as a therapeutic agent During the 1990s, there are advancements in the development of mRNA vaccines for personalized cancer treatment that utilize non-nucleoside modified mRNA. Research into mRNA-based therapies persist, exploring their potential as treatments for cancer, autoimmune disorders, metabolic conditions, and respiratory inflammatory diseases. Moreover, the utilization of mRNA to stimulate cells in producing the desired Cas protein showcases potential benefits for gene editing therapies, including CRISPR-based approaches.[4][5]
2000s–2010s mRNA as a Potential Therapeutic Approach Researchers successfully use mRNA to produce proteins in live animals. In the mid-2000s clinical trials using mRNA-based vaccines for cancer and infectious diseases show promising results. In 2009, BioNTech is founded. In 2010, Moderna, another of the pioneering mRNA companies, is founded. Since the 2010s, RNA vaccines and other RNA therapeutics start being considered to be "a new class of drugs."[6]
2020s-present mRNA Breakthroughs and Advancements Multiple mRNA-based COVID-19 vaccines, including the Pfizer-BioNTech and Moderna vaccines, are authorized for emergency use, demonstrating the efficacy and safety of mRNA technology. mRNA technology gains widespread recognition and acceptance due to the success of COVID-19 vaccines. Ongoing research focuses on expanding the applications of mRNA technology, including therapeutics for cancer, genetic diseases, and personalized medicine. Advancements are being made to optimize mRNA delivery, stability, and immunogenicity for broader clinical use.

Full timeline

Year Condition (when applicable) Event type Details Location
1909 Cancer 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 Streptococcus pneumoniae A significant milestone is reached with the publication of Oswald Avery, Colin Munro MacLeod, and Maclyn McCarty's seminal paper. This influential work identifies the "transforming principle" within pneumococcal bacteria as DNA. The publication marks a pivotal moment in establishing the recognition of DNA's genetic role, firmly establishing it as the carrier of genetic information and its fundamental importance in biological processes and inheritance.[7][8][9] United States (Rockefeller University)[10]
1947 French biochemist André Boivin becomes the first person to propose the concept that DNA is responsible for generating RNA, which subsequently leads to protein synthesis. Boivin's pioneering insight would lay the foundation for the understanding of the central dogma of molecular biology, highlighting the flow of genetic information from DNA to RNA to proteins.[7] 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.[11][12] "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."[7] 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.[13] 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”.[7] United States
1952–1954 French biochemist Jacques Monod's research team and later American biochemist Arthur Pardee conduct experiments that reveal an interesting connection between RNA synthesis and protein synthesis in mutant bacteria. Their findings show that the production of β-galactosidase, an enzyme, was dependent on the presence of a specific RNA nucleotide called uracil. This discovery suggests that RNA synthesis plays a vital role in the process of protein synthesis. The interpretation shared by Crick and the researchers is that the presence of uracil indicates turnover of RNA molecules in the cytoplasm, implying that some RNA molecules undergo degradation and replacement.[14][15][7]
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.[2] United Kingdom
1953 Al Hershey and his research team demonstrate that following phage infection, bacteria exhibits a significant increase in the production of a specific type of RNA, which is synthesized at a high rate but also degraded quickly. However, it remains unclear whether this phenomenon is a result of the infection itself and could be considered a pathological consequence.[7][16]
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.[2][7] United States
1957 The recognition that genes generate a messenger molecule is first realized in Paris when Arthur Pardee visits the Institut Pasteur during his sabbatical. This pivotal observation marks a significant turning point in molecular biology, as it reveals the concept of gene expression through the production of a messenger molecule[17][7][18] France (Pasteur Institute)
1958 RNA-rich microsomal particles are baptised "ribosomes", during informal discussions at a conference.[7]
1958 (September 29) E. Volkin and L. Astrachan conduct research that reveals important findings about the relationship between RNA and DNA. Their experiments demonstrate that after phage infection in bacteria, radioactive RNA appears rapidly. However, when the radioactive isotope is added later, more radioactivity is observed in DNA compared to RNA. This leads them to speculate about the potential role of RNA as a precursor to DNA synthesis.[19][20][7]
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.[7] United Kingdom
1960 Masayasu Nomura, Benjamin Hall, and Sol Spiegelman make important progress in the study of RNA synthesis after phage infection. They build upon the previous work of Volkin and Astrachan and identify two distinct forms of RNA: one present in the ribosomal fraction and the other in soluble RNA. The researchers propose two possible interpretations for the soluble RNA fraction. It could be a precursor of ribosomal RNA or its breakdown product, or it might be involved in the amino acid acceptance process similar to Crick's adaptor molecule concept. Their findings shed further light on the intricate mechanisms of RNA function and its role in protein synthesis. [21][7]
1960 (December) Research American scientists Sol Spiegelman and Benjamin Hall publish an article showing that in enterobacteria phage T2, DNA and transitory RNA show sequence complementarity and would hybridize.[7][22] The invention of DNA-RNA hybridization by Hall and Spiegelman would have a powerful impact on the theory and discourse of molecular biology.[23] United States
1961 Research Aronson and McCarthy describe similar-sized RNA molecules, attached to ribosomes.[24]
1961 (March) Research American biochemist and geneticist Marshall Warren Nirenberg and his post-doctoral researcher, J. Heinrich Matthaei, publish an article in the journal Biochemical and Biophysical Research Communications. The article documents their cell-free protein synthesis system, highlighting the requirement for both ribosomal RNA and soluble RNA for successful protein synthesis. They find that soluble RNA alone is insufficient to drive the process. Their attempt to fractionate the ribosomal RNA indicates that the biological activity responsible for protein synthesis was associated with a fraction that sedimented approximately three times faster than soluble RNA. This research would shed light on the critical role of ribosomal RNA in the process of protein synthesis.[25][7]
1961 Research A groundbreaking discovery is made with the isolation and characterization of messenger RNA (mRNA). This discovery, published in two articles in Nature, highlights the role of mRNA as an intermediary molecule in protein synthesis. The researchers, including Sydney Brenner, François Jacob, and Jim Watson, find that mRNA carries genetic information from DNA to ribosomes for protein production. This breakthrough revolutionized the understanding of gene function and laid the foundation for subsequent research in molecular biology.[26][27][11][5][2]
1961 Research R.V. Eck publishes a paper in Nature leaving the door open to the possibility that genes are made of proteins, not DNA.[28][7]
1961 "Marshall Nirenberg and Heinrich Matthaei decipher the first codon, UUU, as coding for the amino acid phenylalanine."
1963 Research 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.[29][5]
1965 Marshall W. Nirenberg and Philip Leder complete the genetic code by mapping specific codons to amino acids. This achievement is a critical milestone in molecular biology, providing the foundation for understanding how DNA sequences encode proteins. Their work elucidate the universal language of life, revealing the correspondence between nucleotide triplets (codons) in mRNA and the amino acids they specify during protein synthesis. Nirenberg and Leder's groundbreaking research lay the groundwork for deciphering the genetic information encoded in DNA and paved the way for advancements in genetics, biotechnology, and medicine.
1965 October 14 Recognition 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.[2] France
1969 Research Raymond Lockard and Jerry Lingrel from the University of Cincinnati manage to isolate mRNA from a rabbit and introducing it into mouse lymphocytes. This experiment demonstrates that the introduced mRNA could stimulate the production of a specific protein in the lymphocytes. This finding marks a significant step in understanding the role and potential of mRNA in gene expression and protein synthesis.[5][2] United States (University of Cincinnati)
1970 "Discovery of tRNA (transfer RNA) and its role in translation, further elucidating the process of protein synthesis."
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.[30][2] United States
1974 Research Yasuhiro Furuichi from the National Institute of Genetics reports a key discovery regarding mRNA synthesis, when he finds that during the initial stage of transcription of the double-stranded RNA genome, mRNA synthesis could be activated by a specific nucleotide. This finding sheds light on the mechanisms involved in the transcription process and provides insights into the regulation of mRNA synthesis.[2] Japan (National Institute of Genetics)
1975 Research Yasuhiro Furuichi and A. J. Shatkin at AGENE Research Institute in Kamakura, Japan, discover a unique 'cap' structure at the tip end of mRNA. Known as the 5' cap, this structure plays a crucial role in mRNA stability, transport, and translation initiation. The discovery of the mRNA cap provides valuable insights into the molecular mechanisms of gene expression and paved the way for further research in the field of molecular biology.[31][2][2] Japan (AGENE Research Institute)
1977 "Richard J. Roberts and Phillip A. Sharp discover split genes and RNA splicing, leading to the understanding of introns and exons."
1978 Research 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 August Research Dimitriadis, Ostro, Giacomoni, Lavelle, Paxton, and Dray conduct an important experiment at the National Institute for Medical Research and the University of Illinois. They successfully produce proteins in mouse and human cells through the delivery of mRNA that was packaged in a liposome. This groundbreaking approach demonstrates the potential of using mRNA as a therapeutic tool for protein production, opening new avenues for research and development in the field of molecular medicine.[32][2][33] United Kingdom (National Institute for Medical Research), United States (University of Illinois)
1978 "Tom Cech and Sidney Altman independently discover ribozymes, RNA molecules that can catalyze chemical reactions, challenging the belief that only proteins can have enzymatic activity."
1983 Jeffrey et al. report that the distribution of actin mRNA in ascidian oocytes and embryos exhibit an asymmetrical pattern. This finding marks the initial identification of key components in understanding the phenomenon.[11]
1983 "Identification of the 5' cap and 3' polyadenylation of mRNA, essential for stability and translation initiation."
1984 Philipp Felgner, working at Syntex Research, manages to synthesize the first cationic (positively charged) lipid. The use of cationic lipids provide a promising approach for delivering therapeutic drugs and genetic material into cells more efficiently. This breakthrough marks an important step forward in the development of novel delivery systems and paves the way for further advancements in drug and gene therapy research.[2]
1984 Developmental biologists Paul Krieg and Douglas Melton from Harvard University demonstrate the production of abundant and functional mRNA in the laboratory. They achieve this by utilizing an RNA-synthesis enzyme derived from the vaccinia virus and employing various techniques. Their research would pave the way for the generation of significant quantities of biologically active mRNA, contributing to advancements in the field of molecular biology.[34][5] United States (Harvard University)
1985 S. Tabor and C. C. Richardson develop an upgraded version of the T7 polymerase-promoter complex, allowing for precise regulation of gene expression. This innovative approach remains in use today. These groundbreaking experiments initiated a continuous progression of practical research focused on mRNA delivery and commercialization, leading to significant advancements in the field.[35][5]
1987 American physician and biochemist Robert W. Malone conducts an experiment that demonstrates the ability to induce cells to produce luciferase, a light-producing protein. He achieves this by injecting the cells with mRNA that he had prepared using the technique developed by Krieg and Melton, combined with cationic lipids provided by Felgner. This experiment, conducted at the Salk Institute for Biological Sciences in collaboration with Felgner and Verma, shows that mRNA encapsulated into liposomes made with cationic lipids could effectively stimulate protein production when injected into mouse cells. This breakthrough provides further evidence for the potential of mRNA-based therapies and marks an important milestone in the development of mRNA delivery systems for protein expression.[36] United States (Salk Institute)
1989 mRNA as a therapeutic is first put forward "after the development of a broadly applicable in vitro transfection technique."[37]
1989 Dimitriadis uses liposomes 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]
1990 (January 1) Research An experiment by Kariko et al. at University of Pennsylvania shows that mRNA can be used to get cells to produce protein that inhibits blood clot formation.[2] United States
1990 (March 23) A study reports that when naked mRNA and naked DNA were directly injected into the skeletal muscle of mice, it resulted in the production of proteins. The research was conducted by Wolff, Malone, Williams, Chong, Acsadi, and Jani from the University of Wisconsin, Salk Institute for Biological Sciences, and Vical.[2][38] United States (University of Wisconsin, Salk Institute)
1990 Following the initial endeavors in DNA-based gene therapy, the viability of mRNA as a genetic vector is demonstrated. This approach holds theoretical appeal due to the non-integration of mRNA into the genome, its immediate availability for protein translation, and its transient nature that is advantageous for certain applications. Wolff et al., in a notable study, inject naked mRNA encoding chloramphenicol acetyltransferase into the skeletal muscle of mice and successfully observed the expression of specific proteins. This marks the first published account of the effective utilization of in vitro transcribed (IVT) mRNA in animals, where injected reporter gene mRNAs results in detectable protein production.[1][39][40]
1990 The concept of mRNA as a therapeutic agent is established by Wolff J. and colleagues, when they conduct an experiment demonstrating the in-vivo expression of mRNA. The researchers inject naked RNA directly into the muscles of mice, providing evidence of direct gene transfer in living organisms. This study lays the foundation for the use of mRNA as a potential tool for therapeutic applications.[5]
1991 mRNA is proposed as an active pharmaceutical ingredient for the treatment of cancer.[41]
1992 (February 21) Research Jirikowski et al. at The Scripps Research Institute Diabetes demonstrate that mRNA encoding for the hormone vasopressin directly injected into the brains of rats could temporarily relieve diabetes for up to 5 days.[2][5][42] United States
1992 A significant milestone is reached in the utilization of mRNA as a genetic vector. Prior to this, the theoretical advantages of mRNA, such as its non-integration into the genome, immediate availability for protein translation, and transient signaling, had been recognized. The practical demonstration of mRNA's capabilities occurrs in 1990 when Wolff et al. inject naked mRNA encoding chloramphenicol acetyl transferase into the skeletal muscle of mice, resulting in the targeted expression of the specific protein. Building upon this success, a subsequent study in 1992 focuses on the treatment of chronic diabetes insipidus in Brattleboro rats. In this experiment, naked, synthetic mRNA encoding arginine vasopressin was injected into the rats' hypothalami, leading to a successful cure of the condition. These findings exemplify the potential of mRNA as a genetic tool, showcasing its ability to deliver therapeutic benefits in gene therapy approaches.[1]
1992 Research A study demonstrates that administration of vasopressin-encoding mRNA in the hypothalamus could elicit a physiological response in rats.[39][43]
1993 (April 20) Literature Joel G. Belasco and George Brawerman publish Control of Messenger RNA Stability.[44]
1993 (July) The first evidence suggesting that mRNA could serve as a potential method for vaccines occurs when researchers Martinon, Krishnan, Lenzen, Magne, Gomard, and Guillet from INSERM present compelling findings supporting the notion that mRNA could be utilized as a viable approach for vaccine development. This discovery opens up new possibilities for utilizing mRNA as a tool in immunization strategies.[2] France (Inserm)
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 Kozak proposes a hypothesis regarding the structural characteristics of the 5' untranslated region (UTR) of mRNA molecules. According to his postulation, these structures could function as regulatory sequences that facilitate translation by enabling proteins to bind and induce conformational changes downstream. This concept suggest that the specific arrangement of nucleotides in the 5' UTR could play a role in modulating the efficiency of protein synthesis. Kozak's hypothesis provide valuable insights into the mechanisms underlying translational control and the potential regulatory functions of mRNA structures.[45]
1995 Conry et al. publish study on development of mRNA transcripts encoding luciferase and human carcinoembryonic antigen (CEA) as a vaccine vector. The modified mRNA constructs successfully expresses CEA in mouse fibroblasts in vitro and luciferase in vivo after injection. The researchers immunized mice with the mRNA transcripts encoding CEA, resulting in an immune response with anti-CEA antibodies detected in five out of seven immunized mice. This approach shows promise for inducing immune responses against potential cancer-related proteins.[5][46]
1995 Ian Maclachlan and Pieter Cullis publish a study on the development of a lipid nanoparticle system for the delivery of drugs and gene therapy. This research, conducted at Protiva Biotherapeutics and Inex Pharmaceuticals, introduces a novel approach that utilized lipid nanoparticles to effectively deliver therapeutic agents and genetic material. The study opens up new possibilities in the field of drug delivery and gene therapy by providing a promising platform for targeted and efficient delivery of treatments.[47][5]
1996 Gilboa and colleagues demonstrate the potential to elicit robust immune responses against tumors in mice by utilizing dendritic cells that were modified with mRNA encoding surface receptors found on the tumors.[2]
1996 August Research Boczkowski et al. at Duke University show that dendritic cells modified with mRNA elicit strong immune response against tumours in mice.[2] United States
1996 RNA interference (RNAi) is discovered, revealing a mechanism in which small RNA molecules regulate gene expression. This groundbreaking discovery would revolutionize molecular biology and earn the Nobel Prize in Physiology or Medicine in 2006 for its discoverers Andrew Fire and Craig Mello. RNAi would since become a crucial tool in scientific research, enabling precise control over gene expression and offering promising applications in therapeutics, agriculture, and biotechnology.
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.[48]
1997 Merix Bioscience becomes the first-ever mRNA company, marking a significant milestone in the field of mRNA therapeutics. Reflecting its growth and progress, the company would later change its name to Argos Therapeutics in 2004.[5][49]
1997 Merix Bioscience is founded as a Duke University spin-out to develop mRNA for cancer vaccines.[50][2] United States
1997 (October) MRNA Formation and Function.[51]
1998 A small interfering RNA (siRNA) or micro RNA (miRNA), is discovered as a class of naturally occurring RNA. This discovery, made by MK and Kostas, reveals that siRNA and miRNA play a crucial role in the post-transcriptional machinery of cells. By targeting specific mRNAs, siRNA and miRNA can form double-stranded RNA molecules that prompt rapid degradation (known as gene silencing). Consequently, this mechanism offers the potential to regulate gene expression at a post-transcriptional level. The utilization of siRNA and miRNA holds promise in the development of treatments for HIV, cancer, and melanoma.[5]
2000 (January) A significant advancement is made in the field of vaccination when Hoerr, Obst, Ramemenseee, and Jung from the University of Tübingen demonstrate the efficacy of freshly synthesized naked RNA and protamine-protected RNA as viable tools for vaccination. This finding indicates that these RNA molecules could serve as effective agents in vaccine development.[2]
2000 CureVac, a spin-out company, is established with the purpose of developing mRNA for vaccines. Ingmar Hoerr, the founder of CureVac, plays a crucial role in this endeavor. CureVac AG emerges as the pioneer company to successfully apply mRNA in the field of medicine, marking a significant milestone in the utilization of mRNA technology for medical purposes.[2][49]
2000 (October) A major discovery is made at the University of Pennsylvania by Drew Weissman, H. Ni, D. Scales, Dude, Capodici, McGibney, Abdool, SN Isaacs, Cannon, and Kariko. They report that mRNA encoding for HIV is able to activate a powerful immune response in T cells. This finding opens up new possibilities for the development of mRNA-based vaccines targeting HIV, with the potential to stimulate a robust immune defense against the virus.[2] United States (University of Pennsylvania)
2004 (March) A report indicates that mRNA can activate a series of Toll-like receptors, which are signaling receptors of the innate immune system. This research was conducted by Kariko, Houping Ni, Capodici, Lamphier, and Drew Weissman from the University of Pennsylvania.[2]
2005 (August) Research Research team led by Katalin Karikó at University of Pennsylvania finds that RNA is rendered invisible to immune system by replacing its nucleoside uridine with pseudouridine.[52][2] United States
2005 (October 19) MacLachlan and Cullis from Protiva Biotherapeutics and Inex Pharmaceuticals publish an important development in drug delivery and gene therapy. They introduce a lipid nanoparticle system designed for the efficient delivery of drugs and gene therapies. This innovative approach utilizes lipid-based nanoparticles to encapsulate and transport therapeutic agents, offering improved targeting and delivery capabilities.[2]
2005 "First FDA approval of an mRNA-based vaccine, a rabies vaccine for animals, demonstrating the potential of mRNA in vaccine development."
2006 A spin-out company called RNARx is established with the aim of commercializing modified mRNA for the treatment of anaemia. This venture is founded by Kariko and Drew Weissman, who played a crucial role in the development and modification of mRNA technology. The company's focus is to leverage the potential of modified mRNA to address anaemia and explore its therapeutic applications in this specific area. The establishment of RNARx marks a significant step towards translating mRNA research into real-world medical solutions for anaemia treatment.[2]
2006 (March 26) A significant breakthrough is achieved in the field of gene therapy through monkey studies. Researchers conduct experiments using a lipid nanoparticle system to successfully deliver RNA and silence disease-causing genes. This achievement demonstrates the potential of this novel approach for gene therapy. The successful delivery of RNA using the lipid nanoparticle system in monkey studies would pave the way for future advancements in the field of RNA-based therapeutics. The research is conducted under the auspices of Protiva Biotherapeutics, a company at the forefront of developing innovative solutions in the field of gene therapy.[2]
2006 (December 15) A method for producing mRNA with enhanced stability and translational efficiency is published. The method proposes innovative techniques to improve the characteristics of mRNA, making it more stable and efficient in protein translation. This advancement would opened up new possibilities for mRNA-based applications and further contribute to the development of RNA-based therapies and biotechnological tools.[2] Germany (Johannes Gutenberg University)
2008 The initial concept of delivering self-amplifying RepRNA vaccines using synthetic, biodegradable particles is introduced. Since then, the approach of complexing the RNA for targeted delivery to dendritic cells (DCs) would demonstrate its potential through various methods such as polysaccharide, polyplex, and lipoplex formulations.[53][54]
2008 Biopharmaceutical New Technologies (BioNTech) is established with the aim of utilizing mRNA for the development of personalized cancer immunotherapies. The founders recognize the potential of mRNA technology in the field of cancer treatment and seek to harness its capabilities for more accurate and individualized immunotherapy approaches. The establishment of BioNTech marks a significant event in the advancement of mRNA-based therapies, with a focus on tailoring treatments to the specific needs of cancer patients. Since its inception, BioNTech would be dedicated to pushing the boundaries of immunotherapy and would play a role in the development of innovative mRNA-based cancer treatments.[2][49]
2009 A groundbreaking trial is conducted on mRNA-based vaccines for cancer immunotherapy in individuals with metastatic melanoma. The trial demonstrates the potential of mRNA technology to stimulate the immune system and generate vaccine-specific T cells targeted against melanoma. The results show a significant increase in the number of T cells directed against melanoma, indicating the vaccines' ability to elicit an immune response. This trial marks a significant advancement in the development of mRNA-based vaccines for cancer treatment and provides promising evidence for their use in cancer immunotherapy.[5]
2010 Derrick Rossi, a researcher at Harvard Medical School, expands upon Shinya Yamanaka's breakthrough in inducing pluripotency and utilizes RNA to reprogram adult cells into embryonic stem cells. This significant development paves the way for the establishment of Moderna Therapeutics, as it harnesses the potential of RNA technology for various applications in medicine and therapeutics.[5][55] United States (Harvard Medical School)
2010 Eduard Yakubov et al. develop a method to reprogram human fibroblasts into induced pluripotent cells (iPS) using mRNA derived from specific transcription factors. Their approach aim to reduce the risks associated with DNA integration by traditional reprogramming methods. By transfecting the cells with RNA synthesized from cDNA of the transcription factors, the researchers observed successful intracellular protein expression and nuclear localization. Through multiple transfections, iPS colonies expressing embryonic stem cell markers were generated. Importantly, this RNA transfection approach eliminates the need for DNA integration and holds promise as a potential alternative to DNA vectors in iPS generation..[56][5] Israel (Weizmann Institute of Science)
2010 (November) Moderna Therapeutics is established with the objective of commercializing modified mRNA vaccines and therapeutics. Founded by Rossi, Kernneth Chien, and Robert Langer, Moderna enters the scene as the final member of the "mRNA Big Three" companies to be established. Despite being the last to emerge, Moderna would quickly gain significant recognition and is highly valued, surpassing the other two companies in the field. With a focus on mRNA therapies, Moderna would make notable progress in the development of innovative treatments using mRNA as a therapeutic agent.[49][5]
2010 (November 5) A team led by Luigi Warren, Philip Manos, and Chad Cowan report the successful transformation of skin cells into pluripotent stem cells using modified mRNA. The researchers utilized modified mRNA to reprogram the skin cells into a pluripotent state, capable of differentiating into various cell types.[5] United States (Harvard University)
2011 Partnership CureVac partners with Sanofi Pasteur.[49]
2012 Breakthroughs in genetic engineering are made by two separate teams led by Jennifer Doudna and Emmanuelle Charpentier. Their work focuses on utilizing CRISPR for precise genome editing. The CRISPR system, consisting of the Cas9 enzyme and a guide RNA, is found to target specific sequences in the genome. Plasmids or viral vectors are used to introduce these components into target cells. However, the sustained presence of Cas9-encoding plasmid DNA can lead to unintended modifications in non-targeted regions of the genome. These discoveries revolutionize genetic engineering and offer new opportunities for precise genome editing.[57][5]
2013 CureVac partners with Johnson and Johnson's Janssen Pharmaceuticals to develop a mRNA flu vaccine.[49]
2013 RNA Immunotherapies, a Belgian biotechnology company, is founded with the objective of developing immunotherapy for cancer and infectious diseases. The company is established in collaboration with Professor Kris Thielemans, a renowned immunologist from the Free University of Brussels, along with other partners. Their focus is on utilizing their proprietary mRNA TriMix platform for the development of innovative immunotherapies.[49] Belgium
2013 Moderna partners with AstraZeneca.[49]
2013 (October) A group of researchers from Harvard University, Massachusetts General Hospital, Children's Hospital Boston, Mount Sinai School of Medicine, and Karolinska Institute, conduct a study that demonstrates the potential of modified mRNA in improving heart function in mice. Through their research, they utilized modified mRNA and observed significant improvements in heart function in the mice subjects. The findings of this study highlight the therapeutic efficacy of modified mRNA in enhancing heart function. This discovery would open up promising avenues for further investigations into the use of modified mRNA as a potential treatment for heart-related conditions. The study provides valuable insights and set the stage for future research in the development of novel therapies for cardiovascular diseases.[5]
2014 Numerous pre-clinical and clinical trials start being carried out to investigate the utilization of mRNA technology in the development of vaccines targeting infectious diseases, hypersensitivities, and cancer. These trials, as documented by Sahin et al. (2014) and Weissman (2015), encompass a range of studies that aim to evaluate the effectiveness and safety of mRNA-based vaccines in combating these conditions.[5]
2015 (May 11) BioNTech announces a partnership agreement with Eli Lilly, with the purpose to advance the development of new tumor immunotherapy treatments, specifically focusing on T-cell receptor (TCR) therapies. The partnership involved a significant financial commitment, with Lilly investing more than $360 million in the collaboration. The objective of the collaboration was to leverage BioNTech's expertise in mRNA technology and Lilly's experience in the development and commercialization of innovative therapies. By combining their resources and knowledge, the two companies aim to accelerate the progress of tumor immunotherapy treatments, with a particular emphasis on TCR therapies.[58][49]
2015 Katalin Karikó and her colleague Drew Weissmann discover a solution to prevent the activation of the immune response triggered by injected mRNA. It is observed that mRNA activates toll-like receptors (TLR) present on immune cells. To address this, Karikó and Weissmann introduced a modification to the RNA by incorporating a naturally occurring modified nucleoside known as pseudouridine.[5]
2016 BioNTech establishes collaborations with two major companies. The first is with Bayer, aiming to develop innovative mRNA vaccines and drugs for animal health. This partnership aims to leverage BioNTech's mRNA technology platform to advance veterinary healthcare. In September of the same year, BioNTech joins forces with Genentech, a subsidiary of Roche, to develop an individualized mRNA tumor vaccine. This vaccine is designed to target specific neoantigens, which are unique to each patient's tumor. By utilizing mRNA technology, the goal is to develop personalized cancer immunotherapy that could effectively target and treat tumors based on the patient's specific genetic makeup.[49]
2016 Development of CRISPR-Cas9 technology for precise gene editing, offering new possibilities for manipulating mRNA and treating genetic diseases.
2016 Industry Merck expands a collaboration with Moderna, first struck in 2015, to develop and commercialise personalised mRNA cancer vaccines.[2] United States
2016 (November) Translate Bio, a company based in Massachusetts, is officially registered in November 2016 under the name RaNA Therapeutics.[49] United States
2017–2019 Significant advancements are achieved in the effectiveness of mRNA encoding antibodies against HIV and rabies, as evidenced by studies conducted by Pardi et al., Thran et al., and Schlake et al. in 2019. These studies contribute to the growing understanding of the potential of mRNA-based approaches in combating these infectious diseases.[5]
2017 In a study conducted by Stadler et al., researchers demonstrate the effectiveness of mRNA-encoded bispecific antibodies in eliminating large tumors in mice. By using in vitro-transcribed, pharmacologically optimized mRNA encoding the antibody, they achieved sustained endogenous synthesis of the antibody in the mice. The results show that the mRNA-encoded antibodies are as effective as purified bispecific antibodies in eliminating advanced tumors. This approach offers a potential solution to manufacturing challenges and could expedite the clinical development of novel bispecific antibodies due to the fast production of pharmaceutical mRNA.[5][59]
2017 (October) CureVac enters into a strategic partnership with Eli Lilly to jointly develop and commercialize five cancer vaccine products. This collaboration aims to leverage CureVac's expertise in mRNA-based therapies for cancer treatment. Additionally, in November of the same year, CureVac forms a partnership with CRISPR to advance the development of Cas9 mRNA for in vivo gene editing. These partnerships highlight the direction aimed at advancing innovative mRNA technologies for therapeutic applications in cancer treatment and gene editing.[49] United States
2018 U.S. FDA approves mRNA-based therapeutics against hereditary ATTR amyloidosis.[5]
2018 CureVac and Arcturus form a strategic partnership aimed at collaborating on the identification, development, and commercialization of novel mRNA therapies. This partnership brings together the expertise and resources of both companies to advance the field of mRNA-based therapeutics and explore new treatment possibilities.[49]
2019 Cancer Danish biotechnology company Genmab and CureVac partner to develop mRNA-based antibody therapeutics. The collaboration aims to combine CureVac's mRNA technology with Genmab's antibody expertise to create innovative treatment options for cancer patients. Genmab agrees to provide CureVac with a $10 million upfront payment and make a €20 million equity investment. The companies agree to conduct joint research to identify an initial product candidate, with Genmab taking responsibility for its development and commercialization. The partnership is expected to contribute to advancing mRNA-based antibody therapeutics in the field of cancer treatment.[49][60]
2019 A study conducted by Pardi et al. demonstrates the efficacy of nucleoside-modified mRNA in encoding a broadly neutralizing antibody against HIV-1. The researchers generated nucleoside-modified mRNAs encoding the light and heavy chains of the anti-HIV-1 antibody VRC01 and administered them to mice using lipid nanoparticles. The systemic administration of the mRNA resulted in significant levels of the VRC01 antibody in the plasma. Weekly injections of the mRNA maintained sustained antibody levels in mice. Importantly, a single injection of VRC01 mRNA provided protection against intravenous HIV-1 challenge in humanized mice. This study highlights the potential of nucleoside-modified mRNA as a delivery platform for passive immunotherapy against HIV-1 and potentially other diseases.[5][61]
2019 Toxins Research It is reported that mRNA technology could be utilized for the production and administration of antibodies against toxins. In cases where individuals are exposed to venom or toxins, immediate neutralization is crucial. Normally, it takes the body several days or weeks to generate antibodies, but a rapid response is essential in such situations. Traditionally, antibodies against toxins are produced using expensive and less accessible mammalian cell cultures. However, mRNA technology offers a more direct approach for antibody production. These antibodies can be administered through various routes such as intravenous, intradermal, subcutaneous, intramuscular, or intranodal, allowing for a swift response. Therefore, mRNA-mediated neutralization presents a promising and fast-acting alternative to conventional antibody use.[62][5]
2019 Research Lindsay et al. conduct a study on mRNA vaccine behavior within the body, focusing on its uptake and expression by immune cells. They observe a strong mRNA signal in the lymphoid node within 4 hours of intramuscular administration. This successful accumulation of mRNA in the lymphoid node highlights the importance of administration routes for vaccine distribution and immune cell uptake. The findings provide valuable insights into mRNA vaccine behavior, emphasizing the role of administration routes in shaping the immune response. Understanding the timing and localization of mRNA uptake in the lymphoid node contributes to optimizing vaccine delivery strategies and enhancing their effectiveness.[5] United States (Georgia Tech, Emory University)
2019 (December 6) Literature Marlene Oeffinger and Daniel Zenklusen publish The Biology of mRNA: Structure and Function.[63]
2020 COVID-19 Vaccine development Pfizer and BioNTech announce their collaboration to co-develop a potential mRNA-based vaccine, called BNT162, for preventing COVID-19 infection. The companies signed a letter of intent and a Material Transfer and Collaboration Agreement to begin working together immediately. The collaboration aims to accelerate the development of the vaccine. This partnership builds on their previous agreement to develop mRNA-based vaccines for influenza.[64][49] United States, Germany
2020 (July) Infectious diseases Vaccine development GlaxoSmithKline (GSK) and CureVac announce a strategic collaboration agreement for the development of mRNA-based vaccines and monoclonal antibodies (mAbs) targeting infectious diseases. The partnership aims to leverage CureVac's expertise in mRNA technology and GSK's scientific leadership in vaccines and mAbs. The companies agree to work on up to five mRNA-based vaccines and mAbs, with a focus on infectious disease pathogens. GSK agrees to invest £130 million (€150 million) in CureVac, representing a 10% stake, and provide an upfront payment of £104 million (€120 million). CureVac would be responsible for preclinical and clinical development through Phase 1 trials, after which GSK will take over further development and commercialization. The collaboration is expected to contribute to advancing mRNA-based vaccine and treatment technologies and improving responses to future pandemics.[49][65]
2020 (December) COVID-19 Vaccine launch 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) COVID-19 Vaccine launch The U.S. FDA approves the first mRNA vaccine for COVID-19 for emergency use, by BioNTech and Pfizer[2][66] United States
2020 (December 18) COVID-19 Vaccine launch The U.S. FDA approves second mRNA vaccine for COVID-19, by Moderna.[2] United States
2021 Cancer Miao et al. report that mRNA encoding antibodies targeting tumors is an area of active research. Monoclonal antibodies (mAbs) have the ability to directly kill cancer cells or stimulate immune cells to combat cancer. Bispecific antibodies, which can bind to both T cells and cancer cells, are particularly noteworthy as they facilitate the interaction between T cells and cancer cells, leading to the destruction of cancer cells by T cells. At this time, clinical trials currently evaluate mRNA-based vaccines for various types of cancer, including colorectal cancer, prostate cancer, triple-negative breast cancer, bladder cancer, pancreatic cancer, esophageal squamous carcinoma, gastric adenocarcinoma, melanoma, and non-small cell lung carcinoma.[5][67]
2022 (November) Multiple Sarfaraz K. Niazi publishes mRNA Therapeutics: Fast-to-Market Strategies, a 326-page guide covering nucleic acid therapeutics, focusing on mRNA vaccines. The book details manufacturing, formulations, safety testing, and regulatory steps, emphasizing cGMP compliance. It introduces the concept of "biosimilar" mRNA vaccines for rapid approval, providing financial projections for RNA manufacturing facilities and insights into supply chain management. The text also explores the future of nucleic acid products, suggesting a shift towards nucleic acid vaccines for autoimmune disorders' prevention. The book anticipates increased industry engagement, promising significant advancements in drug development.[68]
2022 (December 29) Melanoma Research A study on melanoma treatment unveils promising results with personalized mRNA vaccines combined with the immunotherapy drug pembrolizumab. In the KEYNOTE/mRNA trial, the combination therapy significantly reduces the risk of recurrence or death by 44% compared to pembrolizumab alone in stage III/IV melanoma patients post-surgery. Although there were slightly more adverse events with the combined therapy, experts hail this advancement as a significant step in melanoma treatment. Personalized mRNA vaccines train the immune system to recognize cancer proteins, potentially revolutionizing cancer therapy. This development, reminiscent of the penicillin moment, indicates a promising future for mRNA vaccines in treating various cancers.[69]
2023 (October 2) COVID-19 The Nobel Prize in Physiology or Medicine is jointly awarded to Katalin Karikó and Drew Weissman for their discoveries in nucleoside base modifications, which paved the way for the development of highly effective mRNA vaccines against COVID-19. Their research revolutionized our understanding of mRNA interaction with the immune system, facilitating the rapid development of vaccines during the pandemic. Before the pandemic, vaccines relied on whole viruses, viral components, or vector systems, requiring large-scale cell culture. Karikó and Weissman's work on mRNA technology overcame previous obstacles, offering a promising avenue for vaccine development independent of cell culture. Their breakthrough, published in 2005, anticipated the mRNA vaccine revolution witnessed during the COVID-19 pandemic.[70]
2024 (April 7) Pancreatic cancer Vaccine development In a phase 1 clinical trial, the investigational mRNA-based cancer vaccine autogene cevumeran shows promising results in stimulating a lasting immune response against pancreatic cancer. Administered alongside atezolizumab and mFOLFIRINOX chemotherapy, the vaccine activates T cells specific to neoantigens found in individual patients' tumors, potentially reducing the risk of cancer recurrence. Notably, vaccine-induced T cells persisted for up to three years after treatment in some patients. These findings support the development of personalized mRNA vaccines as a viable approach to targeting pancreatic cancer and warrant further investigation in larger clinical trials.[71]

Numerical and visual data

Google trends

The chart below shows Google Trends data for Messenger RNA, from January 2004 to September 2023, when the screenshot was taken. Interest is also ranked by country and displayed on world map.[72]

Mrnaresearch-googletrends.png

Google ngram viewer

The chart below shows Google Ngram Viewer data for Messenger RNA, between 1950 and 2019.[73]

Messengerrna-googlengram.PNG

Wikipedia views

The chart below shows pageviews of the English Wikipedia article Messenger RNA, from July 2015 to August 2023. See spike of interest around late 2020 during the COVID-19 pandemic, at the time of massive deployment of mRNA vaccines.[74]

MRNA-wikipedia-views.png

Meta information on the timeline

How the timeline was built

The initial version of the timeline was written by User:Sebastian.

Funding information for this timeline is available.

Feedback and comments

Feedback for the timeline can be provided at the following places:

  • FIXME

What the timeline is still missing

Timeline update strategy

See also

External links

References

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  67. ↑ Miao, Zhen; Balzer, Michael S.; Ma, Ziyuan; Liu, Hongbo; Wu, Junnan; Shrestha, Rojesh; Aranyi, Tamas; Kwan, Amy; Kondo, Ayano; Pontoglio, Marco; Kim, Junhyong; Li, Mingyao; Kaestner, Klaus H.; Susztak, Katalin (15 April 2021). "Single cell regulatory landscape of the mouse kidney highlights cellular differentiation programs and disease targets". Nature Communications. 12 (1): 2277. ISSN 2041-1723. doi:10.1038/s41467-021-22266-1. 
  68. ↑ Niazi, Sarfaraz K. (6 December 2022). "mRNA Therapeutics: Fast-to-Market Strategies". books.google.com.ar. CRC Press. Retrieved 3 October 2023. 
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  70. ↑ "The Nobel Prize in Physiology or Medicine 2023". NobelPrize.org. Retrieved 27 May 2024. 
  71. ↑ Stallard, Jim (7 April 2024). "Investigational mRNA Vaccine Induced Persistent Immune Response in Phase 1 Trial of Patients With Pancreatic Cancer | Memorial Sloan Kettering Cancer Center". www.mskcc.org. Retrieved 28 May 2024. 
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