A Timeline of Discoveries Towards mRNA Therapeutics
1947
RNA in the central dogma of molecular biology
mRNA
discovery
Boivin, A. and Vendrely, R. (1947) Experientia. 3, 32–34.
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1950
mRNA
discovery
RNA moves from nucleus to cytosol
Jeener, R. and Szafarz, R. (1950) Arch. Biochem. 26, 54–67.
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1951
Modification
Pseudouridine discovered in RNA
Cohn, W.E. and Volkin, E. (1951) Nature. 167, 483-484.
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1958
Modification
5-methylcytosine discovered in RNA
Amos, H. and Korn, M. (1958) Biochim. Biophys. Acta. 29, 444-445.
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1961
mRNA
discovery
mRNA carries information from genes to ribosomes for protein synthesis
Brenner S., et al. (1961) Nature. 190, 576-581.
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Gros F., et al. (1961) Nature. 190, 581-585.
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Jacob, F. and Monod, J. (1961)
J. Mol. Biol. 3, 318-356.
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Nirenberg, M.W. and Matthaei, H. (1961) Proc. Natl. Acad. Sci. USA. 47, 1588-1602.
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1965/1967
Translation
Discovery of stop codons
Edgar, R.S., Epstein, R.H. (1965) Sci. Am. 212, 70-78.
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Brenner, S., et al. (1965) Nature. 206, 994-998.
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Brenner, S., et al. (1967) Nature. 213, 449-50.
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1971
Poly(A) tail
Discovery of mRNA poly(A) tail
Darnell, J.E., et al. (1971) Proc. Natl. Acad. Sci. USA. 68, 1321-1325.
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Edmonds, M., et al. (1971) Proc. Natl. Acad. Sci. USA. 68, 1336-1340.
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1974
Modification
N6-methyladenosine discovered in mRNA
Desrosiers, R., et al. (1974) Proc. Natl. Acad. Sci. USA.. 71, 3971-3975.
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1975
Caps
mRNA Cap-0, Cap-1 and Cap-2 structures discovered in eukaryotic cells and viruses
Wei, C.M., et al. (1975) Cell. 4, 379-386.
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Furuichi, Y., et al. (1975) Proc. Natl. Acad. Sci. USA. 5, 1904-1908.
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Moyer, S.A., et al. (1975) Cell. 5, 59-67.
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Desrosiers, R.C., et al. (1975) Biochem. 20, 4367–4374.
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1977
Sequence elements
mRNA splicing is discovered
Chow, L.T., et al. (1977) Cell. 12, 1-8.
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Berget S.M., et al. (1977) Proc. Natl. Acad. Sci. USA. 74, 3171-3175.
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1984
Synthetic mRNA
In vitro transcription of functional mRNA
Melton, D.A., et al. (1984) Nucl. Acids Res. 12, 7035-7056.
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1989
Synthetic mRNA
First liposome-mediated transfection of synthetic mRNA into cultured cells
Malone, R.W., et al. (1989) Proc. Natl. Acad. Sci. USA. 86, 6077-6081.
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1990
Synthetic mRNA
First description of synthetic mRNA translation in vivo
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Wolff, J.A., et al. (1990) Science. 247, 1465-1468.
1993
Synthetic mRNA
Immune response from synthetic mRNA reported
Martinon, F., et al. (1993) Eur. J. Immunol. 23, 1719-1722.
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1994
Synthetic mRNA
Self-amplifying RNA as a vaccine
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Zhou, X., et al. (1994) Vaccine. 12, 1510-1514.
1998
Translation
Characterization of closed-loop model of mRNA
Wells, S.E., et al. (1998) Mol. Cell. 2, 135-140.
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2002
Synthetic mRNA
First in-human (ex vivo) clinical trials with synthetic mRNA
2003
Caps
First cap-specific gene expression analysis methods
Shiraki, T., et al. (2003) Proc. Natl. Acad. Sci. USA. 100, 15776-15781.
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2004
mRNA-based vaccines
Improved efficacy of synthetic mRNAs with incorporation of modified bases
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Kariko, K., et al. (2004) Biol. Chem. 279, 12542-12550.
2012
mRNA-based
vaccines
Lipid nanoparticle delivery of self-amplifying RNA improves potency
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Geall, A. J., et al. (2012) Proc. Natl. Acad. Sci. USA. 109, 14604-14609.
2012
mRNA-based vaccines
Directly injected, non-replicating mRNA can induce protective immune responses against an infectious pathogen
Petsch, B., et al. (2012) Nat. Biotechnol. 30, 1210-1216.
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2017
mRNA-based vaccines
Single low-dose nucleoside-modified mRNA vaccination protects against Zika virus
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Pardi, N., et al. (2017) Nature. 543, 248-251.
2017
mRNA-based vaccines
Preclinical and clinical demonstration of immunogenicity by mRNA vaccines against H10N8 and H7N9 influenza viruses
Bahl, K., et al. (2017) Mol. Ther. 25,1316-1327.
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2020
mRNA-based vaccines
Demonstration of safety and tolerability of mRNA-based vaccines against COVID-19 in Phase 1 clinical trials
Jackson, L.A., et al. (2020) N. Engl. J. Med. 383, 1920-1931.
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Translation
Genetic code deciphered
The Nobel Prize in Physiology or Medicine 1968
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1968
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Sequence elements
Sequence determination of a complete cDNA made from an mRNA
Efstratiadis, A., et al. (1977) Cell. 10, 571-585.
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1977
mRNA-based vaccines
Demonstration of efficacy of mRNA-based vaccines against COVID-19 in Phase 3 clinical trials
Polack, F.P., et al. (2020) N. Engl. J. Med. 383, 2603-2615.
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2020/
2021
Baden, L.R., et al. (2021) N. Engl. J. Med. 384, 403-416.
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Walsh, E.E., et al. (2020) N. Engl. J. Med. 383, 2439-2450.
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mRNA-based vaccines
Real-world effectiveness of mRNA-
based vaccines for COVID-19
Haas, E.J., et al. (2021) Lancet. 397, 1819-1829.
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Thompson, M.G., et al. (2021) N. Engl. J. Med. 384, 403-416.
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2021
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Heiser, A., et al. (2002) J. Clin. Invest. 109, 409-417.
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Weide, B., et al. (2008)
J. Immunother. 31, 180-188.