Unknown to the general public before the current pandemic, messenger RNA (mRNA) is a small revolution in the field of biology. Let’s find out about its history and who are the researchers behind this technology which has enabled the rapid development of anti-Covid vaccines.
L’messenger ( ) has been on the front page of all media since the development of very effective anti-Covid in record time. But to better understand what is happening today, we must turn back and go back to the genesis of this fascinating discovery that has long been overlooked.
In the years, researchers thus had the intuition that the local administration of an mRNA could be of great utility in and in immunology by occasionally inducing the production of a active or immunogenic, and therefore a , the basic principle of .
It is possible to fit this type ofin our cells, just like the sequences of ( deoxyribonucleic) but unlike the latter, mRNA cannot enter the nucleus where the material resides . In addition, mRNA is quickly destroyed in the cell – which on the other hand is a guarantee for .
Many attempts had been made, but the inflammatory response was far too strong.
Many laboratories, including some of the most prestigious, have therefore no longer paid much attention to the use of mRNA, a very fragile molecule, preferring to develop techniques based on the use of sequences of.
Katalin Kariko, mRNA pioneer
Isolated researchers, without much means, nevertheless got down to the task. This is the case ofwho began his research on mRNA in Hungary until 1985, then emigrated to the United States at the age of 30. She continued her research at the University of Pennsylvania, but her work did not interest many people and she had great difficulty in finding funding. On the other hand, she had complete confidence in herself, in her projects.
[ACCÈS LIBRE] : “This is where the young student discovers the subject that will fascinate her all her life: ribonucleic acid, or RNA. ” @louVPH portrays Katalin Kariko, a biologist who has worked hard on RNA since 1985. https://t.co/TuTxvqlEGO
– The 1 (@ Le1hebdo) June 30, 2021
To put it simply, these fit into one idea. Since mRNA is too immunogenic, then why not modify it chemically in order to reduce its inflammatory impact while preserving good translation into proteins. Katalin Kariko has selected a certain number of chemical modifications by favoring those which affect the nucleotide bases (the essential building blocks of RNA) and by respecting their pairing by.
Thoseare indeed essential for the translation of mRNA into proteins, as well as for the transcription of DNA into RNA. One of Katalin Kariko’s colleagues, the American , a student of Antony Fauci (the current Covid adviser to the White House) encouraged and helped her a lot in this direction. After many years of perseverance, they discovered that replacing uridine phosphate, one of the mRNA, by a pseudouridin, (a d’ is replaced by an atom of and vice versa) gave extraordinary results in terms of stability and translational capacity of mRNA into proteins.
was filed in 2005 by the University of Pennsylvania in this regard. The advantage of pseudouridin is that it is less fragile than “Natural”. This is also the case with pseudothymidine. In all these cases, the hydrogen bonds with the are preserved, making it possible to understand at the molecular level .
In the years that followed this foundational discovery, many researchers followed the work of Kariko and Weissman, which opened up real medical perspectives. The University of Pennsylvania patent was bought by an American biotech, now Cellscript, depriving Kariko and Weissman of all rights.
The patent license was then purchased in 2010 byincluding the PD-G. is now the French Stéphane Bancel. For the record MODeRNA means Modified RNA, which shows both the objective of and the essential role of chemical modification of the RNA molecule (RNA). Katalin Kariko, for her part, collaborated with doctors Ugur Sahin and Ozlem Tureci, of Turkish origin, creators of the start-up BioNTech in Germany. Vice-President of this start-up, she participates in particular in the work on the efficacy of mRNA-based vaccines on animals with regard to , Where .
When thefrom was known, Moderna and BioNtech were quite well prepared, sure of themselves, to launch their studies, as of January 2020.
BioNTech then joined forces withto increase its industrial production capacity.
How mRNA vaccines are made
We know that the(protein S) composed of 1273 and anchored in the outer shell of the contains motifs involved in the interaction with the receptor of of conversion (ACE2) present on the surface of target cells, allowing the virus with the host cell, then its , causing Covid-19. The S protein is therefore the preferred choice for combating SARS-CoV-2.
The nucleotide sequence offrom (RNA virus) having been established early (end of 2019) and taking into account the previous knowledge acquired on coronaviruses, it was easy to identify the part of the gene encoding the S protein and then to isolate a DNA replica, to serve as a template for large-scale mRNA production.
Thus from this DNA, we were able to produce by transcription in vitro RNA by replacing uridine triphosphate in the reaction medium with pseudouridine triphosphate, the nucleotide chaining taking place by means of an enzyme, RNA polymerase. This transcription outside the cell is facilitated and avoids any risk ofby a possible intracellular infectious agent. A cap and tail (polyadenosine) complete the mRNA sequence encoding the S protein because these structures allow mRNA access to , that is to say to the cellular machinery of protein production.
This mRNA is ultimately encapsulated inpositively charged lipid in order to reinforce its stability, and to facilitate its penetration through the membrane (negatively charged) of the cells of the muscle where it is injected at very low doses. Once in the at the ribosome level, mRNA encodes the synthesis of viral S proteins. These migrate to the cell surface and are recognized by B which produce anti-Covid antibodies. Other fragments of Spike are digested by dendritic cells (called presenters of ). , guarantors of immune memory.
Examples to follow
The chemical modification of mRNA is one of the keys that opened thevaccines. It will probably also be one of the keys to fight against some .
So there are wonderful stories of major scientific discoveries that changed the face of the world. Another had dazzled me a few years ago when I saw Luc Jacquet’s film, Laabout the epic of Claude Lorius (first Frenchman to receive the Blue Planet prize). This is at the origin of the following major discovery: the level of CO2 was relatively stable for 800,000 years then experienced a spectacular increase since the end of the XIXe century, related to temperature.
It has been known since 1896 when Arrhenius, Nobel Prize winner, had predicted it by calculation. But the experimental demonstration has definitely changed, at the highest level, our view of the world. The global reach of of Paris in 2015 is a recent illustration. The reports of (Intergovernmental Panel on the Evolution of ) are read carefully every year by all political decision-makers and numerous NGOs.
If I have linked these two beautiful stories of Claude Lorius and Katalin Kariko, it is because they both bring a major scientific breakthrough for humanity and that they concern rigorous, humble researchers, concerned with real progress. scientists, not necessarily rushing off the beaten track. These are examples for young people, students, doctoral students and researchers. All of them, without their being well aware of it, can be led, with a little luck, by their perseverance and their scientific spirit, to make discoveries of considerable significance.