CRISPR Nobel Prize: The relay race with award just for the last runner

This year 2020 the Nobel Prize in Chemistry has been awarded to a genetics project (it must be remembered that there is no Nobel Prize in Biology). Scientists Emmanuelle Charpentier and Jennifer Doudna have been awarded for their work "The development of a method for genome editing". In their work, they have isolated the components of the CRISPR-Cas system in humans and have managed to direct enzymatic activity towards DNA targets of interest. In this way, a great step has been taken in gene editing not only in humans but in a great variety of animals, since the CRISPR system is evolutionarily shared. The technique that has been tested in humans with great misgivings and controversies.

It is a well-deserved award and one that had been hanging around for years on whether such a discovery was going to be made. After years of unsuccessful attempts this year the award has finally been awarded. But it has left a bitter aftertaste for many scientists when they have seen that the main discoverer of the process, the Spaniard Francis Mojica, was omitted from the prestigious award. This exclusion had already happened to him in other awards, including in his own country when he did not receive the Princess of Asturias Award, which was also awarded to both women. Perhaps it is one of the unfortunate decisions of the world of Nobel laureates in recent years. Obviating the contribution of the Spanish may become the new controversy similar to that of the discovery of DNA and if some more name should accompany those of Watson and Crick. Although only time will tell, the recognition is already granted and the history written, once again.

On the other hand, other awards have been more aware of Mojica's participation. For example, the BBVA foundation recognized his key role in the discovery and shared the recognition with American and French scientists. The prestigious scientific journal Nature also recognized his participation and recalled that even the creation of the name of the technique "CRIPR-Cas" belongs to the Spanish researcher. His fortuitous discovery and the description of the process in a bacterium that the Spanish published allowed the researchers to later replicate the process already described in an artificial way, isolating the components. The immune system discovered by the researcher at his Alicante facility turned out to be a complex machinery for recognizing specific DNA sequences and cutting entire sections of the genome.

In 1987 a research group led by Atuso Nakata in Japan described tandem repeating sequences in the E. coli genome. In 1991 Jan D. A. van Embden in the Netherlands sequenced the Mycobacterium tuberculosis complex, having similar repeated sequences. A little later, in 1993, Haloferax mediterranei was sequenced in the laboratory of Francisco E. Rodríguez Valera, where Mojica received his doctorate. In his thesis he would name for the first time the function of these sequences for genetic editing. In an agreement between the Dutch and the Spanish, it was decided to call these sequences CRISPR.

During the following years, it was discovered how bacteria used these repeats as an immune system based on small RNA molecules and an enzyme capable of cutting the regions of DNA to which these guide RNAs bound. In 2003 and 2005 Mojica would publish these findings with great effort. Finally, in 2010 in collaboration of Silvain Moineau's team would demonstrate the efficiency of the system in bacterial defense against viruses.

In 2011 Charpentier published a new component of the CRISPR system in bacteria. That same year he began to collaborate with Doudna. Both RNA experts created an RNA chimera that made it possible to specifically target the cutting enzyme. This is the key step for them to get the Nobel Prize. Being able to direct the machinery to cut DNA regions at will and not only the virus regions as it happens in nature is the contribution of the scientists deserving of the award.

Undoubtedly, their contribution was key for Mojica's work, who had already described the mechanism and demonstrated its function in nature, to gain relevance. The recognition and cutting mechanism could be guided and therefore amplified to all living beings. Later it was seen that it was actually present in other living beings and that the extrapolation of the mechanism was much greater than expected. The researchers turned a bacterial immune system into one of the most powerful genetic tools today. Since they managed to direct the enzymatic cut, the studies that include this type of techniques have been increased exponentially.

Although the Chinese researcher He Jiankui published that he had manipulated the genome of two fetuses to protect them against HIV and that two girls had been born, the scientific community did not welcome the experiment. These experiments and associated controversy may have slowed the researchers' Nobel laureates.

References

Ishino Y, Shinagawa H, Makino K, Amemura M, Nakata A. Nucleotide sequence of the iap gene, responsible for alkaline phosphatase isozyme conversion in Escherichia coli, and identification of the gene product. J Bacteriol. 1987;169(12):5429-5433. doi:10.1128/jb.169.12.5429-5433

van Embden, J. D., Cave, M. D., Crawford, J. T., Dale, J. W., Eisenach,K. D., Gicquel, B., Hermans, P., Martin, C., McAdam, R. .Strain identification ofMycobacterium tuberculosis by DNA fingerprinting: recommendations for a standardized methodo-logy.J Clin Microbiol 1993. 31, 406–409

Mojica FJ, Juez G, Rodríguez-Valera F. Transcription at different salinities of Haloferax mediterranei sequences adjacent to partially modified PstI sites. Mol Microbiol. 1993; 9(3):613-21.  

Mojica, F. J., Diez-Villasenor, C., Soria, E. & Juez, G. Biological significance of a family of regularly spaced repeats in the genomes of Archaea, Bacteria and mitochondria. Mol. Microbiol.  2000; 36, 244–246.

Deltcheva, E., Chylinski, K., Sharma, C. et al. CRISPR RNA maturation by trans-encoded small RNA and host factor RNase III. Nature 2011 471, 602–607

Makarova, K., Wolf, Y., Alkhnbashi, O. et al. An updated evolutionary classification of CRISPR–Cas systems. Nat Rev Microbiol. 2015; 13, 722–736.

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