Will these CRISPR scientists get a Nobel Prize in Physiology or Medicine?

2020 Nobel Prize for Chemistry was announced on October 7 to be awarded to Jennifer Doudna and Emmanuelle Charpentier for their pioneering work in developing CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) gene editing, a revolutionary technology that can achieve precise DNA surgery. While scientists were thrilled to witness the first time that a science Nobel Prize has gone to CRISPR, many argued that other scientists should be included in the prize as they have also made Nobel-level contributions to CRISPR development. 

How exactly was CRISPR genome editing developed?

The history of CRISPR discovery can be traced back to 1980s when a Japanese molecular biologist Yoshizumi Ishino accidentally uncovered a part sequence of an “unusual DNA” in E. coli (JoB, 1987). He was among the first researchers to have observed CRISPRs in prokaryote. Six years later, the complete gene sequence repeats was finally described by a Spanish microbiologist Francisco Mojica, the one who also coined the term “CRISPR” and suggested that CRISPR was an innate immune system from bacteria (Molecular microbiology, 1993). 

Yoshizumi Ishino (left) and Francisco Mojica (right)

However, it was not until 2010s that scientists turned CRISPR into a tool. In 2011, French microbiologist Emmanuelle Charpentier, the newly awarded Nobel laureate, published a paper in Nature, describing the process where a bacterial enzyme named Cas9 was used to cleave invading pathogens (Nature, 2011). Within a year, Charpentier, together with American biochemist Jennifer Doudna, combined Cas9 with a synthesized single guide RNA (sgRNA) and successfully cut the targeted bacterial DNA sequence (Science, 2012). This Nobel-winning breakthrough gave birth to CRISPR-Cas9 gene editor, the “magic scissor” that can be widely used by scientists to precisely cut specific DNA sequence of almost any gene-based life through simply redesigning and synthesizing a sgRNA. 

Sg RNA can guide the Cas9 enzyme to a targeted locus for genome cutting (Image Credit: OriGene Technologies)

As Chemistry Nobel committee prefers to reward those who actually invent a “tool” rather than pioneers whose work lead to that invention, it was not surprising that Ishino and Mojica weren’t included in the prize. However, when it comes to the Nobel prize in Physiology or Medicine, the story could be different. Could Ishino and Mojica share their parts of glory if CRISPR wins a Nobel prize in Physiology or Medicine? If so, with whom?

Who are the real inventors of CRISPR?

Although it is universally acknowledged that Charpentier and Doudna made a revolutionary discovery, a dispute lasts for years over whether they are the real inventors of current CRISPR technology. After their publication in 2012, the most challenging technical hurdle of CRISPR development was applying the tool to mammals, or even further, to humans. The breakthrough was made just months later and that credit was irrefutably given to Feng Zhang from the Broad Institute and George Church from Harvard Medical School, who independently and simultaneously described the successful CRISPR gene editing in human cells in January 2013, a landmark moment after which the technology was turned into genetic disease treatment (Science, 2013a; Science, 2013b). Instead of relying on a sgRNA developed by our Nobel laureates, Feng Zhang’s lab used tracrRNA and crRNA to induce precise and effective cleavage at endogenous genomic loci in human and mouse cells. That is actually the method adopted by most present-day CRISPR scientists. Besides, Feng Zhang has so far prevailed in the fierce ongoing battle with Charpentier and Doudna over CRISPR patent rights. That’s part of the reason why some people were surprised that he was excluded from the Nobel prize.

Along with Feng Zhang, Virginijus Šikšnys, a Lithuanian biochemist, was also considered as one of the inventors of CRISPR.  As Šikšnys said in an interview, he had studied CRISPR-Cas system since 2007 and made his Nobel-level manuscript submitted in early 2012. However, his article was rejected by Cell Reports without going through peer review process. Although his work was later successfully published in PNAS, the chance to be recognized as first was already missed (Laisvės TV, 2018).

Who should have been a third recipient of this year’s Chemistry Nobel or could be a potential winner of future Nobel in Physiology or Medicine?

According to the Nobel rule that “each award can not be shared by more than two different researches and no more than three different individuals each year”, the 2020 Chemistry Nobel could be awarded to at most three scientists. Nevertheless, the committee didn’t select a third laureate. That’s an understandable decision considering the difficulty of weighing which contributor's work except the “2012 break through” was more worthy. Mojica and Feng Zhang shared Albany Medical Center Prize with Charpentier and Doudna in 2017. Šikšnys won another prestigious award, Kavli Prize, jointly with Charpentier and Doudna in 2018. If you are among this year’s Chemistry Nobel committee, who would you pick as a third recipient? 

It’s also worth noting that CRISPR-based therapeutics have only just entered the clinic, many people speculate that a Nobel from the Physiology or Medicine committee could also be possibly awarded to CRISPR scientists in the future. Again, who do you think could be the potential winner?

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