Few discoveries have revolutionized biomedicine faster and more radically than CRISPR/Cas9, popularly known as the “gene scissors”. These scissors are supposed to do things that were previously almost inconceivable: curing hereditary diseases, defeating cancer, making crops more resistant. This is a tool science has been waiting for, since CRISPR/Cas9 is precise, simple and cheap.

But where did the gene scissors come from? Who discovered them? And how do they work? Their history takes us from the salt flats of the Spanish Mediterranean to the basement of the French Ministry of Defense and Danish yogurt factories. It is about science pioneers who have conducted off-the-mainstream and seemingly exotic research. It is also the fascinating story of Emmanuelle Charpentier, who put together the pieces of the CRISPR system and ensured that the molecular gene scissors would actually start cutting.

Let’s start at the beginning: the official starting signal was given in 1987 but went absolutely unnoticed. At that time, Japanese researchers reported a strange pattern in the genetic information of an intestinal bacterium: repetitive DNA fragments, which are known today under the somewhat unwieldy name of “clustered regularly interspaced short palindromic repeats” (CRISPRs for short).

A few years later, researchers became acutely aware of Haloferax mediterranei, an archaea bacterium. Many of the microbes in the archaea group are known to love extremes. Haloferax likes extremely salty environments and thrives in the salt flats of the Spanish Mediterranean. And again, researchers found this peculiar repetitive DNA code. The science world soon learned that this special DNA code occurs in very different microbes.

Looking for forensic methods to detect bioweapons, the French military investigated plague bacteria from an outbreak in Vietnam – and there it was again, the repetitive CRISPR code. At that point, several scientists surmised that CRISPR could perhaps be a kind of “immunological memory”. Although invisible to our eyes, a brutal battle for survival between bacteria and viruses is fought every day. Viruses infect bacteria, and bacteria have to put up a defense. Did CRISPR contain a license to kill viruses?

What was urgently needed at that point was experimental proof of this extraordinary idea. And again it came from an unusual source. In the production of yogurt and other dairy products, viruses that attack and destroy lactic acid bacteria are a threat. A researcher in the dairy industry realized that lactic acid bacteria were resistant to viruses whenever these bacteria carried the CRISPR code. Slowly, the secret of the gene scissors started to become unveiled.

In a nutshell

The discovery of the CRISPR/Cas9 gene scissors by Emmanuelle Charpentier and Jennifer Doudna was one of the most revolutionary achievements in molecular biology. Their method enables scientists to alter and repair genomes in a precise manner. The technique has had a vital impact on industry, biotechnology, medicine and basic research.


Biochemist Emmanuelle Charpentier Emmanuelle Charpentier and her colleague Jennifer Doudna
In 2020, the Swedish Nobel Committee honored the discoveries of biochemist Emmanuelle Charpentier and her colleague Jennifer Doudna with the Nobel Prize in Chemistry. © Alexander Heinl/picture alliance dpa
Man solves Rubik's cube
Emmanuelle Charpentier is a typical proponent of today's research career trajectories. On her way to winning the Nobel Prize, the biochemist spent time doing research in the USA, Sweden and Germany, and quite some time in Austria. At the onset of her career, the FWF supported her with three research grants. © Olav Ahrens Rotne/unsplash

When a virus infects a bacterium, its genetic information is incorporated into that of the bacterium in the CRISPR code. If a virus infects the bacterium a second time, the CRISPR code is read and the information is used by a protein, Cas9, as a kind of mugshot that helps it to recognize the foreign viral DNA. Cas9 is the actual gene scissors, which then cut the viral DNA in very specific ways, thus rendering it harmless. With the discovery of the Cas9 protein, the components of the gene scissors were almost complete – but their blades were still blunt. Something important was missing.

Emmanuelle Charpentier, a researcher at Max Perutz Labs at the University of Vienna, realized that a short ribonucleic acid (RNA) which she called tracrRNA could activate the gene scissors. The jigsaw was complete and an almost unbelievable vista of possibilities opened up. What if Charpentier could simply replace the mugshot with another one? In other words, what if the bacterial gene scissors were reprogrammed to recognize and change another DNA instead of viral DNA, such as human DNA? Charpentier went to Umeå University in Sweden and accomplished the feat together with her Berkeley colleague Jennifer Doudna. They developed a method to apply the gene scissors to any DNA, enabling them to remove or even repair DNA segments. In 2020, the two researchers received the Nobel Prize in Chemistry for their discovery. As Louis Pasteur noted in 1854, “chance only favors the mind which is prepared.”

By now, CRISPR is everywhere. Hardly any research field in molecular biology can do without the gene scissors, and new applications are reported almost daily. In 2019, permission was granted in the USA for the world's first trial of CRISPR/Cas9 on patients suffering from an inherited eye disease. Other therapeutic approaches are currently being tested in the context of certain blood disorders. All of these gene therapies are performed on somatic cells, not germ line cells. Germ line therapy is ethically problematic and still requires a broad social debate and binding international rules.

What can we learn about basic research from Emmanuelle Charpentier and the CRISPR/Cas9 discovery? Most importantly, medical revolutions are often the result of chance occurrences, detours and mistakes. While a widely ramified ecosystem of researchers was involved in the CRISPR revolution, Emmanuelle Charpentier was prepared and had the right idea at the right time. She had not set out to develop a gene therapy method, but was motivated by simple curiosity. Many of the CRISPR pioneers were young, hungry, willing to take risks, and their papers were rejected by the “top journals”. And maybe that was exactly the secret of success.

Short bio

Emmanuelle Charpentier has been heading the Max Planck Research Unit for the Science of Pathogens in Berlin since 2018; before that, she was Director at the Max Planck Institute for Infection Biology in Berlin. At the onset of her career, the FWF supported her with a total of three research grants. During this FWF-funded phase, in which she conducted research at the Max Perutz Labs of the University of Vienna and the Medical University of Vienna, she achieved a scientific breakthrough together with Jennifer Doudna and PhD student Krzysztof Chylinski (Max Perutz Labs) with the key publication “A programmable dual RNA-guided DNA endonuclease in adaptive bacterial immunity“.


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