For this year’s women and girls in science day, UAR chose to highlight the career of a world-renowned scientist and how animal research shaped her path to becoming one of the most respected and revered researchers. Working in fundamental science and microbiology, Emmanuelle Charpentier gradually obtained prizes, eventually receiving one of the greatest honours in science: a Nobel prize. Inspired by work in genetically modified animals, her discovery of the genomic scissors, CRISPR-Cas9, has since had an immeasurable impact on the world of medicine and medical research.
Encouraged by her parents to explore her own academic interests, the enthusiastic and aspiring Emmanuelle Charpentier understood early on that academia was a place where her budding interest in biology could flourish. She could study, do research, teach, and transfer knowledge, and it soon became clear to her that understanding fundamental science was the basis of innovation.
Charpentier explains : “I identified myself very early on as a scientist rather than as a student – as someone creating knowledge rather than simply absorbing it. It seems small, but this change of mind-set made me more curious and perceptive of the qualities and career paths of the established scientists at the Pasteur Institute. I was inspired by their enthusiasm of and advocacy for basic research in microbiology. I realised that being a research scientist would fit the many aspects of my personality — my curiosity, intellectual drive for knowledge, enjoyment of communicating knowledge to others and working as a team, and my desire to turn complex scientific discoveries into practical applications that would help society. I was excited about being a scientist.
“I never questioned whether women were entitled to a career in the same way as men. At home, my parents were always very supportive with all the choices I made in the course of my career. The same applies for my academic life: I had both male and female mentors. I learned a lot from all of them, and their gender was never an issue. The education I received in France, my mentors and the wonderful scientists that have been accompanying me, have made me the scientist I am today: curious, persistent and always trusting my instinct that I have to concentrate on the basic science, and the rest will follow eventually.”
As so often in science, the discovery that was going to make Emmanuel Charpentier famous, was quite unexpected. For most of her career, Charpentier had been keenly interested in bacteria. During her doctoral thesis, she examined mechanisms that lead bacteria to develop resistance to antibiotics. It was already apparent back then that multi-resistant pathogens would become a problem and microbial research could open up many interesting avenues. Investigations into bacteria in the 1970s had resulted in surprising and important new laboratory techniques such as gene cloning, for example.
Charpentier’s appetite for her discipline was insatiable, motivating her to continuously embark on new adventures, working in labs all over the world, on different bacteria. Constantly leaving her comfort zone, scrutinising, and tweaking her own work, she didn’t want to restrict herself and her science to a niche topic. Moving from her bacteria to their hosts, she began researching on mice, focusing on skin development and how microorganisms trigger skin infections. This work in animal models was going to ignite a spark of innovation within her mind.
Working closely with genetically modified animals opened Charpentier’s eyes to the extraordinary difficulties researchers faced when attempting to modify the mouse, tweaking the genetic code to create suitable models for disease. If only she could find a way to target and cut DNA with the same precision that she had observed in some viruses and bacteria. She was inspired to look again at an old friend among her previous study subjects: Streptococcus –pyogenes, one of the bacteria that is most deadly to humans.
Nested inside the bacterium, there was a previously undiscovered molecule called tracrRNA that was going help make Charpentier’s name. Her work showed that tracrRNA is part of bacteria’s ancient immune system that disarms viruses by cutting up their DNA. When viruses attack a bacterium, enzymes cut out a piece of the viral DNA and integrate it at a very specific location in the bacterial genome: the CRISPR sequence. The cell then transcribes this sequence into an RNA molecule, the CRISPR-RNA, which guides the Cas9 enzyme to a precise location so it can attack the viral genome and incapacitate it.
In 2009, on a plane to her next destination, and research lab at Umeå University in Sweden, Emmanuel Charpentier came up with her Nobel winning idea that was going to change the face of genome editing. Mid-air, everything came together. She imagined the radical concept of bringing together CRISPR and RNA to make precise genetic “scissors”.
In 2011, Charpentier described the new mechanism in nature, showing that three components are involved in the process: two RNA molecules – known as CRISPR-RNA and tracrRNA – and a cutting enzyme initially named Csn1 and now known as Cas9. The year after, she and her colleagues published a paper in Science outlining their discovery that the Cas9 cutting system is guided by the two RNA molecules to precisely identify, target, and cut the viral DNA at the location defined by the CRISPR-RNA sequence. Charpentier had found a system that could safely and precisely target and edit genes.
Working with Jennifer Doudna’s group in Berkeley, California, Charpentier identified a way to combine the two RNA molecules into one, simplifying even further the molecular scissors. This meant that researchers could cut any DNA sequence, with only the knowledge of the relevant gene sequence in hand to help manufacture a matching RNA molecule. The mechanism, now known as the CRISPR-Cas9 mechanism, can reliably and effectively switch genes on or off in any model organism.
Using this mechanism, researchers can change the DNA of animals, plants, human cells, and microorganisms with extremely high precision. Since its discovery, this genetic editing tool has taken laboratories by storm. Scientists from all over the world are taking advantage of the more precise, efficient, fast and cost-effective instrument to make better, more accurate model organisms of disease. CRISPR-Cas9 has the potential for an extremely diverse range of applications, from plant breeding and the breeding of transgenic laboratory mice to treatments for a multitude of diseases.
CRISPR has proven to be the most exciting life science discovery of the last decade, allowing us to identify and validate new targets for medical discovery, model a broad range of pathologies in animals, and to edit genes to enable the treatment – and hopefully cure– of many diseases. This technology has had a revolutionary impact on the life sciences, contributing to new cancer therapies and offering potential treatments for inherited genetic conditions. An immune mechanism in bacteria, until recently known only to a handful of microbiologists, could soon become a medical treatment for millions of patients. CRISPR-Cas9 has become the prime example of one of Charpentier’s core beliefs: “Basic research is essential for progress."
Image credit: Emmanuelle Charpentier by Hallbauer & Floretti
Last edited: 8 February 2024 18:43