The Winners of the Louis-Jeantet Prize for Medicine

Prize Winner 2015

Emmanuelle Charpentier

Winner of the 2015 Louis-Jeantet Prize for medicine

CRISPR-Cas9 has recently emerged as a powerful and universal technology for gene editing with wide-ranging implications across biology and medicine. The technology functions as molecular scissors to perform precise surgery on genes and various versions of the system have been developed to broaden its range of applications to manipulate genes and their expression in a large variety of cells and organisms. CRISPR-Cas9 has quickly been adopted by the community of biologists around the world and is now recognized as a transformative technology in various fields of research with great potential to benefit the understanding and treatment of human genetic diseases, cancers or infectious diseases.
Originally, the system is an ancient mechanism of immunity that allows bacteria to defend themselves against their predators, e.g. the viruses of bacteria also called phages. Bacteria have existed as the first forms of life to appear on earth and are essential to our existences. Yet, we are far from understanding their diversity and the multiple mechanisms they have evolved to interact with their environment that includes their predators and the human host. This is the focus of Emmanuelle Charpentier’s research: decipher fundamental molecular mechanisms involved in bacteria. During the last decades, humans have largely exploited bacteria. Bacteria have revolutionized molecular biology as an unlimited source of enzymes and they are extensively used in industry in various ways (for example, as probiotics, for the manufacture of diary products, production of biological substances such as enzymes, vaccines, antibiotics and biofuels). Most bacteria are harmless or even beneficial but several are pathogenic. This is the case of Streptococcus pyogenes, the source of the CRISPR-Cas9 technology. S. pyogenes also known as Group A streptococcus is a gram-positive bacterial pathogen responsible for a wide range of human diseases including necrotizing fasciitis, commonly known as the flesh eating disease.
Emmanuelle Charpentier’s research is mostly driven by a strong motivation to understand fundamental mechanisms of regulation in bacterial pathogens with the aim to generate new findings that could possibly be translated into innovative biotechnology and biomedical applications. By studying regulatory mechanisms involved in pathogenic bacteria, novel biological targets and pathways can be identified and potentially harnessed for the development of novel anti-infectives. New strategies to manipulate genomes and cells with a broader range of applications can also be unravelled, as exemplified recently by the work of Emmanuelle Charpentier and co-workers on the S. pyogenes CRISPR-Cas9 system (Fig. 1).

Figure 1: The CRISPR-Cas9 system and its applications.
The Cas9 enzyme (blue) generates breaks in double-stranded DNA by using its two catalytic centers to cleave each strand of a DNA target site (light green) next to a PAM sequence (orange) and matching the 20-nucleotide sequence (light green) of the single guide RNA (sgRNA). The sgRNA includes a dual-RNA sequence derived from CRISPR RNA (black) duplexed to a separate transcript (tracrRNA, red) that binds to the Cas9 protein. Cas9-sgRNA–mediated DNA cleavage produces a blunt double-stranded break that triggers repair enzymes to remove or replace DNA sequences at or near the cleavage site. The potential of the system was demonstrated in a large variety of cells and organisms.

Emmanuelle Charpentier’s laboratory is particularly interested in understanding how regulatory RNAs and proteins coordinate the modulation of gene expression at the transcriptional, post-transcriptional and post-translational level in processes of infection and immunity. What are the mechanisms involved in the adaptation of bacteria to various stress conditions, their survival and persistence within the host or their evasion of host immunity? Emmanuelle Charpentier’s team particularly researches on (i) interference systems involved in the defense against mobile genetic intruders (CRISPR-Cas), (ii) small regulatory RNAs that interfere with pathogenic processes, (iii) toxin-antitoxin systems, (iv) protein quality control that regulate bacterial adaptation, physiology and virulence, and (v) the mechanisms of bacterial recognition by immune cells (Fig. 2).

Figure 2: Molecular regulatory pathways involved in the interactions of bacteria with the human host (e.g. epithelial, endothelial and immune cells) and the mobile genomes (e.g. phages, plasmids).