Louis-Jeantet prize lectures

Monday, 7 September 09:45 - 10:45 Hall 1

Introduction by Sir Paul Nurse, UK - incoming president of the Louis-Jeantet Foundation

EMMANUELLE CHARPENTIER DE/SE

Helmholtz Centre for Infection Research, Braunschweig and Laboratory for Molecular Infection Medicine, Umeå University

CRISPR-Cas9: origins, mechanisms and applications of a transformative technology

The RNA-programmable CRISPR-Cas9 system has recently emerged as a transformative technology in biological sciences, allowing rapid and efficient targeted genome editing, chromosomal marking and gene regulation in a large variety of cells and organisms. In this system, the endonuclease Cas9 or catalytically inactive Cas9 variants are programmed with single guide RNAs (sgRNAs) to target site-specifically any DNA sequence of interest given the presence of a short sequence (Protospacer Adjacent Motif, PAM) juxtaposed to the complementary region between the sgRNA and target DNA. The system is efficient, versatile and easily programmable.
Originally, CRISPR-Cas is an RNA-mediated adaptive immune system that protects bacteria and archaea from invading mobile genetic elements (phages, plasmids). Short crRNA (CRISPR RNA) molecules containing unique genome-targeting spacers commonly guide Cas protein(s) to invading cognate nucleic acids to affect their maintenance. CRISPR-Cas has been classified into three main types and further subtypes. CRISPR-Cas9 originates from the type II CRISPR-Cas system that has evolved unique molecular mechanisms for maturation of crRNAs and targeting of invading DNA, which my laboratory has identified in the human pathogen Streptococcus pyogenes. During the step of crRNA biogenesis, a unique CRISPR-associated RNA, tracrRNA, base pairs with the repeats of precursor-crRNA to form anti-repeat-repeat dual-RNAs that are cleaved by RNase III in the presence of Cas9 (formerly Csn1), generating mature tracrRNA and intermediate forms of crRNAs. Following a second maturation event, the mature dual-tracrRNA-crRNAs guide the endonuclease Cas9 to cleave cognate target DNA and thereby affect the maintenance of invading genomes. We have shown that the endonuclease Cas9 can be programmed with sgRNAs mimicking the natural dual-tracrRNA-crRNAs to target site-specifically any DNA sequence of interest. I will discuss the biological roles of CRISPR-Cas9, the mechanisms involved, the evolution of type II CRISPR-Cas components in bacteria and the applications of CRISPR-Cas9 as a novel genome engineering technology.

Biography

Emmanuelle Charpentier studied biochemistry and microbiology at the University Pierre and Marie Curie, Paris, France where she received her PhD in Microbiology for her research performed at the Pasteur Institute. She then moved to the United States, where she held Research Associate positions at the Rockefeller University, New York University Langone Medical Center and the Skirball Institute of Biomolecular Medicine (all in New York, NY) and at St Jude Children’s Research Hospital (in Memphis, TN). Emmanuelle Charpentier returned to Europe to establish her own research group at the Max F. Perutz Laboratories of the University of Vienna in Austria where she habilitated in the field of Microbiology. She was then recruited as an Associate Professor at the Laboratory for Molecular Infection Medicine Sweden (MIMS, Swedish Node of the European Molecular Biology Laboratory (EMBL) Partnership for Molecular Medicine) at Umeå University. In 2012 Emmanuelle Charpentier was appointed Professor at Hannover Medical School (MHH) and head of the department “Regulation in Infection Biology” at the HZI. In 2013, Emmanuelle was awarded an Alexander von Humboldt Professorship.

Recent review in EMBO Molecular Medicine: CRISPR‐Cas9: how research on a bacterial RNA‐guided mechanism opened new perspectives in biotechnology and biomedicine

RUDOLF ZECHNER AT

Institute of Molecular Biosciences, University of Graz

Lipolysis - more than just the catabolism of fat

Obesity, type 2 diabetes and cardiovascular disease continue to grow unabated around the world. These disorders are often caused by dysfunctional lipid metabolism. This in turn leads to accumulations of fats and cholesterol in the liver and heart or on the walls of the arteries, resulting in malfunctions in these organs or tissues.

Rudolf Zechner and his colleagues studied the mechanisms governing the metabolism of lipids for more than 15 years and specifically focused on lipases, enzymes that degrade fats. They found that a new enzyme belonging to this family, adipose triglyceride lipase (ATGL) and its protein co-activator CGI-58, facilitate lipid catabolism in both mice and humans. In other words, these biological molecules play a crucial role in the storage and mobilisation of fats in our body. This discovery revolutionized our understanding of fat turnover. It also offered a mechanistic explanation for the occurrence of rare genetic diseases termed «neutral lipid storage diseases», caused by a deficiency of ATGL or of its protein co-activator.

More recently, Rudolf Zechner and his team sought to understand how the breakdown of fat influences cell functions and the pathogenesis of disease. They were able to show a strong correlation between the catabolism of fats and cardiac function. To their surprise, they also discovered that lipid catabolism was involved in the development of cachexia, which takes the form of an uncontrolled and irreversible loss of weight in numerous cancer patients. The Austrian researchers have thus possibly identified a new direction for the treatment of this serious condition.

Biography

Rudolf Zechner was born in 1954 in Graz, Austria. He studied biochemistry at his hometown university, and in 1980 earned his PhD. He subsequently worked as a post-doctoral fellow at the Rockefeller University of New York. He then returned to the University of Graz and in 1998 became Professor of Biochemistry at the Institute of Molecular Biosciences, University of Graz. A member of the Austrian Academy of Sciences, Rudolf Zechner has already received numerous prestigious awards, in particular the Wittgenstein Prize, Austria’s highest scientific award, as well as an Advanced Grant from the European Research Council.

Recent review in EMBO Molecular Medicine: FAT FLUX: enzymes, regulators, and pathophysiology of intracellular lipolysis