Functional Genetics

This years Wittgenstein Award goes to Josef Penninger, a biomedical researcher whose work has contributed enormously to an understanding of the mechanisms underlying diseases that affect hundreds of millions of people worldwide. One of the worlds most high-profile scholars in the field of life sciences, he has published more than 52 primary papers in Nature, Science and Cell and has been listed twice among the top ten scholars worldwide in the ISI Web of Knowledge. Numerous international distinctions testify to his scientific standing. Honours awarded to him include being elected an AAAS Fellow and receiving the Innovator Award of the U.S. Department of Defence. He is also one of the very few scholars who have been awarded two ERC Advanced Grants. Covering a huge spectrum, Josef Penningers research has been rewarded by several ground-breaking accomplishments. Two of them merit special mention: Josef Penninger and his team succeeded in establishing a system of yeast genetics for pluripotent stem cells in mammals. The researchers created haploid embryonic stem cells in the laboratory and went on to develop systems for the mutagenesis of entire genomes. This feat not only represented a paradigm change in biology, but also led to a technology that could potentially revolutionise functional genetics as we know it today. A second aspect that is inseparably linked to the achievements of Josef Penninger is his work on the Receptor Activator of NF-.B Ligand (RANKL), encompassing everything from first genetic validation to novel therapeutic approaches in medicine. RANKL is connected to virtually all diseases associated with bone loss, a finding that has only been known for a few years thanks to Josef Penningers scientific work. The fact that this could also give rise to a promising angle for the treatment of breast cancer and a new approach to curbing the generation of metastases in bone is an excellent example of the phenomenon of serendipity in scholarly research- luck meets a prepared mind. Penningers developments in the field of haploid stem cells could potentially revolutionise the field of functional genomics. His trailblazing new findings on the fundamental physiology of metabolic processes in bones, the connection to mammary gland biology, the understanding of the processes underlying the phenomenon of (bone) metastasis formation and his achievements in breast cancer research are evidence of the enormous productivity of Josef Penninger and his research teams. With his research, Josef Penninger has made essential contributions to opening up completely new fields of medical therapy.

Diseases are influenced by multiple cells and pathways, including the immune system, hormones, the vascular system, or metabolism. The Penninger lab studies diseases from multidisciplinary angles and merges ideas from different fields (immunity, glycoproteomics, metabolism, vascular biology etc.) to model and assess the complexity of diseases and to develop new and effective treatments. Based on funding by the FWF project Z 271-B19 (Wittgenstein award), we developed and optimized a broad range of tools including haploid ES cells (containing only one complete chromosome set), glycoproteomics (characterization of proteins containing sugar-modifications) and genetically engineered mice and human organoids to reveal the mechanisms underlying different diseases, highly relevant to humans: We established bar-coded, repairable, genome-wide haploid genetics in embryonic stem cells. Using this systems we developed more than 100000 haploid ES cell clones each carrying a single hemizygous mutation in defined genes, targeting ~ 70% of the entire protein-coding genome in the mouse (Elling et al. Nature 2017). This large library of homozygous mutant ES cell lines is shared with the entire research community (www.haplobank.at). Moreover, we developed a novel comparative and high-throughput glycoproteomics platform allowing entirely novel insights into protein glycosylation and sugar modifications involved in nearly all biological systems (Stadlmann et al. Nature 2017 and Stadlmann et al. Proteomics 2018). Applying this method to human and murine embryonic stem cells, we nearly doubled the number of experimentally confirmed glycoproteins, identified previously unknown glycosylation sites and multiple glycosylated stemness factors, and uncovered evolutionarily conserved as well as species-specific glycoproteins in embryonic stem cells. The bioinformatic algorithms we developed to analyze such complex data sets have been made freely available as online tool - termed SugarQb (https://www.imba.oeaw.ac.at/research/josef-penninger/resources/ and http://ms.imp.ac.at/?action=sugarqb). Furthermore, we were taking a holistic approach to study obesity, gestational diabetes, metabolic disorders and also COVID-19, always with the grand vision and mission to fundamentally understand basic physiology and disease and to translate such knowledge into disruptive new medicines.