Bio sketch PD Monica Schaller Tschan, PhD
Academic degree: Assistant Professor (Privatdozent)
- 1994-1996: Master of Science, Molecular Biology & Ecology, University of Fribourg, Switzerland
- 1999: PhD, Laboratory of Professor Urs Nydegger, University Hospital Inselspital, University of Bern, Switzerland
- 2000-2005: Postdoctoral Fellowship, Laboratory of Professor Dennis Burton, TSRI, La Jolla, California
- 2005-2009: Senior Postdoctoral Fellowship, Laboratory of Professor Jürg Schifferli and Professor Marten Trendelenburg, Department Biomedicine, University of Basel, Switzerland
- 2009-2014: Senior Postdoc, Laboratory of Professor Johanna A. Kremer Hovinga, University Hospital Bern, Inselspital, Switzerland
- 2015: Venia Docendi in Molecular Immunhematology from the Medical Faculty, University of Bern; Switzerland
- Since 2019: Coordinator of the Graduate School for Cellular and Biomedical Sciences (GCB), University of Bern (40%)
Autoimmunity is the result of a dysregulated immune response, typically starting in adulthood (30-40 years), mostly in women. Trigger(s) are not well understood with targeted therapy addressing the culprit of autoimmune diseases, the specific- pathological B and T-cells still missing. My research focus on the use of human monoclonal autoantibodies as tools to develop new targeted therapies and to unravel the emergence and progression of the humoral autoimmune response. This is of upmost significant medical interest since the prophylactic vaccines, the most effective medical intervention known to date, are based on the induction of long-lived immune responses and a dysregulated immune system is the underlying cause of many chronic diseases and autoimmunity.
Contribution to science
As a molecular immunologist with longstanding experience in the field of autoimmune diseases. My key research is dedicated to unravel the pathophysiology of different autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus and up to date thrombotic thrombocytopenic purpura and related thrombotic autoimmune diseases. As major leitmotif throughout my entire scientific career, I used my expertise in repertoire cloning of autoantibodies as tools for the development of novel therapeutics. My contribution were:
- Characterized the immune repertoire and proof of existence of autoantibodies in the peripheral blood and synovial fluid directed against the glucose-6-phosphate-isomerase (GPI) in autoimmune rheumatoid arthritis patients. These anti-GPI antibodies, I held a patent on, was bought by Symphogen, Denmark with their goal to develop diagnostic tests (Schaller et al, Nature Immunology, 2000).
- Established anti-GPI antibodies as biomarkers for extracellular complications in rheumatoid arthritis with a more severe diseases course, but also in other inflammatory arthritic conditions such as Felty-Syndrom, Osteoporosed, Reither-Syndrome and Spndylitis ankylosans (Stohl, Schaller et al, Annals of Rheumatic diseases, 2005).
- First confirmation of the hypothesis that a delayed clearance of apoptotic cells is at the origin of systemic lupus erythermatosus (SLE). I could show that autoantibodies directed towards the first complement molecule C1q, shown to correlate with lupus nephritis, only target C1q when bound to early apopototic cells (Schaller and Bigler et al, Jounral of Immunology, 2009). Peptides recognized by the anti-C1q autotantibodies were used to develop a highly sensitive ELISA test to diagnose SLE patients with renal complications by Bühlmann, Schönenbuch, CH (VAnhecke and Schaller et al, Arthritis and Rheumatisme,, 2012).
- As a proof of concept for a new therapy based on neutralizing autoantibodies (anti-ADAMTS13 antibodies (Schaller et al, Blood, 2014) using small anti-idiotypic molecues (Deigned-ankyrin-repeat-proteins, Molecular Partner, Schlieren, CH) for immune-mediated thrombotic thrombocytopenic purpura (iTTP) in vitro. For this research I was awarded the Marie Heim-Vögtlin SNSF grant for two years and got three prizes at an international, European and a national conference.
Major achievements of the last 5 years
In partnership with Johanna Kremer Hovinga
Relying on previous key findings for the autoimmune immune-mediated form of Thrombotic Thrombocytopenic Purpura (iTTP, Schaller et al, Blood 2014) one of my major achievements in the last 5 years was to generate anti-idiotypic small molecules, namely, Designed-Ankyrin-Repeat Proteins (DARPins) neutralizing in vitro the pathological autoantibodies in roughly 74% of all iTTP patients from two separate patient cohorts (n=200) completely, thereby restoring ADAMTS13 activity and preventing microthrombus formation. In partnership with Molecular Partners (Schlieren, Switzerland, holder of the DARPins technology patent), we will develop a safe therapeutic addressing pathological B-cells only.
In partnership with Mario Tschan`s group (ongoing)
In a pilot study we showed that autophagy plays a role in the development and maintenance of the autoimmune status in iTTP. Aberrant autophagy genes (ATG) were observed in monocytes and macrophages opening the door to add and design respective autophagy modulators to improve the outcome of autoimmune patients by reprogramming the dysregulated immune response. We are the first to have shown the expression profile of six ATGs (ATG5, ATG7, ATG16L1, BECN1, LC3B and WIPI1) to be aberrant in autoimmune monocytes, when compared to healthy control. We could show that the in vitro differentiation from monocytes into Mo-DCs as well as the maintenance of monocytes was accompanied by an increased autophagic flux. When comparing basal autophagy of individual Pan-DCs versus Mo-DCs, we found that Mo-DCs have a higher autophagic flux than Pan-DCs. Further we observed the highest autophagic flux in Mo-derived dendritic cells in iTTP patient, while Pan-dendritic cells showed the lowest autophagic flux.
Since my habilitation (venia docendi) at the end of 2015, I have held, coordinated and developed new concepts for practical courses in molecular biology and blood function and disorders, as well as the Biomedical Sciences and Graduate School for Cellular and Biomedical Sciences (GCB) curriculum for the Medical Faculty, University of Bern. In addition I have supervised various master student (2019 Vera Imboden), co-supervised a PhD student (2017, Magdalena Skowronkska) and MD thesis (2020, Tabea Schmocker).
To unravel how autophagy deficiencies, a process orchestrated by the complex assembly and interaction of numerous proteins, encoded by ATG-related genes, contribute to the dysregulated immune response in iTTP. Exploiting these abnormalities by measuring autophagosome formation and autophagic activity in vivo is crucial to get insights and develop pharmacologic interventions strategies as novel therapies for iTTP as wells as various autoimmune diseases. To decide which autophagy pathway plays a role in iTTP, we investigate the relative mRNA expression levels of key autphagy-related (ATG) genes known to be involved in other autoimmune disease and inflammation namely ATG16L1, WIPI1, ATG5 and ATG 7 and p62/SQSTM1 by qPCR analysis in dendritic cells (DCs), B-and T-cells. Additionally specialized autophagy pathways are analyzed as well (a) mitophagy (p62 with NIX), (b) aggrephagy (p62 with NBRL and OPTIN), and (c) chaperone-mediated autophagy (LAMP2A9). Enriched or reduced formation of autophagosome in immune cells, most likely causing accumulation of abnormal proteins leading to defective survival of T- and B-cells are assessed in vitro cultures. Using experimental autophagy inhibitors/activators the impact of blocking or activating autophagy pathways on the systemic inflammation and self-antigen presentation in the acute or remission state of iTTP. For this ATG-related lentiviral vectors will be designed to modulate autophagy expression in vitro in B-cells using RNA interference and CrisprCas9 technology. As a potential new treatment option for iTTP patients, we will evaluate the effect of P140 peptide (Lupuzor, clinical trial phase IIa, Immunopharm, 2018), known to rescue in mouse model of lupus (MRP/lpr) the autoantigen processing in self-reactive B- and T-cells in immune cells in vitro. Lupuzor as an adjunct therapy with the first-line treatment and possibly in the future with B-cell and autoantibody targeted therapies should improve substantially the outcome of the severe cases of iTTP.
List of collaborators
- Prof. Mario Tschan, Pathology, University of Bern, Switzerland, autophagy expert
- PD Dr. Monique Vogel, Department for BioMedical Research
- Prof. Marten Trendelenburg form the Department Biomedicine, University of Basel
- Prof. Sylviane Muller, chair of therapeutic immunology, University of Strasbourg, France for the autoimmune translational research as well as a common application for IMS EURidis program
- Prof. Dennis Burton from the Scripps Research Institute, La Jolla, California, USA leading to the following manuscript to be sent for publication in the 2019.
- Prolongation SNSF grant: “Mechanisms of ADAMTS13 deficiency in thrombotic thrombocytopenic purpura (TTP) and beyond” (2014-02-01 to 2014-04-30) GRANT_NUMBER: 151807: URL: https://app.dimensions.ai/details/grant/grant.5237800
- SNSF grant, Marie-Heim Vögtlin: “Mechanisms of ADAMTS13 deficiency in thrombotic thrombocytopenic purpura (TTP) and beyond” (2012-02-01 to 2014-01-31) GRANT_NUMBER: 139794: URL: https://app.dimensions.ai/details/grant/grant.5235255
- ISTH2007 Presidential Fund Grant, 1 year (2011)
- Co-Investigator SNSF grant “Waste disposal in the pathogenesis of Systemic Lupus Erythematosus (SLE): The role of anti-C1q antibodies (SCORE)” (2005-04-01 to 2010-09-30) GRANT_NUMBER: 107249; URL: https://app.dimensions.ai/details/grant/grant.5210572
- ORCID iD 0000-0002-5002-2238