semper-apertus

This Fellowship is awarded for a period of up to two years to early career clinician scientists undergoing medical specialist training with a strong interest in molecular medicine research topics. The fellows are integrated within the clinical setting of the Medical Faculty and aim at doing research at the interface of medicine and basic molecular biology and have the opportunity to work at a laboratory at the medical campus (e.g. OMZ) or at the EMBL. The fellows conduct their research in collaboration with a matching EMBL group.

Short-term CDF awardees 2019:

Short-term CDF awardees 2019:

Angelika Hoffmann, MD

Angelika is a radiologist and physician scientist at the Department of Neuroradiology of Heidelberg University Hospital.

Biography:

Medical licensing exam, approbation; Technical University of Munich, 2011
Postdoc at the Department of Neuroradiology, University of Virginia, Charlottesville, 2011-2012
Physician scientist at the department of Neuroradiology since 2012; board certified March 2019
Physician scientist fellowship of Heidelberg University Hospital, 2014-2015
Olympia Morata fellowship of Heidelberg University Hospital, 2016-2018
HRCMM short-term Career Development Fellowship 2019

Clinical host: Prof. Dr. med. Martin Bendszus, Department of Neuroradiology, University Hospital Heidelberg

EMBL host
: Dr. Yannick Schwab, Cell Biology and Biophysics

Disease studied: Cerebral Malaria

Cerebral malaria (CM) remains a major health burden causing a high rate of mortality worldwide. Also long-term effects, such as neurocognitive impairment that develop after overcoming CM, have been described. Thus improving clinical outcome after CM is of high importance and a major aim of clinical and experimental malaria research nowadays. An easy accessible test to detect brain damage after CM could identify patients who are at higher risk to develop neurocognitive impairment.

In this project we will measure markers of neurodegeneration in experimental cerebral malaria and correlate the degree of neuronal and axonal damage with behavioral outcome and serum markers of neurodegeneration. Using the high throughput approach of automated transmission electron microscopy (TEM), developed at EMBL and consecutive stereological analysis will allow us to determine the location and ultrastructural extent of neuronal and axonal damage. This ultrastructural analysis will lead to a better understanding of cerebral damage and neurocognitive impairment after surviving CM. It will also form the basis for establishing a unique diagnostic indicator to target sequelae of cerebral malaria, and to improve therapeutic interventions. 

Contact: Angelika.Hoffmann@med.uni-heidelberg.de

Joachim Kunz, MD

Joachim is a physician scientist in the Department of Pediatric Oncology, Hematology and Immunology at the University Medical Center for Children and Adolescents, Heidelberg. His clinical activities focus on childhood leukemias and haemoglobinopathies.

Biography:

2002 MD thesis, approbation/license to practice medicine, University of Tübingen.
Medical specialist in pediatric hematology and oncology, University Medical Center for Children and Adolescents, Heidelberg, since 2009.
Attending physician in pediatric hematology and oncology, University Medical Center for Children and Adolescents, Heidelberg, since 2013.
HRCMM Career Development Fellowship 2013 - 2015.
HRCMM short-term Career Development Fellowship 2019.

Clinical host: Prof. Dr. med. Andreas E. Kulozik, Department of Pediatric Oncology, Hematology, Immunology and Pulmonology
University Medical Center for Children and Adolescents, Heidelberg

EMBL host: Dr. Jan Korbel, Genome Biology

Disease studied: T-cell acute lymphoblastic leukemia (T-ALL) in children

Acute lymphoblastic leukemia (ALL) is an aggressive malignancy of immature white blood cells of B- or T-cell lineage and accounts for about 35% of all pediatric malignancies. Although ALL generally is well treatable, about 20% of children with ALL suffer a relapse. Children with relapsed ALL face a dismal prognosis and survival rates are particularly poor in certain biological and clinical subgroups. One such group is relapsed T-cell acute lymphoblastic leukemia (T-ALL) which is highly resistant to chemotherapy. Mechanisms driving multidrug resistance in these patients remain to be elucidated.

Gene expression analysis in relapsed T-ALL revealed a gene response pattern that is also found in early, but not in late relapse of BCP-ALL (Hogan, et al 2011). Genome-wide analysis in relapsed T-ALL, in contrast to relapsed BCP-ALL, found similar numbers of CNAs compared to matched samples from primary disease. While DNA methylation in T-ALL has been shown to differ from BCP-ALL, systematic comparisons of DNA methylation between primary and relapsed T-ALL are not available. Evolution into relapsed ALL has been attributed to clonal selection and to acquisition of novel mutations (Kunz, et al 2015).

In pilot analyses, we subjected samples from patients with relapsed T-ALL (n=13) to an integrated genomic analysis with whole exome sequencing, targeted ultra-deep sequencing, low coverage whole genome sequencing and 450k methylation array. Samples were obtained at the time of primary diagnosis, remission and relapse. The data obtained show that T-ALL relapse either originates from the major clone of the primary leukemia (“type 1 relapse”) or from an ancestral preleukemic clone (“type 2 relapse”). In all cases, new mutations were acquired in relapse (Kunz, et al 2015). While primary T-ALL is dominated by leukemia specific mutations, relapse-specific alterations are predicted to induce genetic and epigenetic mechanisms that result in a deregulation of genes associated with cancer in general but not specifically with leukemia. However, only very few genes - exemplified by TP53 - are found to be mutated in a relapse-specific manner (Richter-Pechanska, et al 2017). Consequently, only a minor proportion of relapses can be explained by genetic mechanisms.

Patient-derived xenograft (PDX) models of leukemia samples from T-ALL patients have been shown to closely represent features that are also present in primary patient material (Richter-Pechanska, et al 2018). From these well characterized PDX models, sufficient high quality material can be gained for DNA sequencing, DNA methylation array and RNA sequencing. This unique collection of material from matched pairs of primary leukemia and relapse provides the opportunity to perform an integrated genomic and epigenomic analysis of functionally relevant mechanisms that govern the progression from primary leukemia to relapse and determine resistance to treatment. The aim of the project is to understand the mechanisms resulting in relapse of pediatric T-lymphoblastic leukemia and in treatment resistance in relapsed T-lymphoblastic leukemia.

Publications:

Pediatric T-lymphoblastic leukemia evolves into relapse by clonal selection, acquisition of mutations and promoter hypomethylation.
Kunz JB, Rausch T, Bandapalli OR, Eilers J, Pechanska P, Schuessele S, Assenov Y, Stütz AM, Kirschner-Schwabe R, Hof J, Eckert C, von Stackelberg A, Schrappe M, Stanulla M, Koehler R, Avigad S, Elitzur S, Handgretinger R, Benes V, Weischenfeldt J, Korbel JO, Muckenthaler MU, Kulozik AE.
Haematologica. 2015 Aug 20. pii: haematol.2015.129692. Epub 2015 Aug 20. PMID: 26294725

The activating STAT5B N642H mutation is a common abnormality in pediatric T-cell acute lymphoblastic leukemia and confers a higher risk of relapse.
Bandapalli OR, Schuessele S, Kunz JB, Rausch T, Stütz AM, Tal N, Geron I, Gershman N, Izraeli S, Eilers J, Vaezipour N, Kirschner-Schwabe R, Hof J, von Stackelberg A, Schrappe M, Stanulla M, Zimmermann M, Koehler R, Avigad S, Handgretinger R, Frismantas V, Bourquin JP, Bornhauser B, Korbel JO, Muckenthaler MU, Kulozik AE.
Haematologica. 2014 Oct;99(10):e188-92. doi: 10.3324/haematol.2014.104992. Epub 2014 Jun 27.

Pädiatrie 4. Auflage
Kunz J, Kulozik A
Kap 178 Erythrozyten,2014,  S 1429-56 Hrsg: Hoffmann, Lentze, Spranger, Zepp: Springer ISBN 978-3-642-41865-5

Contact: joachim.kunz@med.uni-heidelberg.de

Nora Liebers, MD

Nora is a physician undergoing specialty training for Hematology and Oncology in the Department of Hematology, Oncology and Rheumatology at the University Medical Center for Internal Medicine, Heidelberg.

Biography:

Medical licensing exam, approbation; 2015
Residency in the Department of Hematology, Oncology and Rheumatology at the University Medical Center for Internal Medicine; since 2015
MD thesis, National Center of Tumor Diseases (NCT) Heidelberg, Department Medical Oncology headed by Prof. Dr. Jürgen Krauss, 2017
HRCMM short-term Career Development Fellowship 2019

Clinical host: Prof. Dr.med. Carsten Müller-Tidow; Director of the Department of Medicine V of the University Hospital,
Dr. med.Sascha Dietrich; Department of Internal Medicine V: Hematology, Oncology and Rheumatology, MMPU Group Leader SMCD: Personalized Lymph-Therapy

EMBL host
: Dr. Wolfgang Huber, Genome Biology

Disease studied: Hematologic malignancies

Despite major advances in targeted anti-cancer treatments, treatment response is often restricted to a certain subset of patients. The molecular basis of variable response is multifactorial and can involve multiple layers including clinical factors, gene mutations, gene expression, DNA methylation and many more. While there are countless examples of single mutations associated with phenotypic variability of cancer cells, an understanding of the combinatorial interplay of multiple factors will be essential for a meaningful prediction of drug response.

This project aims to systematically link experimental multi-omics data and clinical outcome. Therefore Nora will implement a structured documentation system in the clinical routine which collects structured data on routine diagnostic reports, patient outcome and cancer treatment details. Using concepts and tools from biostatistics and systems genetics, Nora aims to reconstruct the causal network of gene mutations, molecular states and signaling activities to assess their impact on clinical outcome. Based on the understanding of the impact of omics features on clinical outcome, the long-term goal is to establish a diagnostic-therapeutic procedure for personalized patient response prediction.

Contact: Nora.Liebers@med.uni-heidelberg.de

Alba Sulaj, MD

Alba is a resident in the Department of Internal Medicine I and Clinical Chemistry of Heidelberg University Hospital.

Biography:

MD thesis, Department of Internal Medicine I and Clinical Chemistry of Heidelberg University Hospital; 2014
Medical licensing exam, approbation; 2015
Residency in Endocrinology at the Department of Internal Medicine I and Clinical Chemistry of Heidelberg University Hospital; since 2015
“Gerok” Position (research rotation) in the Collaborative Research Center 1118, German Research Foundation; since 2018
HRCMM short-term Career Development Fellowship 2019

Clinical host: Prof. Dr. Dr. h.c. Peter Nawroth, Medical Director of the Department of Internal Medicine I and Clinical Chemistry, Heidelberg University Hospital

EMBL host
: Dr. Jan Korbel, Genome Biology Unit, Co-Director Molecular Medicine Partnership Unit

Disease studied: Diabetes mellitus type 2 and diabetic late complications

Diabetes mellitus type 2 has reached epidemic proportions in many countries with the list of affected states not limited to the developed world and diabetes prevalence rising faster in developing countries. This disease carries disastrous consequences at individual level, by decreasing both one's life quality and expectancy, and at country level, by placing a significant economic burden on the healthcare system. Blood glucose and glycated hemoglobin (HbA1c) are poor parameters for predicting the development of the late complications of diabetes given that good glycemic control does not always translate to fewer complications, with some individuals still developing complications despite normalization of their glucose status. This gloom picture urges the need for identifying new parameters besides hyperglycemia in the development of the diabetic late complications.

It has been shown that reactive metabolites cause DNA-damage in diabetes mellitus type 2 and DNA-damage/-repair responses are impaired in the diabetic late complications. This project will explore DNA-damage/-repair responses in patients with diabetes mellitus type 2 as well as the genetic rearrangements and somatic variation in patients with and without diabetic complications. Alba will investigate the mechanisms behind somatic genetic variation in the context of diabetes by employing a unique single-cell sequencing technique that distinguishes between the individual homologues of a chromosome in a single cell by detecting in this way several types of variants that are otherwise difficult to detect with conventional techniques. In addition, Alba will investigate the possible effects of a novel dietary intervention on somatic genetic variations in the context of diabetes, which had not been attempted before. In the attempt to translate the findings on genomic variation into molecular mechanisms and clinical setting, Alba will collaborate with Dr. Jan Korbel group, profiting from the group’s extensive previous work on single cell-based omics approaches for investigating mechanisms behind complex phenotypes in humans.

CDF awardees Fall 2017:

CDF awardees Fall 2017:

Isabella Haberbosch, MD

Isabella is a physician scientist in the Department of Hematology, Oncology and Rheumatology of Heidelberg University Hospital.

Biography:

License to practice medicine/approbation; Frankfurt University 2015
Residency in Hematology/Oncology at the Department of Hematology/Oncology and Rheumatology at Heidelberg University; since 2016
HRCMM Career Development Fellowship 2017 - 2018

Clinical host: Prof. Dr. med. Alwin Krämer, Department of Hematology, Oncology and Rheumatology, University Hospital Heidelberg

EMBL host
: Dr. Yannick Schwab, Cell Biology and Biophysics

Disease studied: Acute myeloid leukemia

Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Although much progress has been achieved in the treatment and understanding of AML, the mortality in AML patients remains relatively high. Hence further insights into tumorigenesis are crucial in the process of identifying new therapeutic targets. Centrosome aberrations are a hallmark of cancer and can be detected in all kind of malignancies. Previous studies found that centrosome aberrations represent an early event in the evolution of malignant phenotypes, which makes them a potential driver of tumorigenesis.  So far in contrast to experimentally induced centrosome aberrations nothing is known in regards to composition and consequences of centrosome abnormalities in primary cancer cells.

This project aims to identify the nature of centrosome aberrations in acute myeloid leukemia and further malignancies. Isabella wants to analyze the ultrastructure of centrosome aberrations in primary AML cells using different electron microscopy techniques, in order to obtain a high resolution image of the centrosomes. A better understanding of the ultrastructure and number of centrosome aberrations in primary cancer cells may provide important information of their role in tumorigenesis.

Contact: Isabella.haberbosch@med.uni-heidelberg.de

Publications:

Software tools for automated transmission electron microscopy
Martin Schorb, Isabella Haberbosch, Wim Hagen, Yannick Schwab, David Mastronardedoi: bioRxiv 2018, https://doi.org/10.1101/389502

Matthias Zielonka, MD

Matthias is a physician scientist in the Division for Neuropediatrics and Metabolic Medicine at the Center for Child and Adolescent Medicine of Heidelberg University.

Biography:

Medical licensing exam, approbation; 2012
Residency in General Pediatrics at the Center for Child and Adolescent Medicine, Heidelberg University; since 2012
MD thesis, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim & Heidelberg University; 2014
Fellow of the Physician-Scientist-Program, Medical Faculty of Heidelberg University; 2015-2017
HRCMM Career Development Fellowship 2017 - 2018


Clinical host: Prof. Dr. med. Georg F. Hoffmann, Center for Child and Adolescent Medicine, University Hospital Heidelberg

EMBL hostProf. Dr. Matthias Hentze, Directors' Research, RNA Biology, Metabolism and Molecular Medicine

Disease studied: Inborn Errors of Metabolism

Inborn errors of metabolism constitute a heterogeneous group of various enzyme deficiencies. Although inborn errors of metabolism are individually rare, their cumulative prevalence is estimated to be around 1:500, defining them as highly common and relevant causes of morbidity and mortality in children and adolescents.  In the current concepts for inborn errors of metabolism, specific diseases are caused by mutations leading to a dysfunction of the catalytic site of a respective enzyme, thereby blocking intermediary metabolic pathways. In general, this enzymatic dysfunction results in the accumulation of toxic or complex metabolites and/or depletion of essential end products, ultimately causing a specific dysfunction and, subsequently, a mono- or multisystemic clinical phenotype. However, clear genotype-phenotype correlations are often poor and treatment options predominantly limited, which emphasizes that the understanding of the pathophysiological bases of this group of inherited diseases still remains restricted.

This project aims at elucidating the underlying pathomechanisms of selected inherited metabolic diseases to ultimately improve current and develop new diagnostic and therapeutic strategies. By combining both biochemical and system level approaches, Matthias wants to define genotype-phenotype-correlations of specific mutations in vitro and establish a zebrafish model to study morphological, biochemical as well as genetic alterations contributing to the phenotypic presentation of defined inborn errors of metabolism in vivo. Since several enzymes of intermediary metabolism have been shown to be involved in RNA-binding, one major aim of this project is the exact characterization of RNA-binding enzymes, the investigation of the role of RNA-binding in the context of intermediary metabolism and their pathomechanistic relevance for the respective diseases.

Awards:

February 2018: Urea Cycle Disorders Consortium (UCDC) Training Research Award 2018/2019 from the Baylor College of Medicine, USA

August 2018: Rare Disease Scholars Program 2018/2019 from the Children’s National Health System, USA

Publications:

Ultra-orphan lysosomal storage diseases: A cross-sectional quantitative analysis of the natural history of alpha-mannosidosis.
Zielonka M, Garbade SF, Kölker S, Hoffmann GF, Ries M.
J Inherit Metab Dis. 2019 Sep;42(5):975-983. doi: 10.1002/jimd.12138. Epub 2019 Jul 24.PMID:31222755

Early prediction of phenotypic severity in Citrullinemia Type 1.
Zielonka M, Kölker S, Gleich F, Stützenberger N, Nagamani SCS, Gropman AL, Hoffmann GF, Garbade SF, Posset R; Urea Cycle Disorders Consortium (UCDC) and the European Registry and Network for Intoxication type Metabolic Diseases (E-IMD) Consortia Study Group.
Ann Clin Transl Neurol. 2019 Aug 30. doi: 10.1002/acn3.50886. [Epub ahead of print]PMID:31469252

Impact of Diagnosis and Therapy on Cognitive Function in Urea Cycle Disorders.
Posset R, Gropman AL, Nagamani SCS, Burrage LC, Bedoyan JK, Wong D, Berry GT, Baumgartner MR, Yudkoff M, Zielonka M, Hoffmann GF, Burgard P, Schulze A, McCandless SE, Garcia-Cazorla A, Seminara J, Garbade SF, Kölker S; Urea Cycle Disorders Consortium and the European Registry and Network for Intoxication Type Metabolic Diseases Consortia Study Group.
Ann Neurol. 2019 Jul;86(1):116-128. doi: 10.1002/ana.25492. Epub 2019 May 13.PMID:31018246

Bioenergetic dysfunction in a zebrafish model of acute hyperammonemic decompensation.
Zielonka M, Probst J, Carl M, Hoffmann GF, Kölker S, Okun JG.
Exp Neurol. 2019 Apr;314:91-99. doi: 10.1016/j.expneurol.2019.01.008. Epub 2019 Jan 14.PMID:30653968

Clinical characteristics of 248 patients with Krabbe disease: quantitative natural history modeling based on published cases.
Komatsuzaki S, Zielonka M, Mountford WK, Kölker S, Hoffmann GF, Garbade SF, Ries M.
Genet Med. 2019 Mar 22. doi: 10.1038/s41436-019-0480-7. [Epub ahead of print]PMID:30899093

A cross-sectional quantitative analysis of the natural history of free sialic acid storage disease-an ultra-orphan multisystemic lysosomal storage disorder.
Zielonka M, Garbade SF, Kölker S, Hoffmann GF, Ries M.
Genet Med. 2019 Feb;21(2):347-352. doi: 10.1038/s41436-018-0051-3. Epub 2018 Jun 6.PMID:29875421

Pharmacologic rescue of hyperammonemia-induced toxicity in zebrafish by inhibition of ornithine aminotransferase.
Zielonka M, Breuer M, Okun JG, Carl M, Hoffmann GF, Kölker S.
PLoS One. 2018 Sep 10;13(9):e0203707. doi: 10.1371/journal.pone.0203707. eCollection 2018. PMID:30199544

A cross-sectional quantitative analysis of the natural history of Farber disease: an ultra-orphan condition with rheumatologic and neurological cardinal disease features.
Zielonka M, Garbade SF, Kölker S, Hoffmann GF, Ries M.
Genet Med. 2017 Oct 19. doi: 10.1038/gim.2017.133. PMID:29048419

Contact: matthias.zielonka@med.uni-heidelberg.de

CDF awardee Summer 2015:

CDF awardee Summer 2015:

Jakob Gierten, MD

Jakob is a resident in the Department of Pediatric Cardiology and Congenital Heart Disease at the Hospital for Children and Adolescents of Heidelberg University.

Biography:

MD/PhD Program of the Faculty of Medicine and the Faculty of Biosciences incorporated into HBIGS, since 2008
Residency in General Pediatrics at the Hospital for Children and Adolescents in Heidelberg, 2012-2015Residency in Pediatric Cardiology at the Hospital for Children and Adolescents in Heidelberg, since 2015
HRCMM Career Development Fellowship 2015 - 2017

Clinical host: Prof. Dr. med. Matthias Gorenflo, Department of Pediatric Cardiology and Congenital Heart Disease at the Hospital for Children and Adolescents in Heidelberg

EMBL host: Dr. Lars Hufnagel, Cell Biology and Biophysics

Disease studied:Congenital heart disease

Congenital heart disease (CHD) is one of the most common human birth defect and a leading cause of perinatal morbidity and mortality. The most frequently occurring non-syndromic CHD cases are commonly considered as multifactorial disorders resulting from polygenic effects of common DNA sequence variants with low penetrance that are influenced by environmental factors. The aim of this project is to identify DNA variants relevant to quantitative cardiac phenotypes by systematically dissecting genotype-phenotype correlations in fish. Jakob wants to tackle this question by adapting a light sheet fluorescent microscopy platform for large-scale characterization of morphometric and dynamic cardiac phenotypes. Identifying new disease-relevant alleles might help deducing key pathogenic events and ultimately, facilitate the development of novel therapeutic approaches.

Contact: Jakob.Gierten@med.uni-heidelberg.de

Publications and News:

https://news.embl.de/science/new-3d-microscope/

Instantaneous isotropic volumetric imaging of fast biological processes.
Wagner N, Norlin N, Gierten J, de Medeiros G, Balázs B, Wittbrodt J, Hufnagel L, Prevedel R.
Nat Methods. 2019 Apr 29. doi: 10.1038/s41592-019-0393-z. [Epub ahead of print] PMID:31036959

Automated high-throughput heart rate measurement in medaka and zebrafish embryos under physiological conditions.
Gierten J, Pylatiuk C, Hammouda OT, Schock C, Stegmaier J, Wittbrodt J, Gehrig J, Loosli F. 
bioRxiv doi: 10.1101/548594

Cloning and characterization of zebrafish K2P13.1 (THIK-1) two-pore-domain K+ channels.
Staudacher I, Seehausen S, Gierten J, Illg C, Schweizer PA, Katus HA, Thomas D.
J Mol Cell Cardiol. 2019 Jan;126:96-104. doi: 10.1016/j.yjmcc.2018.11.013. Epub 2018 Nov 22. PMID:30472253

Identification and functional characterization of zebrafish K2P17.1 (TASK-4, TALK-2) two-pore-domain K+ channels.
Staudacher I, Illg C, Gierten J, Seehausen S, Schweizer PA, Katus HA, Thomas D.
Eur J Pharmacol. 2018 Jul 15;831:94-102. doi: 10.1016/j.ejphar.2018.05.007. Epub 2018 May 9. PMID: 29753045

CDF awardee Summer 2015:

CDF awardee Summer 2015:

Susanne Dittrich, MD

Susanne is a physician scientist in the Department of Pneumology and Critical Care Medicine of the Thoraxklinik and the Department of Translational Pulmonology at the University Hospital Heidelberg, both members of the Translational Lung Research Center Heidelberg (TLRC).

Biography:

2013, approbation/license to practice medicine, Dresden University of Technology.
Research fellow at the Department of Translational Pulmonology, Translational Lung Research Center Heidelberg (TLRC), since 2014.
Physician undertaking specialty training at the Department of Pneumology and Critical Care Medicine, Thoraxklinik at the University Hospital Heidelberg, since 2014.

2015, MD Thesis, Dresden University of Technology.
HRCMM Career Development Fellowship, 2015 - 2017.

Clinical host: Prof. Dr. med. Marcus Mall, Department of Translational Pulmonology and Department of Pediatric Oncology, Hematology, Immunology and Pulmonology

EMBL host
: PD Dr. Carsten Schultz, Cell Biology and Biophysics

Disease studied: Chronic Airway Diseases

Airway inflammation is a main characteristic of chronic lung diseases, such as chronic obstructive pulmonary disease (COPD) or cystic fibrosis (CF), the most common lethal inherited disease in western countries. Previous studies indicate that imbalances of protease-antiprotease networks are crucial contributors to structural lung damage and disease progression. Therefore, quantification of protease activity could provide a valuable, non-invasive tool for the monitoring of disease activity, evaluation of anti-inflammatory therapies and a better understanding of the underlying pathophysiology.

In the current project, Susanne studies the role of membrane-associated and free protease activity in airway secretions from patients with CF and COPD. For this purpose, she uses a novel approach based on Foerster resonance energy transfer (FRET).

Awards:

May 2015: American Thoracic Society Abstract Scholarship Award of the Assembly on Clinical Problems

June 2015: Young Investigator Award of the European Cystic Fibrosis Society, pdf

Publkications:

Elastase Exocytosis by Airway Neutrophils Is Associated with Early Lung Damage in Children with Cystic Fibrosis.
Margaroli C, Garratt LW, Horati H, Dittrich AS, Rosenow T, Montgomery ST, Frey DL, Brown MR, Schultz C, Guglani L, Kicic A, Peng L, Scholte BJ, Mall MA, Janssens HM, Stick SM, Tirouvanziam R.
Am J Respir Crit Care Med. 2019 Apr 1;199(7):873-881. doi: 10.1164/rccm.201803-0442OC. PMID:30281324

Cathepsin G Activity as a New Marker for Detecting Airway Inflammation by Microscopy and Flow Cytometry.
Guerra M, Frey D, Hagner M, Dittrich S, Paulsen M, Mall MA, Schultz C.
ACS Cent Sci. 2019 Mar 27;5(3):539-548. doi: 10.1021/acscentsci.8b00933. Epub 2019 Feb 19. PMID:30937381

Elastase activity on sputum neutrophils correlates with severity of lung disease in cystic fibrosis.
Dittrich AS, Kühbandner I, Gehrig S, Rickert-Zacharias V, Twigg M, Wege S, Taggart CC, Herth F, Schultz C, Mall MA.
Eur Respir J.  2018 Mar 15. pii: 1701910. doi: 10.1183/13993003.01910-2017. [Epub ahead of print]PMID: 29545279

One time quantitative PCR detection of Pseudomonas aeruginosa to discriminate intermittent from chronic infection in cystic fibrosis.
Boutin S, Weitnauer M, Hassel S, Graeber SY, Stahl M, Dittrich AS, Mall MA, Dalpke AH.
J Cyst Fibros. 2018 Jan 11. pii: S1569-1993(18)30001-8. doi: 10.1016/j.jcf.2017.12.007. [Epub ahead of print] PMID:29336943

Abstract:
WS02.2 Role of soluble and membrane-associated neutrophil elastase activity in cystic fibrosis sputum.
Dittrich, A. Susanne & Kühbandner, I & Gehrig, Stefanie & Rickert-Zacharias, V & Taggart, Cliff & Twigg, Matthew & Herth, Felix & Schultz, C & Mall, Marcus.
Journal of Cystic Fibrosis. June 2017 16. S3. 10.1016/S1569-1993(17)30163-7.

Chronic but not intermittent infection with Pseudomonas aeruginosa is associated with global changes of the lung microbiome in cystic fibrosis
Sébastien Boutin, Simon Y. Graeber, Mirjam Stahl, A. Susanne Dittrich, Marcus A. Mall, Alexander H. Dalpke
Eur Respir J. 2017 Oct 5;50(4). pii: 1701086. doi: 10.1183/13993003.01086-2017. Print 2017 Oct. PMID:28982777

Contact: Susanne.Dittrich @med.uni-heidelberg.de

CDF awardee February 2015:

CDF awardee February 2015:

Johannes Pfeil, MD

Johannes is a physician for Pediatric Rheumatology and Infectious Diseases at the Hospital for Children and Adolescents of Heidelberg University(General Pediatrics).

Biography:

2007 MD thesis, University Heidelberg
Residency in General Pediatrics, University of Würzburg, Germany (2007-2008)
Physician at the Center for Childhood and Adolescent Medicine (General Pediatrics), University Hospital Heidelberg, since 2008

Board certification in General Pediatrics, 2012
Board certification Pediatric Rheumatology, 2014
Board certification Infectious Diseases, 2015

HRCMM Career Development Fellowship 2015 - 2017.

Clinical host: Dr. Ann-Kristin Müller, Center for Infectious Diseases, Parasitology Unit, University Hospital Heidelberg

EMBL host: Dr. Jeroen Krijgsveld, Genome Biology

Disease studied: Malaria

Malaria, a parasite infection of red blood cells, kills roughly 2000 people per day, most of whom are children in Africa. In experimental immunization trials, intravenous administration of whole attenuated malaria parasites successfully protected humans against wild-type malaria infection. Even though this concept is unfeasible for direct translation towards routine vaccination, it still serves as a model to investigate protective immune responses against malaria.   

By applying advanced mass spectrometric analysis, Johannes wants to identify critical targets of protective immunity induced by whole-parasite immunization at the very early and clinically silent malaria liver stage.  The successful identification of these targets may provide the basis for future development of highly protective subunit malaria vaccines.

Contact: Johannes.Pfeil@med.uni-heidelberg.de

Publications:

Protection from experimental cerebral malaria with a single intravenous or subcutaneous whole-parasite immunization.
Heiss, K., Maier, M. I., Hoffmann, A., Frank, R., Bendszus, M., Mueller, A. K., Pfeil,
J. Scientific reports, 2018, 8(1), 3085.

Performance of the Alere i RSV assay for point-of-care detection of respiratory syncytial virus in children.
Schnee SV, Pfeil J Ihling CM, Tabatabai J, Schnitzler P
BMC Infectious Diseases Dec 2017 17:767

In Vivo Tracking of Edema Development and Microvascular Pathology in a Model of Experimental Cerebral Malaria Using Magnetic Resonance Imaging
Hoffmann A, Helluy X, Fischer M, Mueller AK, Heiland S, Pham M, Bendszus M, Pfeil J
J. Vis. Exp. 2017 (124), e55334, doi:10.3791/55334

Reverse-transcription loop-mediated isothermal amplification for rapid detection of respiratory syncytial virus directly from nasopharyngeal swabs.
Hoos J, Peters RM, Tabatabai J, Grulich-Henn J, Schnitzler P, Pfeil J.
J Virol Methods. 2017 Jan 16;242:53-57. doi: 10.1016/j.jviromet.2017.01.006. PMID: 28093275

Evaluation of Alere™ i RSV for rapid detection of respiratory syncytial virus in children hospitalized with acute respiratory tract infection.
Peters RM, Schnee SV, Tabatabai J, Schnitzler P, Pfeil J.
J Clin Microbiol. 2017 Jan 11. pii: JCM.02433-16. doi: 10.1128/JCM.02433-16. PMID: 28077700

High-Density Peptide Arrays for Malaria Vaccine Development.
Loeffler FF, Pfeil J, Heiss K.
Methods Mol Biol. 2016;1403:569-82. doi: 10.1007/978-1-4939-3387-7_32. PMID: 27076154

CDF awardee 2014:

CDF awardee 2014:

Sascha Dietrich, MD

Sascha is physician undergoing specialty training for Hematology and Oncology in the Department of Hematology, Oncology and Rheumatology at the University Medical Center for Internal Medicine, Heidelberg.

Biography:

2007 MD thesis, University of Jena.
Residency in Internal Medicine and Hematology at Heidelberg University Hospital, since 2006.
Emergency medicine board certification, since 2011.
HRCMM Career Development Fellowship,  2014 - 2016.

Clinical hosts: Anthony D. Ho, Department of Internal Medicine V: Opens external link in new windowHematology, Oncology and Rheumatology, Heidelberg University Hospital
Thorsten Zenz, Department of Translational Oncology, Opens external link in new windowSection Lymphoma Research, National Center for Tumor Diseases (NCT) Heidelberg

EMBL host: Opens external link in new windowWolfgang Huber, Genome Biology

Disease studied: Hematologic cancers, lympho- proliferative diseases (LPD)

Most cancer patients are treated with chemotherapy irrespective of diverse biology, but the discovery of key pathogenetic mutations has already transformed the treatment of specific cancer types. Successful examples of hematologic cancers include BCR-ABL inhibition of chronic myeloid leukaemia and as recently published by us, BRAF inhibition in hairy cell leukaemia.
We are aiming to understand the functional role of critical signalling pathways in lympho- proliferative diseases (LPD) and to determine the biological basis for differential response to genotype specific treatment. Pathway sensitivity and resistance of primary human tumour cells will be systematically mapped ex vivo using large and diverse compound libraries (up to 2500 compounds) across leukaemia s and lymphoma subtypes (refractory CLL, T-PLL, B-PLL, MCL, LPL, FL) to functionally group patients according to drug sensitivities. Paired with detailed molecular characterization of all tumour samples, and available clinical follow-up of the same patients, this novel and innovative approach provides unique opportunities to identify key pathways that determine sensitivity to specific drugs and drug combinations with the immediate potential for clinical translation.

Publications:

Post-transplant cyclophosphamide-based haplo-identical transplantation as alternative to matched sibling or unrelated donor transplantation for non-Hodgkin lymphoma: a registry study by the European society for blood and marrow transplantation.
Dietrich S, Finel H, Martinez C, Tischer J, Blaise D, Chevallier P, Castagna L, Milpied N, Bacigalupo A, Corradini P, Mohty M, Sanz M, Hausmann A, Montoto S, Robinson S, Boumendil A, Sureda A, Dreger P.
Leukemia. 2016 Oct;30(10):2086-2089. doi: 10.1038/leu.2016.125

BRAF inhibitor therapy in HCL.
Dietrich S, Zenz T.
Best Pract Res Clin Haematol. 2015 Dec;28(4):246-52. doi: 10.1016/j.beha.2015.10.001. Epub 2015 Oct 20. Review. PMID:26614903

Recurrent CDKN1B (p27) mutations in hairy cell leukemia.
Dietrich S, Hüllein J, Lee SC, Hutter B, Gonzalez D, Jayne S, Dyer MJ, Oleś M, Else M, Liu X, Słabicki M, Wu B, Troussard X, Dürig J, Andrulis M, Dearden C, von Kalle C, Granzow M, Jauch A, Fröhling S, Huber W, Meggendorfer M, Haferlach T, Ho AD, Richter D, Brors B, Glimm H, Matutes E, Abdel Wahab O, Zenz T.
Blood. 2015 Aug 20;126(8):1005-8. doi: 10.1182/blood-2015-04-643361. Epub 2015 Jun 11. PMID: 26065650

Contact: Sascha.Dietrich@med.uni-heidelberg.de

CDF awardees 2013:

CDF awardees 2013:

Joachim Kunz, MD

Joachim is an attending physician for Pediatric Hematology and Oncology in the Department of Pediatric Oncology, Hematology, Immunology and Pulmonology at the Hospital for Children and Adolescents of Heidelberg University.

Biography:

2002 MD thesis, approbation/license to practice medicine, University of Tübingen.
Medical specialist in pediatric hematology and oncology, University Medical Center for Children and Adolescents, Heidelberg, since 2009.
Attending physician in pediatric hematology and oncology, University Medical Center for Children and Adolescents, Heidelberg, since 2013.
HRCMM Career Development Fellowship 2013 - 2015.

Clinical host: Andreas E. Kulozik, Department of Pediatric Oncology, Hematology, Immunology and Pulmonology
University Medical Center for Children and Adolescents, Heidelberg

EMBL host: Jan Korbel, Genome Biology

Disease studied: T-cell acute lymphoblastic leukemia (T-ALL) in children

Leukemia is the most common malignancy in childhood. T-ALL accounts for approximately 15% of all ALL in children and adolescents. Whereas the primary T-ALL can be cured in more than 80% of patients with current treatment protocols, relapsed T-ALL is almost invariably fatal: during the time between first diagnosis and relapse, T-ALL evolves into a resistant disease by acquiring new mutations induced by chemotherapy and by selection of subclones. Using whole exome sequencing, Joachim hopes to find mechanisms of treatment resistance and understand the evolution of T-ALL during a patient’s course of disease.

Publications:

Pediatric T-lymphoblastic leukemia evolves into relapse by clonal selection, acquisition of mutations and promoter hypomethylation.
Kunz JB, Rausch T, Bandapalli OR, Eilers J, Pechanska P, Schuessele S, Assenov Y, Stütz AM, Kirschner-Schwabe R, Hof J, Eckert C, von Stackelberg A, Schrappe M, Stanulla M, Koehler R, Avigad S, Elitzur S, Handgretinger R, Benes V, Weischenfeldt J, Korbel JO, Muckenthaler MU, Kulozik AE.
Haematologica. 2015 Aug 20. pii: haematol.2015.129692. Epub 2015 Aug 20. PMID: 26294725

The activating STAT5B N642H mutation is a common abnormality in pediatric T-cell acute lymphoblastic leukemia and confers a higher risk of relapse.
Bandapalli OR, Schuessele S, Kunz JB, Rausch T, Stütz AM, Tal N, Geron I, Gershman N, Izraeli S, Eilers J, Vaezipour N, Kirschner-Schwabe R, Hof J, von Stackelberg A, Schrappe M, Stanulla M, Zimmermann M, Koehler R, Avigad S, Handgretinger R, Frismantas V, Bourquin JP, Bornhauser B, Korbel JO, Muckenthaler MU, Kulozik AE.
Haematologica. 2014 Oct;99(10):e188-92. doi: 10.3324/haematol.2014.104992. Epub 2014 Jun 27.

Pädiatrie 4. Auflage
Kunz J, Kulozik A
Kap 178 Erythrozyten,2014,  S 1429-56 Hrsg: Hoffmann, Lentze, Spranger, Zepp: Springer ISBN 978-3-642-41865-5

Contact: joachim.kunz@med.uni-heidelberg.de

lehmann

Lorenz Lehmann, MD

Lorenz is a physician for Cardiology in the Department of Cardiology, Angiology and Pulmonology, at the University Medical Center for Internal Medicine, Heidelberg.

Biography:

2006 MD thesis, University of Heidelberg.
Physician undertaking specialty training at the Department of Cardiology, Angiology and Pulmonology, University Hospital Heidelberg, since 2007.
Research fellow in experimental cardiology, Johannes Backs lab, University of Heidelberg, since 2007.
HRCMM Career Development Fellowship 2013 - 2015.

Clinical host: Opens external link in new windowHugo A. Katus, Department of Cardiology, Angiology and Pulmonology, University Hospital Heidelberg

EMBL host: Eileen Furlong, Genome Biology

Disease studied: Heart failure

Research focus: Heart failure is one of the main causes of death in the western world. Previously, histone deacetylase 4 (HDAC4) was identified as a cardioprotective factor. Understanding the molecular basis of its posttranslational modifications enabled the development of potential therapeutic tools for the treatment of heart diseases. For instance, the N-terminal part of HDAC4 inhibits specific transcription factors such as MEF2, which is one of the key regulators for pathological cardiac remodeling which leads ultimately to heart failure.

During the HRCMM project Lorenz aims to comprehensively identify MEF2 and HDAC4 regulated genes via ChIP-seq experiments. Subsequently, he will study their contribution to the transition from a healthy to a diseased heart. It is the overall goal to gain a deep understanding of the epigenetic modifications driven by HDAC4 and to identify epigenetic drug targets for cardioprotection.

Publications:

Advanced echocardiography in adult zebrafish reveals delayed recovery of heart function after myocardial cryoinjury.
Hein SJ, Lehmann LH, Kossack M, Juergensen L, Fuchs D, Katus HA, Hassel D.
PLoS One. 2015 Apr 8;10(4):e0122665. doi: 10.1371/journal.pone.0122665. eCollection 2015. PMID:25853735

Essential role of sympathetic endothelin A receptors for adverse cardiac remodeling.
Lehmann LH, Rostosky JS, Buss SJ, Kreusser MM, Krebs J, Mier W, Enseleit F, Spiger K, Hardt SE, Wieland T, Haass M, Lüscher TF, Schneider MD, Parlato R, Gröne HJ, Haberkorn U, Yanagisawa M, Katus HA, Backs J. Proc Natl Acad Sci U S A. 2014 Sep 2. pii: 201409026. [Epub ahead of print]

CaM Kinase II mediates maladaptive post-infarct remodeling and pro-inflammatory chemoattractant signaling but not acute myocardial ischemia/reperfusion injury.
Weinreuter M, Kreusser MM, Beckendorf J, Schreiter FC, Leuschner F, Lehmann LH, Hofmann KP, Rostosky JS, Diemert N, Xu C, Volz HC, Jungmann A, Nickel A, Sticht C, Gretz N, Maack C, Schneider MD, Gröne HJ, Müller OJ, Katus HA, Backs J. EMBO Mol Med. 2014 Sep 5. pii: e201403848. doi: 10.15252/emmm.201403848. [Epub ahead of print]

The Cardiac CaMKII Genes δ and γ Contribute Redundantly to Adverse Remodeling but Inhibit Calcineurin-Induced Myocardial Hypertrophy.
Kreusser MM, Lehmann LH, Keranov S, Hoting MO, Kohlhaas M, Reil JC, Neumann K, Schneider MD, Hill JA, Dobrev D, Maack C, Maier LS, Gröne HJ, Katus HA, Olson EN, Backs J.
Circulation. 2014 Aug 14. pii: CIRCULATIONAHA.114.006185. [Epub ahead of print] PMID:25124496

Depletion of globosides and isoglobosides fully reverts the morphologic phenotype of Fabry disease.
Porubsky S, Jennemann R, Lehmann L, Gröne HJ.
Cell Tissue Res. 2014 Jul 4. [Epub ahead of print]

Histone deacetylase signaling in cardioprotection.
Lehmann LH, Worst BC, Stanmore DA, Backs J.
Cell Mol Life Sci. 2013 Dec 6.

The role of endothelin-1 in the sympathetic nervous system in the heart.
Lehmann LH, Stanmore DA, Backs
J. Life Sci. 2014 Mar 13. pii: S0024-3205(14)00317-8. doi: 10.1016/j.lfs.2014.03.005. [Epub ahead of print] Review. PMID: 24632477

Awards:

April 2013: Lorenz Lehmann receives Rudi Busse - Young Investigator Award for his work in experimental cardiovascular research.

Contact: lorenz.lehmann@med.uni-heidelberg.de

singer

Stephan Singer, MD

Stephan is a physician for Pathology in the Department of General Pathology at the Institute of Pathology Heidelberg, IPH.

Biography:

2005 MD thesis, University of Heidelberg.
Physician undertaking specialty training at the Institute of Pathology, University Medical Center Heidelberg, since 2005.
2008 Postdoc Columbia University New York City, USA.
2011 Gerok fellowship SFB/TRR77.
HRCMM Career Development Fellowship 2013 - 2015.

Clinical host: Opens external link in new windowPeter Schirmacher, Institute of Pathology Heidelberg

EMBL host: Martin Beck, Structural and Computational Biology

Disease studied: Liver cancer

Research focus: Hepatocellular carcinoma (HCC) is one of the most frequent malignancies world-wide with an increasing incidence and a poor prognosis. Signalling cascades of (hepato-)carcinogenic pathways pass the nuclear envelope through the nuclear pore complex (NPC). The NPC is a multiprotein complex spanning the nuclear envelope and consists of ~30 nucleoporins (Nups). The project investigates compositional changes of the NPC occurring in the process of hepatocarcinogenesis and to what extent NPC remodelling modulates liver cancer-relevant pathways. In collaboration with the Beck lab (EMBL) Stephan will address this in vitro and in vivo by using targeted and non-targeted mass spectrometry, gene expression arrays, cell-based assays, murine HCC models, and human HCC samples. Tumour-specific alterations of the NPC may provide the basis for novel therapeutic approaches.

Publications:

Karyopherin α2-dependent import of E2F1 and TFDP1 maintains protumorigenic stathmin expression in liver cancer.
Drucker E, Holzer K, Pusch S, Winkler J, Calvisi DF, Eiteneuer E, Herpel E, Goeppert B, Roessler S, Ori A, Schirmacher P, Breuhahn K, Singer S.
Cell Commun Signal. 2019 Nov 29;17(1):159. doi: 10.1186/s12964-019-0456-x. PMID:31783876

Cellular apoptosis susceptibility (CAS) is linked to integrin β1 and required for tumor cell migration and invasion in hepatocellular carcinoma (HCC).
Winkler J, Roessler S, Sticht C, DiGuilio AL, Drucker E, Holzer K, Eiteneuer E, Herpel E, Breuhahn K, Gretz N, Schirmacher P, Ori A, Singer S.
Oncotarget. 2016 Mar 23. doi: 10.18632/oncotarget.8256. [Epub ahead of print] PMID: 27015362

Spatiotemporal variation of mammalian protein complex stoichiometries.
Ori A, Iskar M, Buczak K, Kastritis P, Parca L, Andrés-Pons A, Singer S, Bork P, Beck M.
Genome Biol. 2016 Mar 14;17:47. doi: 10.1186/s13059-016-0912-5. PMID: 26975353 

PI3K/AKT/mTOR-dependent stabilization of oncogenic far-upstream element binding proteins in hepatocellular carcinoma cells.
Samarin J, Laketa V, Malz M, Roessler S, Stein I, Horwitz E, Singer S, Dimou E, Cigliano A, Bissinger M, Falk CS, Chen X, Dooley S, Pikarsky E, Calvisi DF, Schultz C, Schirmacher P, Breuhahn K.
Hepatology. 2016 Mar;63(3):813-26. doi: 10.1002/hep.28357. Epub 2016 Jan 14. PMID: 26901106

Histone Deacetylase Inhibitors (HDACi) Cause the Selective Depletion of Bromodomain Containing Proteins (BCPs).
Mackmull MT, Iskar M, Parca L, Singer S, Bork P, Ori A, Beck M.
Mol Cell Proteomics. 2015 May;14(5):1350-60. doi: 10.1074/mcp.M114.042499. Epub 2015 Mar 9. PMID: 25755299

Overexpression of far upstream element (FUSE) binding protein (FBP)-interacting repressor (FIR) supports growth of hepatocellular carcinoma
Malz, M., Bovet, M., Samarin, J., Rabenhorst, U., Sticht, C., Bissinger, M., Roessler, S., Lorenzo Bermejo, J., Renner, M., Calvisi, D. F., Singer, S., Ganzinger, M., Weber, A., Gretz, N., Zornig, M., Schirmacher, P., and Breuhahn, K.
Hepatology 60,1241-50, 2014

Prosurvival function of the cellular apoptosis susceptibility/importin-α1 transport cycle is repressed by p53 in liver cancer.
Winkler J1, Ori A, Holzer K, Sticht C, Dauch D, Eiteneuer EM, Pinna F, Geffers R, Ehemann V, Andres-Pons A, Breuhahn K, Longerich T, Lorenzo Bermejo J, Gretz N, Zender L, Schirmacher P, Beck M, Singer S.
Hepatology. 2014 May 6. doi: 10.1002/hep.27207. [Epub ahead of print]

Awards:

July 2014: Stephan Singer receives the Hella-Bühler-Award for his outstanding work in cancer research.

Contact: Stephan.Singer@med.uni-heidelberg.de