Institute for Computational Biomedicine and Disease modelling with focus on phase transitions between phenotypes

Prof. Dr. Thomas Stiehl

Thomas Stiehl’s research focusses on stem cell dynamics in homeostasis, regeneration and cancer. He develops mechanistic mathematical and computational models to understand the development and progression of stem-cell-driven diseases. His main field of research are malignancies of the blood forming (hematopoietic) system, such as acute myeloid leukemia (AML), myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). The models help to unravel the determinants of disease progression based on clinical data. Main research topics include:

  • Mathematical modeling of stem cell dynamics and disease progression in blood cancers (AML, MDS, MPN). The models account for the role of clonal competition, systemic feedback-mechanisms, treatment-related selection and stem cell – niche interactions.                      
  • Mathematical modeling of resistance development and cancer treatment.
  • Model-based risk-stratification and personalized prediction of disease progression in blood cancers.                               
  • Mathematical modeling of blood cell formation in health and disease, including reconstitution after bone marrow transplantation (recovery of blood       cell counts) and white blood cell formation in sepsis.                
  • Mathematical modeling of stem cell aging including blood-forming stem cells, neural stem cells and mesenchymal stromal cells.                  
  • Mathematical modeling of neurogenesis in the adult brain.              
  • Mathematical modeling of methylation patterns during aging and disease.

More information can be found at http://thomas-stiehl.de/Research.html

Metabolic injury as driver of organ-dependent phase transition - P13: Using real-world data to identify and validate repurposing drugs for liver/heart disease:
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Lundbeck Fellowship "Personalized prediction of blood cancer progression using clinical data and mathematical modeling" (Roskilde University, Roskilde, Denmark):
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Prof. Dr. Thomas Stiehl

Thomas Stiehl studied mathematics and medicine in Heidelberg. He also received his PhD degree in mathematics from Heidelberg University. Thomas Stiehl develops mechanistic mathematical models of stem cell driven processes in health and disease. The models help to understand the patho-mechanisms underlying disease development and progression. His focus of research are cancers of the blood forming system, such as acute myeloid leukemias (AML), myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS). The models can be used to predict the course of the disease based on clinical data and to simulate novel treatment approaches.

Chenxu Zhu

Chenxu Zhu studied Biomedical Engineering at Southeast University in Nanjing (China) and at RWTH Aachen University. Her doctoral research is devoted to mechanistic modeling of blood cancers with a special focus on acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPN). She develops ordinary differential equation models which are applied to clinical data of AML chemotherapy, hematopoietic regeneration and MPN cell population dynamics. The models aim to understand the mechanisms of hematopoietic malignancy and to predict disease evolution.

Gina Maria Wilms

Gina Maria Wilms studied Human Medicine at RWTH Aachen University and became a licensed physician this year. In collaboration with the Clinic for Oncology, Hematology and Stem Cell Transplantation (Chief Physician, Translational Hematology and Oncology), she is currently working on her doctoral thesis focused on the engraftment following autologous stem cell transplantation. Her thesis explores the regeneration of the blood cell counts in multiple myeloma patients. This project aims to investigate factors influencing the outcome of autologous stem cell transplantation and supports further mathematical modeling.

Qiujie Wang

Qiujie Wang studied Biomedical Engineering at Southeast University in Nanjing (China) and he is now a master student in Biomedical Engineering at RWTH Aachen University. His research is focused on mechanistic modeling of myeloproliferative neoplasms (MPN), with a specific emphasis on Primary Myelofibrosis (PMF). Through the development of ordinary differential equation models, he aims to investigate the dynamics of PMF cell populations and the capacity of the bone marrow niche they reside in. The models aim to gain a deeper understanding of the underlying mechanisms of primary myelofibrosis and to provide
insights into the prediction of disease evolution.

Internship Students

Daniel Láinez González

Daniel Láinez González obtained a BSc in Physics at Universidad Complutense de Madrid and a MSc in Biology at Universidad de Alcalá. His doctoral research is focused on the quiescence of leukemic stem cells at Instituto de Investigación Sanitaria Fundación Jiménez Díaz – Universidad Autónoma de Madrid. During his stay at RWTH Aachen University he develops ordinary differential equation models which are applied to his experimental data of cell cycle studies.

Journal Articles and Preprints       

RK. Pedersen, M. Andersen, V. Skov, L. Kjaer, HC. Hasselbalch, JT. Ottesen, T. Stiehl. "HSC niche dynamics in regeneration, pre-malignancy and cancer: Insights from mathematical modeling." Stem Cells. 41(3):260-270, 2023. 

RK. Pedersen, M. Andersen, T. Stiehl, JT. Ottesen. "Understanding Hematopoietic Stem Cell Dynamics - Insights from Mathematical Modelling." Current Stem Cell Reports. 9: 9-16, 2023. 

L. Kjaer, V. Skov, MK. Larsen, TI. Boklund, M. Andersen, M. Kefala, TA. Knudsen, C. Schjellerup Eickhardt-Dalbøge, T. Stiehl, J. Gudmand-Hoyer, J. Snyder, M. Holmstroem, MH. Andersen, JT. Ottesen, C. Ellervik, HC. Hasselbalch. Case Report: First longitudinal study of a patient with CALR positive clonal hematopoiesis of indeterminate potential developing into pre-fibrotic myelofibrosis." Front Oncol. 13:1176173, 2023. 

Y. Pan, MR. D'Orsogna, M. Tang, T. Stiehl, T. Chou. "Clonal abundance patterns in hematopoiesis: Mathematical modeling and parameter estimation." Front. Syst. Biol. 3:893366, 2023. 

P. Desai, A. Dasgupta, AM. Sofias, Q. Pena, R. Goestl, I. Slabu, U. Schwaneberg, T. Stiehl, W. Wagner, S. Jockenhoevel, J. Stingl, R. Kramann, C. Trautwein, TH. Bruemmendorf, F. Kiessling, A. Herrmann, T. Lammers. "Transformative Materials for Interfacial Drug Delivery" Adv Healthc Mater. 12(20):e2301062, 2023. 

JL. Gerardo-Nava, J. Jansen, D. Guenther, L. Klasen, AL. Thiebes, B. Niessing, C. Bergerbit, AA. Meyer, J. Linkhorst, M. Barth, P. Akhyari, J. Stingl, S. Nagel, T. Stiehl, A. Lampert, R. Leube, M. Wessling, F. Santoro, S. Ingebrandt, S. Jockenhoevel, A. Herrmann, H. Fischer, W. Wagner, RH. Schmitt, F. Kiessling, R. Kramann, L. De Laporte. "Transformative Materials to Create 3D Functional Human Tissue Models In Vitro in a Reproducible Manner." Adv Healthc Mater. 12(20):e2301030, 2023. 

Y. Zhang, T. Stiehl, M. Tang. "A Continuous Integral Model for White Blood Cell Production." SIAM J Appl Math. 82(6), 2022. 

MK. Larsen, V. Skov, L. Kjaer, NA. Møller-Palacino, RK. Pedersen, M. Andersen, JT. Ottesen, S. Cordua, HE. Poulsen, M. Dahl, TA. Knudsen, CS. Eickhardt-Dalbøge, S. Koschmieder, KM. Pedersen, Y. Çolak, SE. Bojesen, BG. Nordestgaard, T. Stiehl*, HC. Hasselbalch*, C. Ellervik*. "Clonal haematopoiesis of indeterminate potential and impaired kidney function-A Danish general population study with 11 years follow-up." Eur J Haematol. 109(5):576-585, 2022. * shared last 

USA. Stalmann, F. Ticconi, IAM. Snoeren, R. Li, HFE. Gleitz, GS. Cowley, ME. McConkey, AB. Wong, S. Schmitz, SNR. Fuchs, S. Sood, NB. Leimkühler, S. Martinez-Hoyer, B. Banjanin, D. Root, TH. Brümmendorf, JE. Pearce, A. Schuppert, EMJ. Bindels, MA. Essers, D. Heckl, T. Stiehl, IG. Costa*, BL. Ebert*, RK. Schneider*. "Genetic barcoding systematically compares genes in del(5q) MDS and reveals a central role for CSNK1A1 in clonal expansion." Blood Adv. 6(6):1780-1796, 2022.

L. Orsatti*, T. Stiehl*, K. Dischinger*, R. Speziale, P. Di Pasquale, E. Monteagudo, C. Müller-Tidow, A. Radujkovic, P. Dreger, T. Luft. "Kynurenine pathway activation and deviation to anthranilic and kynurenic acid in fibrosing chronic graft-versus-host disease." Cell Rep Med. 2021, 2(10):100409. * shared first.

L. Harris, P. Rigo, T. Stiehl, Z. Gaber, S. H. L. Austin, M. del Mar Masdeu, A. Edwards, N. Urban, A. Marciniak-Czochra, F. Guillemot. "Progressive changes in hippocampal stem cell properties ensure lifelong neurogenesis." Cell Stem Cell, 2021, doi: 10.1016/j.stem.2021.01.003.                     

T. Stiehl, A. Marciniak-Czochra. "Computational reconstruction of clonal hierarchies from bulk sequencing data of acute myeloid leukemia samples." Front Physiol. 12:596194, 2021.            

LPM. Kremer*, S. Cerrizuela*, S. Dehler**, T. Stiehl**, J. Weinmann, H. Abendroth, S. Kleber, A. Laure, J. El Andari, S. Anders, A. Marciniak-Czochra, D. Grimm, A. Martin-Villalba. "High throughput screening of novel AAV capsids identifies variants for transduction of adult NSCs within the subventricular zone." Mol. Ther. Methods Clin. Dev. 23:33-50, 2021. * shared first authorship, ** shared second authorship.            

RK. Pedersen, M. Andersen, T. Stiehl, JT. Ottesen. "Mathematical modelling of the hematopoietic stem cell-niche system: Clonal dominance based on stem cell fitness." J Theor Biol. 2021, doi: 10.1016/j.jtbi.2021.110620   

T. Stiehl, W. Wang, C. Lutz, A. Marciniak-Czochra, "Mathematical modeling provides evidence for niche competition in human AML and serves as a tool to improve risk stratification", Cancer Res. 2020.                    

F. Klawe*, T. Stiehl*, P. Bastian, C. Gaillochet, JU. Lohmann, A. Marciniak-Czochra, "Mathematical modeling of plant cell fate transitions controlled by hormonal signals", PLoS Comput Biol, 16(7):e1007523, 2020. * shared first authorship. https://parcomp-git.iwr.uni-heidelberg.de/peter/dune-dr

T. Stiehl. "Using mathematical models to improve risk-scoring in acute myeloid leukemia." Chaos 30(12):123150, 2020.               

Y. Han, J. Franzen, T. Stiehl, M. Gobs, CC. Kuo, M. Nikolic, J. Hapala, BE. Koop, K. Strathmann, S. Ritz‐Timme, W. Wagner. "New Targeted Approaches for Epigenetic Age Predictions" BMC Biol , 18(1):71, 2020.  

F. Knauer, T. Stiehl, A. Marciniak-Czochra. Oscillations in a white blood cell production model with multiple differentiation stages, J. Math Biol. 80(3):575-600, 2020.                  

R. Stace, T. Stiehl, A. Marciniak-Czochra, T. Lorenzi, "Discrete and continuum phenotype-structured models for the evolution of cancer cell populations under chemotherapy.", Math. Mod. Natural Phenomena15:14, 2020.  

S. Chulian, A. Martínez-Rubio, A. Marciniak-Czochra, T. Stiehl, C. Blazquez Goni, JFR. Gutierrez, MR. Orellana, AC. Robleda, VM. Perez-Garcia, M. Rosa. "Dynamical properties of feedback signalling in B lymphopoiesis: A mathematical modelling approach", BioRxive

G. Kalamakis, D. Brune, S. Ravichandran, J. Bolz, W. Fan, F. Ziebell, T. Stiehl, F. Catala-Martinez, J. Kupke, S. Zhao, E. Llorens-Bobadilla, K. Bauer, S. Limpert, B. Berger, U. Christen, P. Schmezer, J.P. Mallm, B. Berninger, S. Anders, A. Del Sol, A. Marciniak-Czochra, and A. Martin-Villalba. "Quiescence Modulates Stem Cell Maintenance and Regenerative Capacity in the Aging Brain", Cell, 176(6):1407-1419.e14, 2019.                           

T. Lorenzi, A. Marciniak-Czochra, T. Stiehl, "A structured population model of clonal selection in acute leukemias with multiple maturation stages", J Math Biol. 79(5):1587-1621, 2019.             

T. Stiehl, A. Marciniak-Czochra, “How to characterize stem cells? Contributions from mathematical modeling.", Current stem cell reports, 5 (2): 57–65, 2019. (Review)"         

T. Stiehl, A. D. Ho, A. Marciniak-Czochra, "Mathematical modeling of the impact of cytokine response of acute myeloid leukemia cells on patient prognosis", Scientific Reports 8:2809, 2018.                              

A. Marciniak-Czochra, A. Mikelic, T. Stiehl, "Renormalization group second order approximation for singularly perturbed nonlinear ordinary differential equations", Math. Methods in Applied Sciences 41: 5691-5710, 2018.        

T. Stiehl, A. Marciniak-Czochra, "Stem cell self-renewal in regeneration and cancer: Insights from mathematical modeling", Current Opinion in Systems Biology 5: 112-120, 2017. (Review)                          

C. Gaillochet, T. Stiehl, C. Wenzl, JJ. Ripoll, LJ. Bailey-Steinitz, L. Li, A. Pfeiffer, A. Miotk, J. Hakenjos, J. Forner, MF. Yanofsky, A. Marciniak-Czochra, JU Lohmann, "Control of plant cell fate transitions by transcriptional and hormonal signals", eLife 6:e30135, 2017.                           

W. Wang, T. Stiehl, S. Raffel, V. T. Hoang, I. Hoffmann, L. Poisa-Beiro, B. R. Saeed, R. Blume, L. Manta, V. Eckstein, T. Bochtler, P. Wuchter, M. Essers, A. Jauch, A. Trumpp, A. Marciniak- Czochra, A. D. Ho, C. Lutz, "Reduced hematopoietic stem cell frequency predicts outcome in acute myeloid leukemia", Haematologica 102: 1567-1577, 2017.

T. Stiehl, C. Lutz, A. Marciniak-Czochra, "Emergence of heterogeneity in acute leukemias", Biology Direct 11: 51, 2016.                  

T. Stiehl, N. Baran, A. D. Ho, A. Marciniak-Czochra, "Cell division patterns in acute myeloid leukemia stem-like cells determine clinical course: a model to predict patient survival", Cancer Research 75: 940-949, 2015.  

T. Walenda*, T. Stiehl*, H. Braun, J. Fröbel, A. D. Ho, T. Schroeder, T. Goecke, U. Germing, A. Marciniak-Czochra, W. Wagner, "Feedback Signals in Myelodysplastic Syndromes: Increased Self-Renewal of the Malignant Clone Suppresses Normal Hematopoiesis", PLoS Comp. Biol. 10: e1003599, 2014. * shared first authorship              

T. Stiehl, N. Baran, A. D. Ho, A. Marciniak-Czochra, "Clonal selection and therapy resistance in acute leukemias: Mathematical modelling explains different proliferation patterns at diagnosis and relapse", J. Royal Society Interface 11: 20140079, 2014.             

T. Stiehl, A. D. Ho, A. Marciniak-Czochra, "The impact of CD34+ cell dose on engraftment after Stem Cell Transplantations: personalized estimates based on mathematical modeling", Bone Marrow Transplantation 49: 30-37, 2014.           

T. Stiehl, A. D. Ho, A. Marciniak-Czochra, "Assessing hematopoietic (stem-) cell behavior during regenerative pressure", Adv Exp Med Biol 844: 347-67, 2014.         

F. Clement, P. Michel, D. Monniaux, T. Stiehl, "Coupled Somatic Cell Kinetics and Germ Cell Growth: Multiscale Model-Based Insight on Ovarian Follicular Development", SIAM Multiscale Model. Simul. 11: 719-746, 2013.      

T. Stiehl, A. Marciniak-Czochra, "Mathematical modelling of leukemogenesis and cancer stem cell dynamics", Math. Mod. Natural Phenomena 7: 166-202,     2012.   

A. Schellenberg, T. Stiehl, P. Horn, S. Joussen, N. Pallua, A. D. Ho, W. Wagner, "Population dynamics of mesenchymal stromal cells during culture expansion", Cytotherapy 14: 401-411, 2012.  

T. Stiehl, A. Marciniak-Czochra, "Characterization of stem cells using mathematical models of multistage cell lineages", Math. Comput. Model 53: 1505-1517, 2011.        

D. Cholewa*, T. Stiehl*, G. Bokermann, S. Joussen, C. Koch, T. Walenda, N. Pallua, A. Marciniak-Czochra, C. V. Suschek, W. Wagner, "Expansion of Adipose Mesenchymal Stromal Cells is Affected by Human Platelet Lysate and Plating Density", Cell Transplantation 20: 1409-22, 2011. * shared first authorship  

A. Marciniak-Czochra, T. Stiehl, W. Wagner, "Modeling of replicative senescence in hematopoietic development", Aging 1: 723-732, 2009.                         

A. Marciniak-Czochra, T. Stiehl, A. D. Ho, W. Jäger, W. Wagner, "Modeling asymmetric cell division in hematopietic stem cells regulation of self-renewal is essential for efficient repopulation", Stem Cells Dev. 18: 377-385, 2009.                  

 

Book Chapters                     

T. Stiehl. "Multiplicity of time scales in blood cell formation and leukemia: Contributions of computational disease modeling to mechanistic understanding and personalized medicine.", in B. Booss-Bavnbek, J. Christensen, K. Richardson, O. Codina (Eds.), Springer, accepted.

T. Stiehl, A. Marciniak-Czochra. "How smart are equations and algorithms? - An attempt to transfer the notion of intelligence to mathematical concepts.", in R. Holm-Hadulla, J. Funke, M. Wink (Eds.), Intelligence: Theoretical foundations and practical applications, Springer 2022, pp. 201-218.

T. Stiehl, A. Marciniak-Czochra. "Intelligente Algorithmen und Gleichungen? – Eine Annäherung an die Intelligenz mathematischer Konzepte", in R.M. Holm-Hadulla, J. Funke, M. Wink (Hrsg.). Heidelberger Jahrbücher online, Band 6, Heidelberg University Publishing, 2021, pp. 279-304.

J. Ottesen, T. Stiehl, M. Andersen. "Systems biology of blood cancer and immune surveillance", in O. Wolkenhauer (Ed), Systems Medicine: Integrative, Qualitative and Computational Approaches, Volume 3, Elsevier, 2021, pp. 261-268. 

A. Marciniak-Czochra, T. Stiehl. "Mathematical models of hematopoietic reconstitution after stem cell transplantation", in Model Based Parameter Estimation: Theory and Applications H. G. Bock, T. Carraro, W. Jäger, S. Körkel, R. Rannacher, J. P. Schlöder (Eds.), Contributions in Mathematical and Computational Sciences Volume 3, Springer, 2013.