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Laboratory of Molecular dynamics of the immune response

Head: Karel Drbal, PhD

Lab twitter: Image result for twitter logo link

News

 

Joe Song is a Fulbright scholar in our laboratory

 

Joe Song (Department of Computer Science, New Mexico State University) joined our lab from January to July 2019. He is specialized in statistical foundations for pattern discovery, data science algorithm design, and applications to molecular biological systems for molecular networks discovery in cancer, brain, plant, and microbe. Joe will be teaching the semestral course of "Single-cell data analysis" together with FEE CTU (FEL ČVUT).

Announcement - a new publication is out:

Second version of the preprint is out: April 8th, 2019. It has reached substantial attention: is in the 94th percentile: it's in the top 10% of all research outputs ever tracked by Altmetric.

Our new paper in collaboration with Miroslav Kratochvil is out - finally a preprint on bioRxiv on Dec, 20th, 2018. The development of a fast TDA (topological data analysis) based on FlowSOM clustering is suitable for high dimensional data visualization (clustering/embedding) - not just in biology. 
Algorithms EmbedSOM and DiffSOM are on GitHub.
Video showing the fast processing speed is on YouTube.

Long-term goals of the laboratory

comprise:

1/ understanding the dynamics of molecular switches within the immune system during the response towards continuous selection pressure of tumors and infectious diseases in vivo,
2/ the disease manipulation and modeling in vitro and in vivo, using all available technologies at the proteome level,
3/ supported by the in vitro evolution systems-based development of next-gen high-affinity binders specific for selected biomarkers of a particular human pathology and their fast transfer into a dedicated systems diagnostics in the clinical practice.

The main area of interest

is the visualization and manipulation of an immediate immune response to fast-evolving agents of cancer and infectious diseases plus the understanding of long-term adaptation of this mutual relationship at the molecular level.

Our immune system is continuously facing the selective pressure of dangerous substances in terms of toxins, pathogenic microorganisms and transformed tumor cells in our body and reacts accordingly. The natural role of the immune system is to effectively control body homeostasis in this microevolutionary process full of mutation events on both sides of the equation. Simply: keeping the balance and personal wellbeing.
The driving force of major human pathologies is a skewed chronic inflammatory status of the organism as a consequence of immune response deregulation. Here, the immune response is being actively modified by the pathology, it is not shut down while it clears the dangerous harmful agent from the body and thus generates the pathology itself or it is not capable of the destruction of the agent. The final result of the misbalanced reactivity is a disease - either a pathology associated with an inefficient response to infection/tumor growth or excessive response to innocent targets by fault (allergy and autoimmunity).

Molecular processes on the interaction borderline between the host immune system and the danger source (being either a pathogenic microorganism or a self tumor in my research projects) are extremely dynamic and show very high plasticity. These interaction events do occur frequently in our bodies, usually unseen and undetected. Our current understanding of these interactions is rather a primitive one - symptomatic and non-dynamic picture of long-term genome mutations and the presence/absence of specific end-point pathology. Modern immunology, on the other hand, focuses on quantitative parameters of immune reactions and their application in early disease prevention/progression leading to the wide array of systems approaches in precision medicine leading to personalized diagnostic and treatment modalities.

What we eagerly need are better tools.

My professional experience

First, most of my research career I generated and characterized binding reagents in the form of monoclonal antibodies in the Laboratory of Molecular Immunology, IMG AS CR and recently also their modern scaffold alternatives generated by molecular synthetic approaches using in vitro evolution systems.

Second, broad use of model systems: stem cells, tissue cultures, and xenotransplantation animal models - all that endow my laboratory with the essential technological and knowledge base for the research on the phenotypic events associated with the immune response at the molecular level in single cells.

During the years 2010-2013 I headed the R&D department of the Czech biotech company with the responsibility to optimize the development of monoclonal antibodies as well as non-antibody alternatives.

In the year 2013, I joined the Faculty of Science to focus on the study of early tumorigenesis/relapse of cancer and host response to the mutation events in pathogens and cancer cells. In particular, my main interest is focused on the most varying proteomes - the cell surface and the secreted ones. These changes dictate the functional outcome of intercellular interactions governing the efficient maintenance of the organismal homeostasis.

 

The ambition of the laboratory is to cover
3 fundamental and 1 accessory project areas

Two projects are devoted to understanding the dynamics of the counter immune response towards the escape mutation events within two types of human disorders - one infectious agent from the outside world and one originating from self tumor tissue. The technologies behind comprise multiparametric flow cytometry equipped with automated data analysis pipeline (unsupervised clustering/embedding algorithms) and sensitive 3D microscopy (including lightsheet and superresolution approaches). We are able to achieve a fast and precise description of patient sample heterogeneity and a direct pathogen or tumor-initiating cell detection in patient samples using both technologies.
The other two projects are more oriented towards biotechnology, leading to the development of modern types of binding molecules of high selectivity and specificity, coupled to the next-gen diagnostic tools:

  • Lyme borreliosis is the infectious prototype disease in my research. It is rather a frequent disease in the Western world with over 4000 cases/year in the Czech Republic. The current diagnostic methods suffer from low sensitivity and the absence of a gold standard method. Lyme borreliosis is still poorly diagnosed as a result.
    Spirochetes of multiple Borreliae spp. are the infectious agent which undergoes rapid phenotypic change during the infection in each patient. In contrast, the population analysis of Borreliae spp. in its natural vector shows tight geographic distribution and limited clade intermixing.
    The goal of this project is the development of new generation diagnostic tests based on the structural analysis of major pathogen virulence factors. These tools enable us to analyze the immune response dynamics of cellular reactivity in a model system and compare it with the standard clinical analysis of antibody response, which is not a causative readout during the course of the disease. Detection of a direct pathogen mutation rate in a single individual completes the dynamic picture of both interacting parties. Predictive value of novel tests will be tested under controlled clinical settings.

  • In tumor biology, I am mainly concerned with solid tumors of adulthood, preferentially of the most frequent epithelial cancers of bladder, lungs, and colon as well as melanomas, their comparative analysis of early tumorigenesis and relapse during in vivo progression in the patient and in parallel in the experimental model of zebrafish. The alternative in vitro system is based on 3D organoid cell cultures. My main research goal is the plasticity of the epithelial differentiation process in all directions, mainly towards the progenitor cells. These might be responsible for the tumor initiation as well as for the resistance to standard antitumor therapies. My objective is to detect and describe the function of cancer stem cells (CSCs). Primary material is tested for therapeutic sensitivity and for its in vivo tumor-initiating capacity in engraftment experiments of xenotransplantation models.
    The goal of this project is fast and early patient stratification with respect to treatment selection including modern alternatives, including immunotherapy.
  • In the field of technological advancement, I am involved in the development of novel synthetic alternatives of binding proteins (new endogenous and exogenous structures), their in vitro evolution using display technologies. Strong experimental background and computer prediction methods in collaborating laboratories build the framework of structure/function characteristics of each binding pair.
    The goal of this project is the development of proprietary libraries of binding proteins using a rapid iterative process of rational design and experimental confirmation, followed by competitive selection screens. Ultimately, the resulting highly selective, specific and high-affinity binding proteins are generated in the timeframe of several days. Such dedicated proteins are deployed in a highly parallelized system of proteomic tests in the clinical diagnostics.
  • Other technologies involve collaboration with technical-oriented research groups and comprise new solutions of microfluidic chips and static sensor technology, down to the level of single molecule detection. Strong features of the laboratory are the established state-of.-the-art technologies of microscopy, flow cytometry and sorting, cell manipulation using molecular biology, protein in vivo assays and interaction testing, all in a very sensitive fashion with high sample throughput.

What are your benefits after you finish the study?

The area of translational medicine in respect to the immune-related parameters of each individual shall become the driving force of personalized medicine in major diseases. Most human health threats originate in abnormal immune reactivity, being either inefficient or excessive. Currently, there are new laboratories or institutions starting to study phenotypic changes in organisms and patients using a systems approach.
It is absolutely essential to provide both research labs and clinical community with access to defined and high-quality binding reagents as tools for biomarker detection. This is the current hurdle of modern research, which must be solved.
Your involvement in the laboratory and the experience you gain here is a good basis for your personal scientific career. It allows you to apply for top positions in both academic and commercial arena worldwide in the fields of biomedicine, bioinformatics, and biotechnology.

The team

I have joined the faculty in March 2013 and I plan to build a strong research team aspiring for the Biocenter Campus Albertov position. Currently, I apply for the financial support in the EU and US including private resources and Czech application calls.

I accept applications from students, who became interested (more on thesis assignment, see SIS).

Team members:

Current PhD students:
Abhishek-Vallabhbhai Koladiya: Functional and phenotypic characterization of cancer stem cells of bladder carcinoma
Katarína Otavová, MD - Časná diagnostika a monitorace nádorů močového měchýře
Betül Melike Oğan - PřF UK - STARS pozice: Precision medicine approach to human carcinoma diagnostics: functional characterization of cancer stem cells

Current Mgr. students:
Petra Hadlová
Jaromír Novák
Michaela Šímová
Monika Smrčková

Current Bc. students:
Naďa Pravcová
Karolína Vaníčková
Alois Zdrha

Erasmus+ students:
none

Key collaborations:
Charles University (CUNI):
Dept. of Software Engineering (Faculty of Mathematics and Physics)
Dept. of Microbiology (Faculty of Medicine in Pilsen)
CLIP (2nd Faculty of Medicine)
local academic: IOCB ASCR, IMB ASCR, IMG ASCR, CEITEC, MUNI, ISI ASCR
local clinical: FTN, NNB, VFN, FNMOTOL (all Prague, CUNI), FN Brno (MUNI)
international: VIB Gent, MPI-CBG Dresden, EMBL Heidelberg, TUW Wien, MUW Wien
commercial: PROTEAN České Budějovice, PSI Drásov, EXBIO Praha

Alumni

My former students have been successful both in an academic career as well biotech:

Naďa Brdičková - CLIP, 2nd Faculty of Medicine, Charles University, Prague
Claudia Jursik - Bender MedSystems
Michaela Prchal-Murphy - University of Veterinary Medicine, Vienna
Elke Fürtbauer - N/A
Fridolin Müller - N/A
Wolfgang Paster - University of Oxford, Medical University od Vienna
Manuel Moertelmaier - Howard Hughes Medical Institute, Stanford Medical School; Operalgo; Keysight Technologies
Radek Blatný - CEBIOSYS, s.r.o, KRD s.r.o
Linda Turková - Apronex Praha s.r.o.
Lukáš Chmátal - UPenn, MIT
Jitka Šulcová - ETH Zürich, Roche Basel
Pavel Pitule - Faculty of Medicine in PilsenAbCheck
Matouš Hrdinka - the University of Magdeburg, University of Oxford, University of Ostrava

former students at the Faculty of Science, CUNI:
Nils Müller - Erasmus+
Meet-Sanjaykumar Jariwala - Erasmus+
Abhishek-Vallabhbhai Koladiya - Erasmus+ and MSc.
Ilaria Piga - Erasmus+ and MSc.
Kasper Sjodin - Erasmus+
Édel Álvarez Ochoa - Erasmus+ and Bc.
Nuria Andrés Sánchez - Erasmus+ and Bc.
Marc Zarzoso Rodriguez - Erasmus+ and Bc.
Lorena Meusel - Erasmus+ and Bc.
Clara Munoz Lopez - Erasmus+ and Bc.
Carla  Cruces Marques - Erasmus+ and Bc.

Research history

New publications 2018: bioRxiv - EmbedSOM data visualization
Publications: PubMed list of my publications

ResearcherID: G-9329-2011
ORCID ID: 0000-0003-4450-4625
Scopus Author ID:  6701440300
Google Scholar User: HFSJ7lEAAAAJ

Running grants:
Abhishek-Vallabhbhai Koladiya: GA UK project #1610218

Commercialized outputs:
(certified technology, pilot plant, prototype, utility model and industrial design, patent):
17 prototypes & 1 international patent

Other research and education activities (in Czech):

 

Faculty of Science education activity

(courses are managed within the Moodle environment, external Guests login without a password unless specified otherwise)

 

Contact coordinates

Laboratory: Vinicna 7, Prague 2, 1st floor, room 141

Office: Vinicna 7, Prague 2, 1st floor, room 143

E-mail: karel.drbal@natur.cuni.cz

 

Other personal information


Update: 9. 2. 2019

 

 

 

 

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