Building EU-level Hungarian Excellence in Molecular Medicine

Science

The Hungarian Center of Excellence for Molecular Medicine (HCEMM), with its headquarters in Szeged, is building a world-class European-level facility for research and development related to healthy aging. Whether you are a medical researcher looking for challenging opportunities, or a company in need of the right partners, the answers you are looking for may well be found in the south of the country.

Supported by the European Union’s Horizon Program and the Hungarian National Laboratory and Thematic Excellence Programs, HCEMM is driving innovation in so-called translational medical research, which aims to convert basic research into medical applications.

With the backing of the Heidelberg-based European Molecular Biological Laboratory (EMBL) as its advanced partner, HCEMM is bringing tried and tested European-level institutional research and expertise to Hungarian life sciences.

R&D at HCEMM is carried out by Research Groups and Advanced Core Facilities (ACFs). The main focus is on healthy ageing. To administer the program, HCEMM Ltd. was incorporated by the Biological Research Center Szeged (BRC), the Semmelweis University in Budapest and the University of Szeged and took over administration for the so-called EU Teaming Grant from the National Research, Development and Innovation Office.

The Hungarian Center of Excellence for Molecular Medicine received National Laboratory status in Hungary in 2020. It is the third EMBL partnership in molecular medicine, meaning the center can access a network of partner institutes of excellence in the life sciences. Besides opportunities for scientific collaborations, the framework also allows HCEMM to participate in EMBL Partnership Conferences, open to partners only, as well as other events.

A vital component of the operational model for HCEMM is the development of its ACFs. The main goal is to ensure the efficiency of HCEMM’s research groups is increased in terms of excellence (output of high-quality scientific papers) and sustainability (ability to generate income by competitive grants, spin-offs, and technology transfer agreements), but each of HCEMM’s owners also utilizes the ACFs.

The core facilities present a range of services tailored to the requirements of the researchers. It also acts as an EU-level infrastructural, competence and training base that offers its capacities for any Hungarian and EMBL partner researcher, as well as external industrial users.

The ACFs connect with their European Molecular Biological Laboratory counterparts and work together on projects throughout the entire European network. The idea is to do as much as possible in Hungary but use the help of EMBL for specific specialized tasks for which the infrastructure is currently not available here.

Hungarian scientists travel to EMBL facilities regularly and several larger projects are now evolving that, over time, should be able to continue as EU-funded joint projects.

HCEMM ADVANCED CORE FACILITIES

HCEMM-USZ IN VIVO IMAGING ACF

Facility Head: Domokos Máthé DVM PhD

The In Vivo Imaging Advanced Core Facility of HCEMM was set up with the aim of providing all the expertise, tools and possibilities for any principal HCEMM investigator to obtain inside, quantitative information on biodistribution of drugs, biochemical processes in different organs, and organ functions as a whole.

Domokos Máthé, the head of the facility explains that In Vivo images are created using anatomical and functional measurements (MR, CT, fluorescent or bioluminescent) of reporter genes and fluorescent proteins, as well as the most sensitive isotope-based tracer measurements using PET and SPECT. The ACF offers very high resolution in all types of imaging. In terms of optical imaging, unprecedented soft tissue penetration capabilities are available.

The ACF offers its expertise in isotopic measurements (a biochemical kinetic measurement that requires special data analysis technique encompassing physics and knowledge of measurement physics with medical imaging systems) to investigators interested in measuring therapeutic or disease models.

“We help investigators mechanistically understand different processes of cellular compartments in the intrinsic complexity of an organism,” says Máthé. “We provide a reproducible and robust measurement where one animal serves as its own control over time, because we can repeatedly measure a therapeutic drug with regards to its distribution and effect, or the effect of a gene knockout in the same organism over an extended period.”

He says the ACF has a decade of experience in radiomic data extraction of images and in the algorithm and code development for multidimensional large image data analysis and decision support sytems. Imaging measurements of preclinical models at the ACF are directed towards easy and quick translation of the given biomedical solution to the clinical domain.

HCEMM-BRC SINGLE CELL OMICS ACF

Facility Head: Zsuzsanna Darula PhD

Led by Zsuzsanna Darula, the Single Cell Omics ACF provides high quality multi-omics (biological analysis) services to HCEMM research groups, academia and industrial partners. The facility is equipped with high resolution mass spectrometers suitable for a broad range of applications including protein identification, relative protein quantification, phosphorylation analysis, and identification of protein interacting partners using co-immunoprecipitation.

Characterization of purified proteins, de novo peptide sequencing, protein crosslinking experiments and molecular mass determination of purified single-protein samples are available upon request. High-pH chromatographic fractionation for more comprehensive analysis of complex biological samples is also available. The ACF also provides assistance in study design and performing data analysis and storage.

Uniquely in Hungary, the ACF can also provide comprehensive shotgun lipidomic analysis with identification and quantification of hundreds of lipid species including principal phospholipid, sphingolipid and neutral lipid classes.

Finally, the ACF offers single cell transcriptomics services. Innovative single cell technology is used in combination with Illumina next generation sequencing. Unlike conventional bulk sequencing, it can detect rare cell types, uncover tumor heterogeneity, trace lineages, discover drug-resistant cell populations, and characterize complex cell populations such as immune cells in peripheral blood.

HCEMM-USZ FUNCTIONAL CELL BIOLOGY AND IMMUNOLOGY ACF

Facility Head: Ferhan Ayaydin PhD

Under the supervision of Ferhan Ayaydin, the Functional Cell Biology and Immunology ACF provides state-of-the-art infrastructure and extensive know-how for high-resolution advanced confocal laser scanning and electron microscopy imaging services, detection of cell surface markers and intracellular markers, as well as the possibility for sorting cells based on their expressed protein markers for cellular and immunology studies.

The ACF can produce multi-coloured, three-dimensional, and extremely clear images with its latest generation laser scanning confocal microscope. It also has access to an incubator type, live cell analysis microscope suitable for temperature-controlled long-term observations of proliferating and differentiating cells and tissues. The ACF offers imaging of medical, biological, and pharmaceutical samples in the nanometer to millimeter range with the help of scanning electron microscope and various laser scanning confocal microscopes.

Unique to the region, the four laser and four detector cell sorter system at the ACF can simultaneously sort and enrich four different types of cells under aseptic conditions from a mixed population such as blood samples. Immunological analyses or cell division cycle population analyses, separation and enrichment of specific cell types are among the scientific applications that may be performed with the cell sorter.

HCEMM SCIENTIFIC COMPUTING ACF

Facility Head: Gergely Röst PhD

The explosion of the amount of data generated in biomedicine necessitates the application of advanced computational tools. The facility headed by Gergely Ršst supports HCEMM-affiliated research groups and external partners in their computational, modelling, and statistical needs to make the most of insights from their experimental data.

The ACF aims to develop and implement new tools for efficient data collection, generation, storage, processing, mining, analysis, and presentation to enhance the scientific output from quantitative life science research. The support provided by the ACF starts with consultations for experiment planning to ensure that the output will have sufficient statistical power. Throughout a research project, the ACF can assist with mechanistic modelling of biological phenomena as well as high resolution computer simulations.

Once data is collected, cutting-edge data science methods can be applied, including machine learning and AI, to uncover patterns in the data, understand relationships, generate novel biological hypotheses, and create predictive models. With the help of a EUR 500,000 infrastructure investment, the computational capabilities of the ACF will reach full capacity in 2023.

HCEMM RESEARCH GROUPS

HCEMM HUMAN NEURON PHYSIOLOGY AND THERAPY CORE GROUP

Group Leader: Karri Lämsä PhD

Finnish researcher Karri Lämsä investigates human neuron phenotypes in their function, structure and molecular profile. The group aims to identify neuronal features specific to humans and investigate their significance in physiological aging and pathological processes to find their therapeutic potential against neurodegenerative diseases.

Lämsä considers Hungary a great place to live and work for people in scientific R&D as the field is well supported by national funding programs. Because Hungary is part of the European Union, scientists can apply to various EU-funded research programs, such as Horizon Europe.

“Another great aspect I have noticed as an expat here is that science, research and development generally are well appreciated. In many countries, the media closely follows sports, politics, arts and culture, but in Hungary, science is also visible in the media,” says Lämsä.

“The visibility of R&D in media also makes it easy for us to explain the significance and impact of our job to the general public. This is very important in many ways: it is important that people know what we do, why we do it and how our work can possibly improve their everyday life and benefit business development in Hungary,” he explains.

HCEMM-SU NEUROBIOLOGY AND NEURODEGENERATIVE DISEASES RESEARCH GROUP

Group Leader: Karolina Pircs PhD

The main goal of Karolina Pircs’ Semmelweis University-based research group is to study a process called autophagy during healthy physiological brain aging and also under pathophysiological conditions. Autophagy (a lysosomal degradation pathway that ensures cytoplasmic homeostasis) declines during aging and age-related neurogenerative diseases. However, limited knowledge is available about how this decline causes cellular dysfunction and neuronal death.

The group aims to understand how and why neurons age during normal, physiological and during pathophysiological, age-related, currently uncurable neurodegenerative diseases.

In collaboration with other researchers during her postdoctoral years at Lund University in Sweden, Pircs has developed an induced neuronal model relying on transdifferentiation (also known as direct reprogramming) where patients skin cells are reprogrammed into neurons that keep the aging signature of the donor; basically, they study human-derived “aged” cells.

Fibroblasts are taken from healthy and diseased patients of various age groups. These cells are then cultured and converted via induced neuronal conversion to contain the aging signatures of the donors. With this methodology, thousands and thousands of human neurons can be generated easily and efficiently. The technique offers a novel source of cells that can be used to study aging-related neurogenerative diseases such as Parkinson’s, Alzheimer’s and Huntington’s disease.

The model can be used as a new drug screening platform for age-related cognitive disorders. The reprogramming methodology can provide a new, robust, quick, and easily reproducible drug screening method for novel drug identification and validation which, if successful, can help delay the onset or prevent age-related neurodegenerative disorders.

HCEMM-USZ CEREBRAL BLOOD FLOW AND METABOLISM RESEARCH GROUP

Group Leader: Eszter Farkas PhD, DSc

The Farkas Group studies cerebral blood flow. Strokes, which occurs due to the obstruction of a blood vessel supplying the brain, can cause life-long disability, and are the third leading cause of death after cancer and cardiovascular disease.

Between 40,000-50,000 new stroke cases are registered annually in Hungary, which translates to a new stroke attack every 10 minutes. Worldwide, one in every six people suffers a stroke at one point over their lifetime. Aging is a very significant risk factor for strokes, and stroke incidence increases exponentially after the age of 50. With Western societies aging, strokes are expected to affect increasingly more people and to pose an accumulating burden on health care.

Strokes have a high mortality rate. In Hungary, a stroke-related death occurs every half an hour. Mortality is particularly high when a stroke is accompanied by brain edema formation. The primary intervention to alleviate stroke symptoms is the removal of the clot obstructing a brain blood vessel either by non-invasive thrombolysis or invasive thrombectomy. Yet, medical stroke guidelines do not consistently list edema treatment as part of standard or personalized care.

Research is being done to better understand the underlying cellular mechanisms of brain edema formation and the associated progressive brain injury in stroke. New revelations shed light on the crucial role of astrocytes (specialized cells that provide physical and chemical support to neurons) in the maintenance of brain equilibrium. Some data shows that astrocytes represent the most numerous cell population in the brain, even outnumbering neurons.

The rapid swelling of astrocytes after the onset of stroke is thought to initiate a process known as reactive astrogliosis. The astrocytes produce substances which tip the balance towards neuronal death as opposed to neuronal survival. The swelling also increases the excitability of the nervous tissue, causing overstimulation of neurons. The ensuing impairment of the effective regulation of cerebral blood flow disrupts the blood-brain barrier and sets the stage for the formation of vasogenic edema.

The supposition is that the swelling of astrocyte cells is the initial step towards the dysfunction of the blood-brain barrier and the later development of malignant brain edema. The Farkas Group set out the identify the blood serum biomarkers indicative of astrocyte swelling. Successful detection of these could predict the later formation of malignant brain edema, which should offer the possibility of timely, targeted and non-invasive preventive measures.

“Taken that edema formation is a very serious complication of stroke, the goals of our research efforts include i) understanding cellular processes that cause brain edema formation and the loss of brain tissue after stroke, and ii) identifying targets to prevent brain edema formation and brain injury progression after stroke,” says Farkas.

HCEMM-SU MOLECULAR ONCOHEMATOLOGY RESEARCH GROUP

Group Leader: Csaba Bödör PhD

Csaba Bödör’s HCEMM-affiliated Semmelweis University research group is interested in a subgroup of hematological (or blood disorder-related) malignancies, the so-called B-cell lymphomas. These represent a heterogeneous group of diseases with highly variable clinical outcomes.

Although the recent introduction of targeted therapies has led to significant improvements in the chances of survival, a specific subset of patients develop resistance which ultimately results in them succumbing to the disease. There is, therefore, a clear unmet clinical need for novel molecular biomarkers successfully guiding the application of targeted therapies.

The group has a hypothesis that currently available diagnostic methods of B-cell lymphomas do not take into consideration the genetic heterogeneity of the tumors. In a response to this issue, liquid biopsies, namely the plasma-derived, cell-free circulating tumor DNA (ctDNA) has emerged as a novel non-invasive tool for precise genomic profiling and diagnosis and for sensitive response monitoring to the extent that it is also suitable for the detection of resistant subclones.

Bödör says he is fortunate to work with a group of highly motivated and talented young scientists.

“Utilizing advanced genomic technologies such as next generation sequencing, digital droplet PCR as well as spatially resolved transcriptomics, the Research Group aims to identify novel biomarkers associated with therapy response and resistance. The clinically applicable tools developed under this translational research program support more accurate risk stratification and the individualization of therapies for patients with B-cell lymphomas,” he explains.

HCEMM-BRC PHARMACODINAMIC DRUG INTERACTION RESEARCH GROUP

Group Leader: Viktória Lázár PhD

The Lázár Group studies how drugs combine to affect bacterial population clearance and persistence by combining high-throughput drug interaction screens, genome engineering and systems biology approaches.

Through a novel procedure, Viktória Lázár has shown that using multiple antibiotics at once often proved to be inferior to the success of each individual drug. Combination antibiotic therapy is recommended for many life-threatening infectious diseases such as tuberculosis or polymicrobial septic infections because combinative therapy is believed to enhance individual antibiotic effects despite an overall lower dose.

Lázár’s revelations have shown that combined use of antibiotics may often harm the long-term effectiveness of the treatment by increasing the number of so-called persistent bacteria that can survive the treatment until the antibiotics are gone. However, they point to specific combinations of antimicrobial agents that do manage to destroy the resistant bacteria orders of magnitude more efficiently than their sensitive counterpart. Determining and utilizing these newly discovered differentially selective drug combinations can help prevent the spread and continuous evolution of drug resistant bacteria, easing the ever-increasing pressure of having to develop new antibiotics because of widespread antibacterial resistance.

The HCEMM-BRC Pharmacodinamic Drug Interaction Research Group aims to systematically explore the map of interactions between pharmaceuticals and bacteria, paving the way for novel, personalized antimicrobial therapies where treatment could specifically target resistant bacteria, or take into account how medication that the patient takes daily affects the efficacy of the antibiotics that are used.

This article was first published in Invented in Hungary 2022-2023 on December 2, 2022.

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