Research / 16.07.2021
The new old-fashioned way
When Rudolf Virchow started studying medicine in Berlin in October 1839, the theory of the four humors of antiquity was still the mainstay of medical belief. Barely two decades later, the textbooks had to be rewritten: Virchow, who had since received his doctorate in medicine, succeeded in showing that the entire human body consists of cells – tiny units that can undergo disease reflecting morphological alterations.. Virchow’s revolutionary “cellular pathology” offered an entirely new understanding of causes of disease. His teachings, valid to this day, laid the foundation for modern, science-based medicine.
And yet, by today’s standards, the prerequisites for such a momentous discovery were modest. Virchow examined tissue samples under a simple microscope with the aid of a mirror and sunlight. To make cell structures visible, he stained tissue with dyes mixed together for him by chemists. Using this method, the “father of cellular pathology” managed to diagnose 20 diseases, including leukemia and thrombosis.
21st century physicians and scientists still use staining techniques to identify morphological patterns of cells, the detailed diagnosis of cancer being a prominent example. Only today, the dyes are fluorescent and the equipment differs somewhat from that of the 19th century. A glance at the Screening Unit at the FMP in Berlin-Buch shows just how far things have progressed: The state-of-the-art technology features a fully automated confocal microscope equipped with two cameras that automatically records 1,000 morphological characteristics for each individual cell. Given that almost 400 experiments can be performed simultaneously on one test plate (the FMP compound library has 200 of them), no fewer than 400 million data sets are generated in one run per single test plate alone. Not even a mastermind like Rudolf Virchow would have been able to analyze such huge volumes of data. The high-resolution microscope is therefore connected to a fleet of supercomputers that use artificial intelligence to detect tiny changes in cells and assign them to specific classes or diseases.
“We work in the tradition of Virchow, but using computer power that was unimaginable back then,” explained Dr. Jens von Kries, Head of the Screening Unit. “Virchow 2.0” is the term he gives to the concept of computer-aided pattern recognition, which is ideal for both drug discovery and disease diagnosis.
The team led by von Kries is currently using the new technology for cell toxicity profiling. The researchers want to find out which of the 70,000 chemical substances in their compound library are toxic. This classification should make drug screening assisted by robotic arms even more efficient
in the future. “Virchow 2.0” is soon to be used for personalized medicine. When cancer patients have developed resistance to drugs, for example, researchers can use tissue samples to search for alternative medications. Requests to this effect have already been received from Virchow’s long-time workplace – Charité. According to Jens von Kries, there are plans for further fields of application, and machine pattern recognition still has further potential.
“Virchow pushed the boundaries,” he remarked, “and we are trying to do the same using current technological means.”
Translation: Teresa Gehrs
Research / 05.07.2021
A glitch in the heart’s protein factory
MDC researchers have discovered a previously unknown cause of cardiac hypertrophy. As they report in the journal “Genome Biology”, genetic variation results in heart cell ribosomes not working properly. This disrupts protein production, which in turn causes the heart to grow too large.
An abnormal increase in heart muscle mass is considered the most common cause of sudden cardiac death. Now, a team of scientists led by Professor Norbert Hübner, head of the Genetics and Genomics of Cardiovascular Diseases Lab at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) in Berlin, has figured out what’s behind this hypertrophy. Another MDC research group – the “Non-coding RNAs and Mechanisms of Cytoplasmic Gene Regulation Lab”, led by Dr. Marina Chekulaeva – was also involved in the study.
The scientists have uncovered a complex molecular mechanism that interferes with the overall protein production in the ribosomes of heart cells. As a result, the heart does not get the proteins it needs. This production defect, in turn, promotes abnormal growth of heart muscle cells. The study, which involved 19 researchers from six countries, has been published in the journal “Genome Biology”.
The entire protein production is impaired
“We wanted to find out how natural genetic variation, which is present in every living being, can contribute to the development of complex diseases,” says Dr. Sebastiaan van Heesch, who is the study’s co-last author along with Hübner. Until June 2020 the Dutchman was a postdoc in Hübner’s lab at the MDC. He has since set up his own lab back in his home country, at the Prinses Máxima Center for Pediatric Oncology in Utrecht.
“It was already known that differences in the genome can influence whether and how genes are read in the cell nucleus,” says van Heesch. This process, known as transcription, is the first step in protein production. Scientists were also aware that certain changes in the DNA can lead to the production of defective heart proteins. “But the fact that genetic variants can affect the heart’s entire protein production by interfering with cellular protein factories – the ribosomes – was new and rather surprising,” says van Heesch.
Particularly devastating for long proteins
“In our study, we worked with a group of rats for which we know all the genetic variants and we also know that about half of the animals in this panel of hybrid strains develop heart disease,” reports Dr. Jorge Ruiz-Orera, a scientist from the same group. Ruiz-Orera is co-lead author of the study along with Dr. Franziska Witte, who was a doctoral student in Hübner’s lab during the first years of the study and now works at the Berlin-based research firm Nuvisan.
“To find out more about the reasons behind the rats’ cardiac hypertrophy, we looked for a link between the animals’ DNA and the function of their ribosomes. That’s where translation, or protein production, takes place,” says Ruiz-Orera. The researchers also examined whether errors in protein production could be related to the known enlargement of the hearts.
In these investigations, the team came across an altered region in the rats’ genome that results in a defect in overall protein synthesis. However, this defect affects long and short proteins differently. “The effect is not as devastating in short proteins,” explains Ruiz-Orera. “But long proteins, such as the important muscle protein titin, are produced much less efficiently. We were able to show that this has a negative effect on the assembly of sarcomeres, the smallest functional unit of the muscle fiber.” Ultimately, this defect leads to a thickening of the heart chambers and heart failure.
Similar effects even seen in yeast cells
“What is especially remarkable is that similar genetic variants also have the same effects on protein synthesis in other species – for example, in mice, humans, and even in unicellular organisms like yeast,” reports Hübner. This shows, he says, just how widespread the genetically determined defect is in the cellular protein factories, how little it has changed over the course of evolution, and how important a role it plays in the development of complex diseases that also affect humans.
“The mechanism we uncovered may explain why some people are genetically predisposed to develop cardiac hypertrophy,” says Hübner. “In addition, our work lays the groundwork for future studies on the genetic predisposition to complex diseases that can affect organs other than the heart.”
Text: Anke Brodmerkel
- Van Heesch Lab at the Prinses Máxima Centrum für Pädiatrische Onkologie in Utrecht
- Unknown mini-proteins in the heart
- Hübner Lab
- Genetics and Genomics of Cardiovascular Diseases
Franziska Witte, Jorge Ruiz-Orera et al. (2021): “A trans locus causes a ribosomopathy in hypertrophic hearts that affects mRNA translation in a protein length-dependent fashion”. Genome Biology, DOI: 10.1186/s13059-021-02397-w
Research / 17.06.2021
Probing deeper into tumor tissues
Researchers at the MDC, the BIH and Charité have developed methods for performing comprehensive analyses of fixed tumor tissue samples. These analyses make it possible to shed new light on the clinical course of various cancer types, as the team reports in Nature Communications.
Today as they did 100 years ago, doctors diagnose cancer by taking tissue samples from patients, which they usually fix in formalin for microscopic examination. In the past 20 years, genetic methods have also been established that make it possible to characterize mutations in tumors in greater detail, thus helping clinicians select the best treatment strategy.
Even tiny tissue samples can be used to detect proteins
Now, a group of researchers from the Berlin-based Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), the Berlin Institute of Health (BIH), Charité – Universitätsmedizin Berlin and the German Cancer Consortium (DKTK) have succeeded in analyzing in detail more than 8,000 proteins in fixed samples of lung cancer tissue using mass spectrometers.
“Using the methods we have developed, it has become possible to conduct an in-depth analysis of molecular processes in cancer cells at the protein level – and to do so in archived patient samples that are collected and stored in large numbers in everyday clinical practice,” says Dr. Philipp Mertins, head of the Proteomics Platform at the MDC and the BIH. “Even very small tissue samples, such as those obtained in needle biopsies, are sufficient for our experiments.”
The study, published in the journal Nature Communications, is considered a major success for the Multimodal Clinical Mass Spectrometry to Target Treatment Resistance (MSTARS) research project, which has been funded by the German Federal Ministry of Education and Research (BMBF) to the tune of around €5.7 million since 2020.
The team of researchers, led by Mertins and Professor Frederick Klauschen from the Institute of Pathology at Charité, has been able to show that proteins – unlike the frequently studied yet quite sensitive RNA molecules – remain stable in the samples for many years and can be precisely quantified. “In addition, the proteins that are present in the tumor tissue map disease progression especially well,” says lead author Corinna Friedrich, a PhD student in the labs of Mertins and Klauschen. “This is because they provide information about such things as which of the genes that promote or inhibit tumor growth are particularly active in the cells.”
The methods promise to help identify the best treatment for each tumor
The picture gained from the team’s analysis of two forms of lung cancer – adenocarcinomas and squamous cell carcinomas – has also become so detailed because the researchers have not only uncovered a great many of the proteins present in the cell, but have also quantified more than 14,000 phosphosites. With the help of phosphorylation, a mechanism that regulates the reversible attachment of phosphate groups to proteins, the cell controls almost all biological processes by switching certain signaling pathways on or off.
“Our paper thus provides a good basis for gaining a better understanding of disease progression in lung cancer and also in other types of cancer,” says Klauschen, who, along with Mertins, is co-corresponding author of the study. Klauschen has since become director of the Institute of Pathology at Ludwig-Maximilians-Universität München, but continues to conduct research at Charité. “The methods we have developed will also enable us to better explain in the future why a very specific therapy works for some patients but not for others,” adds the pathologist. This will, he says, make it easier, to find the best treatment option for each patient.
Methods also suitable for researching cardiovascular diseases
Mertins also hopes that the mass spectrometric analysis of the proteome in tissue samples will pave the way for the discovery of not only new biomarkers for therapeutic decisions and patient survival predictions, but also other molecular structures that could serve as targets for future drugs.
And, according to the researcher, there is yet another plus to the new approach: “Our methods are not only suitable for researching cancer, but can also be applied very broadly.” For example, the Proteomics Platform has already successfully analyzed the proteome of fixed immune cells from COVID-19 patients. The authors have also provided guidelines on which mass spectrometric methods are best suited for different types of clinical studies.
Next on the agenda for the MDC platform is the mass spectrometric analysis of additional fixed immune cells as well as fixed cardiovascular tissue for the presence of proteins and phosphosites. “The aim here is to get a better understanding of infectious and cardiovascular diseases,” explains Mertins, “so that one day it might be possible to treat these diseases in a much better way than has so far been the case.”
Text: Anke Brodmerkel
Corinna Friedrich et al (2021): “Comprehensive micro-scaled proteome and phosphoproteome characterization of archived retrospective cancer repositories,” in: Nature Communications, DOI: 10.1038/s41467-021-23855-w
Source: Joint press release by the MDC, the BIH and Charité
Research / 14.06.2021
$7 million to advance cardiovascular research
Diverse messenger RNAs are produced in cells by “alternative splicing.” The Leducq Foundation is now supporting a transatlantic network dedicated to investigating this process in heart muscle cells and how changes in this process contribute to disease. Professor Michael Gotthardt of the MDC and Professor Leslie Leinwand of the University of Colorado Boulder are coordinating the project.
Despite advances in prevention and therapy, cardiovascular diseases are still one of the leading causes of death worldwide. Scientists have only recently begun to understand the key role of alternative splicing – the “stitching together” of messenger RNA during gene transcription – in cardiovascular diseases. The Leducq Foundation is providing 7 million U.S. dollars over the next five years to support the Cardiac Splicing as a Therapeutic Target (CASTT) project, which is comprised of six European and U.S. researchers. They will focus on examining the regulation and disease relevance of alternative splicing in different types of heart cells.
“Our goals include mapping the path from splicing factor discovery to drug development, and creating a database that will make it easier in the future to incorporate complex splicing information into heart disease diagnostics,” says Professor Michael Gotthardt, group leader at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) and the European coordinator of CASTT. Professor Leslie Leinwand, biologist and founder of several successful BioPharma companies who is the North American Coordinator adds: “The Leducq Foundation allows us, as scientists and clinicians, to think outside the box of what is traditionally considered effective treatments for heart disease. It enables us to connect different research directions from animal models to patients with innovative genomic and computational approaches."
Other network members include Professor Euan Ashley, a cardiologist at Stanford University; Professor Maria Carmo-Fonseca, a cell and oncobiologist at the University of Lisbon; Professor Benjamin Meder, a cardiologist at Heidelberg University Hospital; and Professor Lars Steinmetz, a geneticist at the EMBL Heidelberg and Stanford University.
Splicing errors can cause heart disease
Heart muscle cells require a variety of proteins so that they can develop, contract, transmit electrical impulses to neighboring cells, and respond to external influences such as stress. The blueprints for producing these proteins are contained in the genes and are transcribed into messenger RNA (mRNA), which then carries this information to the cell’s protein factories – the ribosomes.
Some cells, especially those of higher organisms, use a trick to produce a wide variety of protein molecules. The genes of these cells do not only encode one particular protein, but
can serve as the blueprint for several proteins. Genes usually contain alternating coding segments called exons, and non-coding regions called introns. The latter can be removed as needed during transcription, while exons can be linked together in a variable fashion. This creates mRNAs with different exon compositions. This process, known as “alternative splicing,” is executed by the spliceosome – a complex machinery made up of splicing factors and splicing regulators. Errors in the splicing process can lead to heart disease. “While remodeling processes dominate in the embryonic heart, allowing the heart to grow and mature, the most important processes at work in the adult heart are those that ensure effective pumping,” explains Gotthardt. “In diseased hearts, however, we see gene expression patterns that partly transition back toward the embryonic state in terms of protein formation. As a result, the heart no longer operates within the normal range.”
A heart for large meals
The researchers work both clinically as well as experimentally with human cell lines, artificial heart tissue, and animal models. In addition to mice, this includes Burmese pythons, because this powerful strangler is one of only a few living creatures capable of rapidly growing the size of its heart – within a day of swallowing its large prey. This increases blood flow and speeds up the distribution of nutrients throughout the reptile’s body. The organ then shrinks back to its original size when digestion is completed. “We want to elucidate the very specific regulation of splicing processes in the python heart because we think these findings could be of therapeutic use – for example, in patients suffering from hypertrophic cardiomyopathy, which involves a thickening of the heart muscles,” says Leinwand, chief scientific officer for the BioFrontiers Institute at University of Colorado Boulder.
The Leducq Foundation was created in 1996 in Paris by industrialist Jean Leducq and his wife Sylviane to drive forward transatlantic collaboration on cardiovascular disease and stroke research. Since then, the foundation has supported more than 70 international networks in these areas, involving more than 800 investigators at more than 100 institutions in 25 countries.
Text: Catarina Pietschmann
Source: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
Research, Innovation, Patient care / 10.06.2021
Founder Kieback gets T-knife off to a flying start
Best-funded start-up in Germany’s biotech sector
A young Berlin-based company called T-knife is a rising star in Germany’s biotech sector. Co-founder Dr. Elisa Kieback, along with colleagues, has catapulted the joint spin-off from the MDC and Charité to the top of the German biotech start-up universe.
Dr. Elisa Kieback says, for about a year, she has felt like “she’s on a rocket launch pad.” In 2015, the now 40-year-old researcher and entrepreneur teamed up with Professor Thomas Blankenstein of the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) and Holger Specht, Investment Director at IBB Beteiligungsgesellschaft, to found T-knife as a spin-off from the MDC and Charité. This leap from science to business was preceded by almost 20 years of basic research at the MDC – that’s how long Blankenstein has been working to realize his vision of curing cancer with the help of genetically modified immune cells, known as T cells.
For about ten years Blankenstein carried the idea of a spin-off around with him. He met Elisa Kieback in 2004 when he served as the second examiner for her doctoral thesis. “She is an exceptionally intelligent, motivated, organized and hard-working young scientist who has dedicated herself to T-cell receptor (TCR) gene therapy,” is how Blankenstein describes his co-founder. In 2015, the biologist moved from Professor Wolfgang Uckert’s lab to Blankenstein’s team and coordinated the first clinical trial on TCR gene therapy, which began in January this year at Charité –Universitätsmedizin Berlin. “When she learned that I was planning a spin-off from the MDC, she was eager to be part of it. I immediately agreed, and it is a decision I’ll never regret,” Blankenstein recalls. The name T-knife is as old as the founding idea itself. It is derived from genetically modified T cells – cells of the immune system – that are designed to cut tumors from healthy tissue much like a precision surgical knife.
Until 2018 T-knife existed only on paper. “Setting up the company as a joint venture was important because it allowed us to take the first organizational steps, such as hiring a law firm,” says Kieback. Then the founders converted T-knife into a limited liability company, Holger Specht dropped out and the technology transfer company Ascenion stepped in. The venture capital firms Boehringer Ingelheim and Andera Partners provided €8 million in initial financing. This enabled Kieback to hire a team of 15 employees and set up the first independent offices and labs on the Berlin-Buch campus. In 2020, she launched a second round of financing and raised an impressive €66 million – again from Andera Partners and Boehringer Ingelheim but also from US-based venture capitalists Versant Ventures and RA Capital Management. That made T-knife the best-funded start-up to date in the German biotech sector. She also brought Thomas Soloway on board as chief executive officer and Camille Landis as chief financial officer. Kieback herself is chief technology officer, which means she oversees product and platform development, while Blankenstein sits on the supervisory board.
There has been no stopping T-knife ever since. Being well-funded enables Kieback and her team to search for more TCR candidates to fight different types of cancer. The researchers have discovered several promising antigens that appear in tumors. “We will now produce and test suitable receptors,” says Kieback. Yet the 450-square-meter-space that T-knife moved into on the Berlin-Buch campus is starting to get cramped. At the end of 2020, 20 people were working there. That number grew to 40 by the first half of 2021. “The number will double again by the end of this year,” Kieback estimates. Besides, T-knife is opening a new office in Berlin-Mitte for the team responsible for clinical trials.
Off to the U.S. – and around the globe
T-knife has also set up a presence in the biotech stronghold of San Francisco. For one thing, most of the capital invested in T-knife comes from the United States. “If we want to take a long-term view and position ourselves well for further rounds of funding or for an IPO, then we have to be attractive to U.S. investors,” Kieback explains. For another thing, she is seeking to conduct clinical trials in U.S. hospitals. “The United States currently has more scientific expertise in advancing T-cell therapies into clinical trials compared to Germany,” she adds. Last but not least, Kieback hopes this move will lead to faster approval and quicker access to the U.S. market.
But that doesn’t mean she’s turning her back on Germany. “Berlin has a lot going for it as a science city,” Kienback enthuses, adding that the numerous universities and research institutes and the research hospital Charité produce many researchers that T-knife can recruit. San Francisco, she says, is the key to breaking into the U.S. market – but Kieback wants to enter the global market.
A unique technology with huge potential
She is confident this goal can be achieved. “The technology Thomas Blankenstein developed is unique,” she explains confidently. “Even people without a background in biotech recognize very quickly that it’s something very special and novel – with great potential both medically and economically.” It was this fact, Kieback says, that enabled her to win over investors. She also knows it would have been impossible without the large injection of money. “This form of therapy is very capital-intensive,” she explains. The German Federal Ministry of Education and Research provided €4 million in funding for the clinical trial that she got up and running at Charité. “That seems like a lot, and it’s great support,” she says. “But in the field of cell therapeutics, that amount doesn’t go very far if you want to develop a real product that will benefit a large number of people.” The clinical trial, the monitoring, the production of the patient-specific cell products – that’s completely new territory and extremely costly. “Because of the need to raise money for further development,” she says, “we had no choice but to start the company.” Financing is now in place until 2023.
Inventors need entrepreneurs
Kieback is totally comfortable in her new role as an entrepreneur. She is also convinced that the research world “needs to be more open to the fact that entrepreneurship is necessary if inventions are to make the leap from research to practice.” Besides, she continues to do research, albeit with a different focus: away from basic research, which formed the basis, and towards new product candidates and ultimately new therapeutics.
She has always wanted to go into research, so she decided to study biology in Heidelberg after finishing her Abitur. After an Erasmus year in Scotland, Kieback wrote her thesis at the German Cancer Research Center (DKFZ). In 2004, she applied for the PhD program at the MDC in Uckert’s research group on cellular gene therapy. “Gene therapy absolutely fascinated me,” she says. “Back in the 2000s, there was a lot of hype about the possibility of curing diseases by fixing broken genes and inserting new genes into cells. That’s what I wanted to do.” For her doctoral work, she developed a sort of safety switch that can stop cell and gene therapy if there are any unwanted side effects.
A role model for women in science and business
At some point she decided explore new career paths, leading her to apply for a study coordinator position in Blankenstein’s research group. “It was an all-around job and had the great advantage of providing a glimpse into many areas,” she recalls. When she heard of Blankenstein’s spin-off plans, she was immediately excited and eager to get on board. She enjoys building teams, identifying strengths and weaknesses, and encouraging and supporting people in their careers. One thing is very important to her: “Being a role model for women in science and business. I never thought I’d care about this, but my experience at T-knife has shown me how much it matters.” She is also keen to find out if the T-knife technology really works for patients. That is something only clinical data will tell. “We are committed to creating the best possible conditions for testing our platform in an optimal way. That’s what’s been driving me,” she stresses.
The breathtaking pace at which T-knife is growing requires constant change. You need a good amount of perseverance. Kieback admits that it is not always easy to manage if the number of employees doubles – from 20 to 40 – in a short time . “But I’m someone who thrives more on activity than stagnation. I become frustrated when things stand still,” she says, laughing a little.
There is no question of standing still for the time being. In July she will give birth to her second child. But if things do indeed slow down a little next year, she hopes to find time again for her hobby, dancing. It is a fitting pastime as it combines hard work with agility and lightness of foot.
Text: Jana Ehrhardt-Joswig
"A long and winding road" – a film with Thomas Blankenstein, Elisa Kieback, Mathias Leisegang, Antonio Pezzutto and Wolfgang Uckert. (with English subtitles)
Innovation, Patient care / 08.06.2021
Eckert & Ziegler: Affiliate Receives Additional NIAID Funding to Advance Pharmaceutical Development
Myelo Therapeutics GmbH, an affiliate of Eckert & Ziegler (ISIN DE0005659700, TecDAX) focused on developing medical countermeasures (MCM) and therapies for cancer supportive care, announced that the U.S. National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, extended their contract to advance the development of the new chemical entity Myelo001. The extension into year two of the three-year contract provides an additional $2 million to Myelo Therapeutics to develop clinical-stage Myelo001 as an oral formulation MCM for the treatment of Hematopoietic Acute Radiation Syndrome (H-ARS). The total contract, initially awarded in April 2020, is valued at up to $ 6.2 million over three years if all options are exercised.
The additional funds will advance the development of Myelo001 as an H-ARS monotherapy, and in polypharmacy regimens in laboratory models ranging from rodents to larger animals toward an Investigational New Drug Application (IND) with the U.S. Food and Drug Administration (FDA). The candidate MCM development program is funded in whole or in part by the Radiation and Nuclear Countermeasures Program (RNCP), NIAID, part of the National Institutes of Health (NIH), in the Department of Health, and Human Services (HHS), under Contract No. 75N93020C00005. Only a select number of companies are funded by the RNCP, based on a highly competitive application process.
About Acute Radiation Syndrome
ARS, also known as radiation toxicity or radiation sickness, is an acute illness that presents after exposure of large portions of the body to high levels of radiation, like those that might be experienced during a radiological or nuclear incident. The primary manifestation of ARS is the depletion of hematopoietic stem and progenitor cells, constituting one of the major causes of mortality. The U.S. government encourages development of new drugs to treat bodily injuries resulting from ARS.
About Myelo Therapeutics
Myelo Therapeutics is a pharmaceutical company based in Berlin, Germany, that is developing innovative treatments in areas of high unmet medical needs, such as Chemotherapy-Induced Myelosuppression (CIM), Radiation-Induced Myelosuppression (RIM), and ARS. Myelo's lead candidate, Myelo001 is a clinical-stage, adjuvant cancer therapy for treatment of chemotherapy - and radiotherapy-induced myelosuppression. It is delivered as an oral tablet formulation and is stable at room temperature for at least three years. Preclinical and clinical studies have shown that Myelo001 has both prophylactic and therapeutic efficacy at reducing hematopoietic symptoms caused by radiation and chemotherapy. Eckert & Ziegler is one of Myelo's largest shareholder and has funded a substantial portion of the Myelo001 development activities. www.myelotherapeutics.com.
About Eckert & Ziegler.
Eckert & Ziegler Strahlen- und Medizintechnik AG with her 800 employees is a leading specialist for isotope-related components in nuclear medicine and radiation therapy. The company offers a broad range of services and products for the radiopharmaceutical industry, from early development work to contract manufacturing and distribution. Eckert & Ziegler shares (ISIN DE0005659700) are listed in the TecDAX index of Deutsche Börse.
Research / 07.06.2021
Tracking RNA through space and time
A research team at the MDC has succeeded in tracking genes through space and time within a one-cell zebrafish embryo – even before cell division occurs. They have now described a method in the journal “Nature Communications” that may one day allow scientists to measure cell response to drugs, for example, in organoids.
The “miracle of life” is most obvious at the very beginning: When the fertilized egg cell divides by means of furrows into blastomeres, envelops itself in an amniotic sac, and unfolds to form germ layers. When the blastomeres begin to differentiate into different cells – and when they eventually develop into a complete organism.
“We wanted to find out whether the later differences between the various cells are already partly hard-wired into the fertilized egg cell,” says Dr. Jan Philipp Junker, who heads the Quantitative Developmental Biology Lab at the Berlin Institute for Systems Biology (BIMSB) of the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC). Junker and his team are investigating how cells make decisions and what dictates whether they become nerve, muscle, or skin cells. This involves creating cell lineage trees that allow them to determine the lineage and cell type of thousands of individual cells from an organism. Using these lineage trees, they can understand how and by what mechanisms cells come together to form a functioning organism or how they respond to perturbations.
Blueprints for different cell types already exist in the one-cell embryo
Yet this search for clues by means of cell lineage trees begins at a later stage – namely, when cell division and differentiation is already under way. What’s more, the observations cover long time periods. In their current study, which has just been published in the journal “Nature Communications”, Junker and his team focus on a very short time period: the first hours after fertilization, from the one-cell stage to the process of gastrulation – the formation of the germ layers – of the embryo. The scientists wanted to know whether the one-cell embryo already contains parts of the blueprint for the multitude of different cell types that later develop from it. To do this, they studied zebrafish and clawed frog embryos. Researchers had previously succeeded in finding individual genes whose RNA is localized at specific sites within one-cell zebrafish embryos. The Berlin scientists have now shown that there are many more such genes. “We have discovered ten times more genes whose RNA is spatially localized in the fertilized egg cell than previously known,” explains Karoline Holler, lead author of the study. “Many of these RNA molecules are later transported into the primordial germ cells. This means that the program for subsequent cell differentiation is hard-wired into the fertilized egg cell.”
New approaches in transcriptomics
State-of-the-art methods of single-cell transcriptomics provide a good understanding of cell differentiation. Scientists order individual cells according to the similarity of their transcriptome – the complete collection of RNA molecules present in a cell – and can use the patterns that emerge to decipher how the cells became what they are. However, they cannot use this method to reconstruct the earliest stages of embryonic development, because here the spatial arrangement of RNA
molecules is crucial. His team instead used a specialized technique called tomo-seq, which Junker developed at the Hubrecht Institute in the Netherlands in 2014. It enables scientists to spatially track RNA molecules within the cell. This is achieved by cutting embryos of the model organisms into thin slices. It is then possible read the RNA profiles on the cut surfaces and convert them into spatial expression patterns. Holler refined the tomo-seq technique to now measure the spatial distribution of the transcriptome within the fertilized egg cell.
The scientists used another new technique to study which localized genes later contribute to which cells. “We labeled the RNA molecules so as to be able to track them over different developmental stages. This allows us to observe the RNA not only in space but also over time,” explains Junker. In this way, the scientists can distinguish the RNA transferred to the embryo by the mother from the RNA produced by the embryo itself. This RNA labeling method, called scSLAM-seq, was fine-tuned at BIMSB in the labs of Professor Markus Landthaler and Professor Nikolaus Rajewsky, enabling it to be applied in living zebrafish. “Labeling RNA molecules allows us to measure with high precision how gene expression changes in individual cells, for example, after an experimental intervention,” explains Junker.
How do drugs affect cell differentiation?
RNA labeling opens up completely new avenues for studying such things as the mechanism of action of drug therapies. “We can use it in organoids to investigate how different cell types respond to substances,” explains the physicist. The method, Junker says, is not suitable for long-term processes of change. “But we can see which genes change within five to six hours after treatment, providing a pathway to understanding how we might influence cell differentiation.”
Spatial analysis also has medical relevance: Looking further into the future, it could be useful for studying those diseases that result from mislocalized RNA, such as cancer or neurodegenerative diseases. In such diseases a large number of molecules are transported through the cell. “If we understand these transport processes, then we may be able to identify risk factors for these diseases,” explains Holler. But, for now, that is a long way off. “There is still much work to be done before the one-cell zebrafish embryo can be used as a model system for studying human neurodegenerative diseases,” stresses Junker.
The scientists next want to uncover the mechanisms involved in RNA localization: How does the detected RNA differ from other transcripts in the cell? Junker’s team plans to work with Professor Irmtraud Meyer’s lab at BIMSB to characterize the sequence features of the localized RNA. With the help of algorithms, they hope to predict whether the localized genes share a two- or three-dimensional fold. They are also working on further developing their method so that it can be used in other systems than the one-cell zebrafish embryo.
Text: Jana Ehrhardt-Joswig
Innovation / 03.06.2021
Eckert & Ziegler and Telix Pharmaceuticals Enter Co-Promotion Agreement for Prostate Cancer Diagnostic in the United States
Eckert & Ziegler (ISIN DE0005659700, TecDAX) and Telix Pharmaceuticals (Telix) will cooperate closely in the commercialization of GalliaPharm® (68Ge/68Ga Generator) and investigational product Illuccix® (Kit for the preparation of Ga-68 PSMA-11 injection) in the United States. An agreement to this effect has now been signed by the two companies. Illuccix® is a preparation for imaging prostate cancer by positron emission tomography (PET) and is currently under review for regulatory approval in the United States and multiple markets worldwide.
Eckert & Ziegler and Telix will expand their existing collaboration to further develop access to Ga-68 supply in the United States. The parties will both promote the combination of GalliaPharm® and Illuccix® to national radiopharmacy networks, commercial and hospital-based nuclear pharmacies, and other target institutions.
"After previously being granted distribution rights for Germany, our home market, the latest collaboration marks another important milestone for our 68Ga generator GalliaPharm® and our nuclear medicine activities”, explained Dr Harald Hasselmann, Eckert & Ziegler Executive Director and responsible for the Medical segment. “We are pleased to have Telix as a partner and to be able to jointly provide leading edge diagnostic products to prostate cancer patients in the USA.”
“This important cooperation between EZAG and Telix sales teams is highly complementary to our efforts in rolling out 68Ga-PSMA imaging across the US. Subject to FDA approval, we will together raise awareness of this state-of-the-art imaging modality and facilitate coast-to-coast access for US men living with prostate cancer.”, added Telix Americas President Dr Bernard Lambert.
Following regulatory approval, Illuccix® will be offered as a cold kit preparation for the diagnosis of prostate cancer. For this purpose, Illuccix® enables PSMA-11 to be radio-labelled with the radionuclide 68Ga directly before injection by medical personnel. After preparing the radiopharmaceutical and injecting it into the patient, sites exhibiting prostate cancer are localized and imaged via the presence of the prostate-specific membrane antigen.,
Prostate cancer is the most common type of cancer in men in the United States, with approximately 210,000 cases in 2020, a significantly higher incidence than either lung cancer (116,000 new cases) or bowel cancer (82,000 new cases). Prostate cancer was also the second most common cause of cancer death in men, with over 32,000 men dying from the disease in the United States in 2020. More than 812,000 American men were estimated to be living with prostate cancer in 2020.
 Fendler W et al. JAMA Oncol. 2019; 5(6): 856-863.
 Hofman M et al. The Lancet. 2020; 395: 1208-1216.
 IARC Global Cancer Observatory, 2020.
About Eckert & Ziegler
Eckert & Ziegler Strahlen- und Medizintechnik AG with around 800 employees, is one of the world's largest providers of isotope-related components for nuclear medicine and radiation therapy. The company offers services for radiopharmaceuticals at its worldwide locations, from early development to commercialization. Eckert & Ziegler shares (ISIN DE0005659700) are listed in the TecDAX index of Deutsche Börse.
Contributing to saving lives.
About Telix Pharmaceuticals
Telix is a clinical-stage biopharmaceutical company focused on the development of diagnostic and therapeutic products using Molecularly Targeted Radiation (MTR). Telix is headquartered in Melbourne, Australia with international operations in Belgium, Japan, and the United States. Telix is developing a portfolio of clinical-stage products that address significant unmet medical needs in oncology and rare diseases. Telix is listed on the Australian Securities Exchange (ASX: TLX). For more information visit www.telixpharma.com and follow Telix on Twitter (@TelixPharma) and LinkedIn.
Telix's lead investigational product, Illuccix® (TLX591-CDx) for prostate cancer imaging, has been accepted for filing by the U.S. FDA, and is under priority evaluation by the Australian Therapeutic Goods Administration (TGA). Telix is also progressing marketing authorisation applications for Illuccix® in the European Union and Canada. None of Telix's products have received a marketing authorisation in any jurisdiction.
Telix Pharmaceuticals Contact:
Dr. Stewart Holmstrom, Investor Relations
Suite 401, 55 Flemington Road, North Melbourne, VIC 3051, Australia
economic development, Innovation / 18.05.2021
Eckert & Ziegler Granted Exclusive Distribution Rights by Telix Pharmaceuticals for Prostate Cancer Diagnostic
Eckert & Ziegler (ISIN DE0005659700, TecDAX) has signed an agreement with Telix Pharmaceuticals (Telix), an Australian-headquartered company, for the exclusive distribution of Illuccix® (Kit for the preparation of Ga-68 PSMA-11 injection) in Germany. Illuccix® is a preparation for imaging prostate cancer with positron emission tomography (PET), currently under review for regulatory approval in multiple markets worldwide, including Germany.
“Illuccix® is anticipated to be one of the most important imaging products for prostate cancer. Widespread approval of a preparation for the diagnosis of prostate cancer is urgently needed and we are pleased to have Telix, a pioneer in bringing this drug to market, as a partner," explained Dr Harald Hasselmann, Eckert & Ziegler Executive Director and responsible for the Medical segment. "Together with our other products, we will be able to offer nuclear medicine practices and clinics in Germany a fully comprehensive product portfolio for the production of Ga-68 PSMA, once approval has been attained."
“We are pleased to have entered this commercial distribution agreement with Eckert & Ziegler so that, subject to German regulatory approval, we will together be able to deliver a commercial product to German patients living with prostate cancer as efficiently as possible. Partnering with such a capable and patient-centric leader in nuclear medicine uniquely aligns with Telix’s mission of helping patients with cancer live longer, better quality lives”, explained Telix Chief Executive Officer Dr Christian Behrenbruch.
Illuccix® is offered as a so-called kit preparation for the diagnosis of prostate cancer. For this purpose, Illuccix® enables PSMA-11 to be labelled with the radionuclide Ga-68 directly before injection by medical personnel. After preparing the radiopharmaceutical and injecting it into the patient, tumours that show the so-called prostate-specific membrane antigen can be localised by PET.,
Prostate cancer is the most common type of cancer in men in Germany, with approximately 68,000 cases in 2020, a significantly higher incidence than either lung cancer (38,000 new cases) or bowel cancer (31,000 new cases). Prostate cancer was also the second most common cause of cancer death in men, with over 15,000 men dying from the disease in Germany in 2020. More than 290,000 German men were estimated to be living with prostate cancer in 2020.
(1) Fendler W et al. JAMA Oncol. 2019; 5(6): 856-863.
(2) Hofman M et al. The Lancet. 2020; 395: 1208-1216.
(3) IARC Global Cancer Observatory, 2020.
About Eckert & Ziegler.
Eckert & Ziegler Strahlen- und Medizintechnik AG with more than 800 employees, is one of the world's largest providers of isotope-related components for nuclear medicine and radiation therapy. The company offers services for radiopharmaceuticals at its worldwide locations, from early development to commercialization. Eckert & Ziegler shares (ISIN DE0005659700) are listed in the TecDAX index of Deutsche Börse.
About Telix Pharmaceuticals
Telix is a clinical-stage biopharmaceutical company focused on the development of diagnostic and therapeutic products using Molecularly Targeted Radiation (MTR). Telix is headquartered in Melbourne, Australia with international operations in Belgium, Japan, and the United States. Telix is developing a portfolio of clinical-stage products that address significant unmet medical needs in oncology and rare diseases. Telix is listed on the Australian Securities Exchange (ASX: TLX). For more information visit www.telixpharma.com
Telix’s lead investigational product, Illuccix® (TLX591-CDx) for prostate cancer imaging, has been accepted for filing by the U.S. FDA, and is under priority evaluation by the Australian Therapeutic Goods Administration (TGA). Telix is also progressing marketing authorisation applications for Illuccix® in the European Union and Canada. None of Telix’s products have received a marketing authorisation in any jurisdiction.
economic development, Innovation / 17.05.2021
Eckert & Ziegler: Record Income Due to Sale of Division and Strong Core Business
One-off effects from the deconsolidation of the tumor irradiation business, a waning of the Corona slump, and continued strong demand in particular for pharmaceutical radioisotopes more than doubled net profit at Eckert & Ziegler Strahlen- und Medizintechnik AG (ISIN DE0005659700; TecDAX) in the first quarter of 2021. With sales revenues of 44 million EUR (PY: 44), the Berlin-based technology company posted a net profit of 13.8 million EUR, 8.8 million EUR more than in the same period of the previous year
6.8 million EUR of the quarterly profit were booked as a one-off in the Medical Segment due to the deconsolidation of the tumor irradiation business. Another 4.9 mm EUR of net income (36% more than last year) was generated in this segment in particular through stronger sales of pharmaceutical radioisotopes, but also of laboratory devices and nuclear production equipment. The performance in these sub-segments more than compensated a weak start in the project business (services for companies). The Industrial segment returned to pre-Corona profitability and closed the quarter with a net income of EUR 2.5 million. The holding, the group’s third segment, where pre-clinical development expenses are booked, showed a loss of 0.4 mm EUR.
Although almost half (48%) of the 2021 annual income goal of EUR 29 million was already achieved in the first quarter, the Executive Board for now sticks to the guidance published in March due to the ongoing pandemic, the travel restrictions that continue to hamper business, and the extended delivery times for preliminary products, for example in plant construction.
The complete quarterly report can be viewed here:
Innovation / 28.04.2021
Eckert & Ziegler Signs Long-Term Supply Agreement with Sirtex Medical on Yttrium-90 for Treating Liver Cancer
Eckert & Ziegler AG (ISIN DE0005659700, TecDAX) and Sirtex Medical (Sirtex) have executed a long-term supply agreement for the use of EZAG’s Yttrium-90 in Sirtex SIR-Spheres® Y-90 resin microspheres for liver cancer. The arrangement has an initial term of five years and guarantees Eckert & Ziegler a substantial share of Sirtex’s rising global demand. It supplements the existing broad-based supply agreement that Sirtex and Eckert & Ziegler have been operating since 2009. The Eckert & Ziegler sales forecast for the 2021 financial year remains unaffected.
"This agreement cements our long-term relationship and makes it easier for both parties to plan accordingly. The order once again underlines our strong market position and competence as a leading production partner for the pharmaceutical industry", explains Dr. Lutz Helmke, member of the Executive Board of Eckert & Ziegler AG and responsible for the Medical segment. “With our geographic expansion strategy, we offer our customers a reliable and worldwide supply of high-quality radioisotopes.”
"With its global manufacturing network, Eckert & Ziegler is an ideal partner for us to supply yttrium-90 worldwide. Our therapy is used in more than 50 countries to treat liver cancer, and with our recently announced prospective, multi-center study for the treatment of hepatocellular carcinoma, we have the potential to expand our FDA-approved indication for the use of SIR-Spheres® in the U.S.," explains Kevin R. Smith, CEO of Sirtex Medical.
From its production facilities in Braunschweig, Germany, and Boston (MA), USA, Eckert & Ziegler supplies the Sirtex sites in Frankfurt, Boston and Singapore with yttrium-90.
Radioembolisation or selective internal radiotherapy (SIRT) uses tiny radioactive beads inserted directly into the liver tumours. The clinical data of this form of therapy, which has been used since 2002, is becoming increasingly convincing. In February 2021, the renowned British National Institute for Health and Care Excellence (NICE) issued a positive recommendation for the treatment of advanced liver carcinomas with SIR-Spheres® Y-90 resin microspheres. Every year, around 840,000 people worldwide develop liver cancer (source: Globocan, 2018).
To meet the increasing demand for radiopharmaceutical substances, Eckert & Ziegler is currently expanding its production sites. A new GMP facility will be added to the Boston (MA), USA site at the end of 2021. In Berlin, a new GMP facility with a total area of around 270 m² will be ready for operation in the first quarter of 2022. In Jintan (China), Eckert & Ziegler is investing up to EUR 50 million in the construction of a production facility for radiopharmaceuticals.
This expansion strategy positions Eckert & Ziegler as a global partner to the radiopharmaceutical industry, offering complete early development services, including process development and scale-up, CMC development, manufacturing and packaging, product release and stability programmes. This will enable the company to be a radiopharmaceutical contract manufacturer of phase I, II and III clinical scale products and for commercial use.
About Eckert & Ziegler.
Eckert & Ziegler Strahlen- und Medizintechnik AG with more than 800 employees, is one of the world's largest providers of isotope-related components for nuclear medicine and radiation therapy. The company offers services for radiopharmaceuticals at its worldwide locations, from early development to commercialization. Eckert & Ziegler shares (ISIN DE0005659700) are listed in the TecDAX index of Deutsche Börse.
Innovation / 16.04.2021
Eckert & Ziegler Acquires Direct Majority Stake in Drug Developer PENTIXAPHARM
Eckert & Ziegler Strahlen- und Medizintechnik AG today acquired several share packages from the founders of the drug developer PENTIXAPHARM GmbH. Together with another internal share transfer, Eckert & Ziegler AG will directly hold a total of about 83% of the shares in the Würzburg-based company as of closing of the transactions. The total cost for the three share packages amount to approximately EUR 30 million. About a quarter of the purchase price payments will be made in cash, the remainder in shares of Eckert & Ziegler AG, which the seller has committed to hold at least until the date at which an advanced clinical trial approval is expected. The management of PENTIXAPHARM, which holds the remaining 17% of PENTIXAPHARM shares, has been granted additional options to sell its remaining shares.
PENTIXAPHARM is developing a radiopharmaceutical combination product against lymphoma and a number of related tumors. Depending on whether chelated with Gallium-68 or Yttrium-90, the product will be able to be used both for the diagnosis and the therapy of cancer. For the lead diagnostic PENTIXAFOR, PENTIXAPHARM recently received the green light for advanced clinical trials from the European Medicines Agency in a form of preliminary notification. The management of PENTIXAPHARM expects that it will be able to go through the approval process in approximately three years. Eckert & Ziegler AG intends to raise funds for the approval process through further investments in the aftermath of its acquisition of PENTIXAPHARM.
Research / 16.04.2021
Large Molecules Transported into Living Cells: Researchers Achieve Breakthrough into Cell Interior
It is one of the big pharmacological questions: How do you get large functional biomolecules like proteins or antibodies into a living cell?
Linking antibodies or proteins with cell-penetrating peptides is a promising approach—but it has not yet fully led to the anticipated results. Researchers from the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) in Berlin and the TU Darmstadt present a new solution: If these peptides are also attached to the cell surface, then proteins or antibodies are transported much better into the cell interior. The groundbreaking results have just been published in the journal Nature Chemistry.
Our cell interior is protected from unwanted visitors by a cell membrane for a good reason. However, from a pharmacological point of view, this protection is a troublesome obstacle, as large proteins or antibodies find it difficult, if not impossible, to enter the so-called cytoplasm. Most drugs circumvent this barrier by targeting the cell surface. Meanwhile, making active ingredients cell-permeable remains one of the most pressing questions for biomedical research and the pharmaceutical industry.
Research into cell-penetrating peptides has been going on for more than two decades. This involves linking a protein or an antibody, for example, with a chemical or biochemical "tag" intended to facilitate its entry into the cell. But despite worldwide efforts, many of these approaches fail when it comes to transporting such large biomolecules.
Christian Hackenberger's group at the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) in Berlin seeks to produce cell-permeable proteins and is collaborating closely with Dr. M. Cristina Cardoso of the Technical University of Darmstadt, a world-leading expert in the field of cell-penetrating peptides.
Double manipulation significantly improves transport
The research team from Berlin and Darmstadt has taken a decisive step toward transporting even large molecules into the cell interior. The key finding: the researchers link the molecules not only to the cell-penetrating peptides but also the cell surface. As experiments on living cells showed, this significantly improves the intracellular uptake of functional proteins and antibodies. The results have just been published in the journal Nature Chemistry.
"Even though we are still a long way from the first medical applications, the work represents a real paradigm shift for the cellular transport of functional molecules," says a delighted Christian Hackenberger, head of the research group. "This is because we have been able to show on living cells that proteins and antibodies can not only pass through the cell membrane seemingly effortlessly but are also active in the cell without triggering toxicity."
The cargo is more easily cell-permeable
A decisive factor in this success is that the new method requires only about one-tenth of the substance concentrations as before. This simplifies the method significantly, making it more robust and versatile. "We can now reduce the concentrations to such an extent that the cargo can really reach the inside of the cell reliably," says the study’s first author Anselm Schneider, who recently completed his doctorate. "This was not possible before."
As part of his doctoral thesis, Anselm Schneider had the groundbreaking idea of equipping the cell surface with the same cell-penetrating peptides as the cargo intended to enter the cell. Together with Martin Lehmann, the head of the Microscopy Facility at the FMP, Schneider observed how the cell membrane was seemingly effortlessly overcome. "It is this synergy that now makes it possible to transport a whole range of molecules into the cell interior, which is a real breakthrough," says Schneider.
Door opens to new pharmacological interventions
The potential applications of cellular molecular transport are broad. Active cell-permeable proteins or antibodies can be used, for example, to influence signaling pathways in a cancer cell deliberately or to switch off cancer-driving gene mutations. Likewise conceivable is the replacement of a missing enzyme in the case of a hereditary disease, for example, or the use of gene editing—that is, the genetic manipulation of cells using ready-made proteins equipped with additional properties. Clearly, the research team has a lot on the to-do list!
Innovation / 14.04.2021
Eckert & Ziegler to Build cGMP Facility for Radiopharmaceutical Services in Berlin
2021-04-14 / Eckert & Ziegler is proud to announce that it is expanding its production site in Berlin, Germany, with a new production facility for the contract manufacturing of radiopharmaceuticals. This new cGMP clean room suite with a total area of around 270 m² will be a 21 CFR 211 compliant, radiopharmaceutical manufacturing facility dedicated to late stage investigational and commercial stage radiopharmaceuticals and be operational from the first quarter of 2022. Together with a new U.S. based cGMP facility, Eckert & Ziegler will be able to provide radiopharmaceutical development services to companies looking for Europe, US and worldwide contract manufacturing.
“We have decided to make this investment to meet the growing global demand for radiopharmaceutical services in both imaging and therapy products. At the moment, a large number of radiopharmaceutical substances from international pharmaceutical companies are in advanced clinical trials, some of them for broad indications such as prostate cancer," explains Dr. Lutz Helmke, member of the Executive Board of Eckert & Ziegler AG and responsible for the Medical segment. “The new cGMP facility enables positioning as a European production and development partner for specialized pharmaceutical companies and innovative scientists. We offer them a wide range of radiopharmaceutical services under GLP and cGMP conditions."
The new cGMP suite, will enable Eckert & Ziegler to offer complete early development services, including process development and scale-up, CMC manufacturing, product release, stability programs and packaging. The company will be able to manufacture products on a clinical scale for phases I, II and III as well as for commercial use as a radiopharmaceutical contract manufacturer.
Eckert & Ziegler has a global presence as one of the leading partners of the radiopharmaceutical industry and has production and sales sites in 13 countries in Europe, North and South America and Asia.
In Wilmington (MA), USA, a production plant is currently being completed to manufacture Yttrium-90 solution for liver cancer treatment. In the future, the company will expand its European production capacity for Lutetium-177 labeled drugs to its U.S. site. Lutetium-177 is a coveted active ingredient in many new cancer therapy drugs. "Due to the large number of studies in which Lutetium-177 is being clinically tested worldwide, we expect an increasing demand for this isotope and related services in the coming years. Our production sites in Europe, Asia and North America ideally position Eckert & Ziegler to meet this demand," adds Dr. Lutz Helmke.
In Jintan (China), Eckert & Ziegler is investing up to EUR 50 million in the construction of a production facility for radiopharmaceuticals.
Innovation / 12.04.2021
Eckert & Ziegler Receives Technetium Generator Licenses for Brazil
The Brazilian regulator ANVISA has provided Eckert & Ziegler Brasil Comercial Ltda., a fully owned subsidiary of Eckert & Ziegler Strahlen- und Medizintechnik AG (ISIN DE0005659700, TecDAX), with a license to import and distribute technetium generators. This is the second license ever given to an organization in Brazil, and only the first one for a private company. Technetium generators are a core component for a nuclear imaging procedure called SPECT, which is used for the detection of medical abnormalities. In Brazil, the SPECT market has a volume of about 100 mm Euro annually. Eckert & Ziegler already services about 500 hospitals and clinics in this country with medical devices and radioisotopes, and hopes to start shipping SPECT products in the third quarter of 2021.
Claudia Goulart, CEO of Eckert & Ziegler Brasil, commented: “We are very excited that Eckert & Ziegler has now been given the opportunity to service the Brazilian nuclear medicine community with SPECT products. It compliments perfectly our existing portfolio of radiopharmaceuticals, among them Lu-177 and O-18, and the services we provide for international pharmaceutical companies.”
Disclosure of inside information according to Article 17 MAR
Research / 31.03.2021
Fasting acts as diet catalys
Those who need to change their eating habits to normalise their blood pressure should start with a fast. In the journal “Nature Communications”, MDC and ECRC scientists explain why patients can use it as a tool to improve their health in the long term.
One in four Germans suffers from metabolic syndrome. Several of four diseases of affluence occur at the same time in this ‘deadly quartet’: obesity, high blood pressure, lipid metabolism disorder and diabetes mellitus. Each of these is a risk factor for severe cardiovascular conditions, such as heart attack and stroke. Treatment aims to help patients lose weight and normalise their lipid and carbohydrate metabolism and blood pressure. In addition to exercise, doctors prescribe a low-calorie and healthy diet. Medication is often also required. However, it is not fully clear what effects nutrition has on the microbiome, immune system and health.
A research group led by Dr Sofia Forslund and Professor Dominik N. Müller from the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) and the Experimental and Clinical Research Center (ECRC ) has now examined the effect a change of diet has on people with metabolic syndrome. The ECRC is jointly run by the MDC and Charité Universitätsmedizin Berlin. “Switching to a healthy diet has a positive effect on blood pressure,” says Andras Maifeld, summarising the results. “If the diet is preceded by a fast, this effect is intensified.” Maifeld is the first author of the paper, which was recently published in the journal “Nature Communications”.
Broccoli over roast beef
Dr Andreas Michalsen, Senior Consultant of the Naturopathy Department at Immanuel Hospital Berlin and Endowed Chair of Clinical Naturopathy at the Institute for Social Medicine, Epidemiology and Health Economics at Charité – Universitätsmedizin Berlin, and Professor Gustav J. Dobos, Chair of Naturopathy and Integrative Medicine at the University of Duisburg-Essen, recruited 71 volunteers with metabolic syndrome and raised systolic blood pressure. The researchers divided them into two groups at random.
Both groups followed the DASH (Dietary Approach to Stop Hypertension) diet for three months, which is designed to combat high blood pressure. This Mediterranean-style diet includes lots of fruit and vegetables, wholemeal products, nuts and pulses, fish and lean white meat. One of the two groups did not consume any solid food at all for five days before starting the DASH diet.
On the basis of immunophenotyping, the scientists observed how the immune cells of the volunteers changed when they altered their diet. “The innate immune system remains stable during the fast, whereas the adaptive immune system shuts down,” explains Maifeld. During this process, the number of proinflammatory T cells drops, while regulatory T cells multiply.
A Mediterranean diet is good, but to also fast is better
The researchers used stool samples to examine the effects of the fast on the gut microbiome. Gut bacteria work in close contact with the immune system. Some strains of bacteria metabolise dietary fibre into anti-inflammatory short-chain fatty acids that benefit the immune system. The composition of the gut bacteria ecosystem changes drastically during fasting. Health-promoting bacteria that help to reduce blood pressure multiply. Some of these changes remain even after resumption of food intake. The following is particularly noteworthy: “Body mass index, blood pressure and the need for antihypertensive medication remained lower in the long term among volunteers who started the healthy diet with a five-day fast,” explains Dominik Müller. Blood pressure normally shoots back up again when even one antihypertensive tablet is forgotten.
Blood pressure remains lower in the long term – even three months after fasting
Together with scientists from the Helmholtz Centre for Infection Research and McGill University, Montreal, Canada, Forslund’s working group conducted a statistical evaluation of these results using artificial intelligence to ensure that this positive effect was actually attributable to the fast and not to the medication that the volunteers were taking. They used methods from a previous study in which they had examined the influence of antihypertensive medication on the microbiome. “We were able to isolate the influence of the medication and observe that whether someone responds well to a change of diet or not depends on the individual immune response and the gut microbiome,” says Forslund.
If a high-fibre, low-fat diet fails to deliver results, it is possible that there are insufficient gut bacteria in the gut microbiome that metabolise fibre into protective fatty acids. “Those who have this problem often feel that it is not worth the effort and go back to their old habits,” explains the scientist. It is therefore a good idea to combine a diet with a fast. “Fasting acts as a catalyst for protective microorganisms in the gut. Health clearly improves very quickly and patients can cut back on their medication or even often stop taking tablets altogether.” This could motivate them to stick to a healthy lifestyle in the long term.
Text: Jana Ehrhardt-Joswig
economic development, Innovation / 25.03.2021
Eckert & Ziegler: Dividend Proposal EUR 0.45 per Share. Profit Increase in 2020. Positive Outlook for 2021.
Eckert & Ziegler AG (ISIN DE0005659700, TecDAX) achieved sales of EUR 176.1 million (previous year EUR 178.5 million) and a net profit of EUR 22.9 million (previous year EUR 22.0 million) in the 2020 financial year. Earnings per share amounted to EUR 1.11. Executive Board and Supervisory Board today resolved to propose to the Annual General Meeting the payment of a split-adjusted dividend in the amount of EUR 0.45 (previous year: EUR 0.42) per share entitled to dividend.
For the current financial year 2021, the Executive Board expects revenue to remain at the previous year’s level, net profit of around EUR 29 million and EPS of around EUR 1.40. The forecast is based on a weighted average exchange rate of USD 1.15 per euro and the assumption that no shutdowns of significant production sites or other disruptions will be ordered due to the COVID19 pandemic.
The income statement, balance sheet and cash flow statement for the past financial year can be found here: https://www.ezag.com/home/investors/reports/
The complete, audited annual financial statements 2020 will be published on 16 April 2021.
Research / 24.03.2021
Grand opening of the Käthe Beutler Building
The Käthe Beutler Building has opened. Germany’s Federal Research Minister, Berlin’s Governing Mayor, the Chairman of the Jewish Community of Berlin and many guests inaugurated it. Around 200 specialists will work at the BIH & MDC Center for Vascular Biomedicine medicine – for the benefit of patients.
Federal Research Minister Anja Karliczek and Berlin’s Governing Mayor and Senator for Higher Education and Research Michael Müller inaugurated today a new building for translational medical research at the science, health and biotechnology park Campus Berlin Buch. The facility will be jointly run by the Berlin Institute of Health (BIH) at Charité and the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC). The federal government financed €26.2 million of the new building’s total cost of around €29 million. A former clinic facility that stood on the site has been renovated and expanded to create the new Käthe Beutler Building, which now provides 3,000 m2 of space where some 200 scientists will conduct research with a focus on vascular medicine. The name of the building commemorates Jewish doctor and scientist Käthe Beutler, who was forced to emigrate to the United States under the Nazis in 1935. Her son and grandson both gave speeches at the event, as did the Chairman of the Board of the Jewish Community of Berlin. The Käthe Beutler Building is the first BIH research building to go into operation.
Käthe Beutler serves as a role model
“The new Käthe Beutler Building will further interconnect research activities in Berlin - both spatially and substantively. It creates a joint research site for the BIH and the MDC at the Buch campus. The namesake of the building, the pediatrician and researcher Dr. Käthe Beutler, exemplifies through her personal life story the traits of determination, perseverance and foresight. She thus serves as a role model today, especially for young female scientists, researchers and students. I wish the BIH and the MDC, all other participating research institutions and all future occupants of the Käthe Beutler Building every success and good fortune in their joint work,” said the Federal Research Minister Anja Karliczek on the occasion of the Käthe Beutler Building’s inauguration, where only a few guests were physically present due to Covid-19 restrictions.
Karliczek delivered her speech by video message, as did Berlin’s Governing Mayor and Senator for Higher Education and Research Michael Müller: “The Käthe Beutler Building plays an important bridging role in the Privileged Partnership between the MDC and the BIH at the Charité. Their joint research activities are of great importance to science, health policy and society, and now they have the ideal conditions in which to flourish. I am very grateful that with this special research building, Käthe Beutler’s name is returning to Berlin and will embody our growing medical metropolis.”
A first home of ist own for the BIH
Professor Christopher Baum, Chair of the BIH Board of Directors and Chief Translational Research Officer of Charité – Universitätsmedizin Berlin, is delighted with this first BIH building, which is now ready to be handed over to researchers. “Up to now, BIH research groups have been spread across various buildings all over Berlin. We are very pleased that the BIH now has a physical location and a first home of its own with the Käthe Beutler Building. In close partnership with the MDC, important research will take place here within the Focus Area ‘Translational Vascular Biomedicine.’ Blood vessels play a role in many diseases, so hopefully this work will soon benefit many patients.”
At the opening of the new building, where research groups from the MDC and BIH will work together under one roof, interim Scientific Director of the MDC Professor Thomas Sommer said: “I am delighted that we are opening the Käthe Beutler Building here on Campus Berlin Buch today – and, with it, strengthening our productive partnership with the BIH and Charité. For many years, MDC scientists have been working closely and successfully with physicians and clinical researchers in a variety of ways. The Experimental and Clinical Research Center of the MDC and Charité is just next door, and represents a wonderful example of successful patient-oriented research. Today, this successful model of translation (“from bench to bedside”) is being extended to include vascular research and medicine. I wish all those involved every success.”
The border between Berlin and Brandenburg runs through the middle of the Käthe Beutler Building. So it is fitting that this facility also bridges the border between basic research and clinical practice. Professor Axel R. Pries, Dean of Charité, considers this an essential aspect: “It is of the utmost importance that doctors, researchers and, not least, patients meet under the same roof every day. Direct interaction allows new ideas to develop and research findings to be quickly translated into real-world solutions. This is the only way to turn research into health.”
Representative for expelled Jewish scientists and doctors
The building is named after Jewish doctor Käthe Beutler, who studied medicine in Berlin and went on to work as a pediatrician, first at Charité and then in her own practice. In 1935, she had to flee with her family from the National Socialists and establish a new home in the United States. Her son Frederick Beutler and grandson Bruce Beutler are also scientists; Bruce Beutler received the Nobel Prize in Medicine in 2011 for his work in the field of innate immunity. Both also attended the inauguration of the Käthe Beutler Building virtually, where they shared memories of their mother and grandmother. “We knew her as a strong person who always tried to do good, even in a world that had been particularly hard on her,” Bruce Beutler said in his tribute. “If she were here today, she would be delighted – and certainly very surprised – that Charité has chosen to name a building after her. We are proud that her exemplary life has been recognized by this prestigious institution, which played a formative role in her professional career.”
Dr. Gideon Joffe, Chairman of the Board of the Jewish Community of Berlin, was pleased with the choice of name for the new research facility: “Käthe Beutler represents the many Jewish scientists and doctors who were expelled during the Third Reich. By commemorating her today, we ensure that the memory of this injustice lives on. At the same time, we are happy that science today is pursued without borders and that international cooperation has become a matter of course.”
A memorial plaque at the entrance to the new building commemorates Käthe Beutler.
A center for vascular biomedicine
On behalf of the scientists who will work in the Käthe Beutler Building, Professor Holger Gerhardt, spokesperson for the BIH & MDC Center for Vascular Biomedicine and Professor of Experimental Cardiovascular Research at the MDC, said: “With the Käthe Beutler Building, we are facilitating encounters between us, the Vascular Biomedicine research teams, and patients. And we are fostering lively interaction between cutting-edge science and technology. Here, we use the latest omics technologies, such as gene sequencing and single cell analysis, and have state-of-the-art microscopy methods at our disposal. Our goal is the translation of basic research discoveries into clinical practice – while also making sure clinical knowledge is fed back to the lab. Translation bridges gaps between disciplines, between their different languages, cultures and ways of thinking, thus creating new understanding and insights. This will permanently change how we view, treat and prevent disease.”
Facts and figures
- Address: Käthe-Beutler-Haus, Lindenberger Weg 80, 13125 Berlin
- Builders: Charité – Universitätsmedizin Berlin, Max Delbrück Center
- Architect: kleyer.koblitz.letzel.freivogel, Gesellschaft von Architekten mbH
- Costs: 29.1 Mio Euros
- Floor space: 3030 qm
- Construction peroid: 2017 – 2021
- Completion: March 2021
- BIH & MDC Center for Vascular Biomedicine
- Käthe Beutler: „Do something!“
- Profile Holger Gerhardt: When new blood vessels sprout
Innovation / 24.03.2021
Eckert & Ziegler Divests From Tumour Irradiation Business
Eckert & Ziegler Strahlen- und Medizintechnik AG (ISIN DE0005659700, TecDAX) will divest its tumour radiation equipment (HDR) business. As a first step, it has sold 51% of the shares in BEBIG Medical GmbH, into which it had transferred the HDR business, to the Chinese company TCL Healthcare Equipment (TCL) in Shanghai today.
The divested HDR business generated sales of around EUR 11 million in 2019. For the remaining 49% of the shares in BEBIG Medical GmbH, TCL received a call option until the beginning of 2024 and Eckert & Ziegler received a put option to TCL thereafter. The purchase price upon exercise of the call option is fixed in accordance with the purchase price regulation of the current contract; the purchase price upon exercise of the put option may be higher depending on the development of the EBITDA of BEBIG Medical GmbH.
Last year, the HDR business with the so-called afterloader devices generated a low double-digit million turnover. The growth market for the medical devices is in Asia, especially in the People' s Republic of China. "Only with a strong Chinese partner the HDR business will unfold its full potential," Dr Harald Hasselmann, Member of the Executive Board of Eckert & Ziegler AG, explained the transaction. "It makes sense for us to put this business in other hands and focus even more on the fast-growing radiopharmaceuticals business." The production of tumour radiation equipment will remain in Germany.
TCL Healthcare Equipment (Shanghai) Co., Ltd. (上海惠影医疗科技有限公司), headquartered in Shanghai, is one of the innovative suppliers of medical imaging diagnostic products with the vision to provide affordable healthcare for everyone. www.tcl-healthcare.com
Insider information pursuant to Article 17 MAR
Innovation / 08.02.2021
Eckert & Ziegler Wins Order for Hot Cell Construction from Dutch Research Center
Eckert & Ziegler has been awarded a contract to build hot cells with a value of several million euros. The order was placed by the Nuclear Research and Consultancy Group (NRG) in Petten (NL), a global market leader in producing medical isotopes.
The contract includes the planning and construction of hot cells for the GMP-compliant processing of alpha and beta emitters in NRG's so-called FIELD-LAB at the Petten (NL) site. The FIELD-LAB is intended to provide a practical environment for companies and research institutes to develop radiopharmaceuticals for the personalized treatment of cancer and other diseases.
"The order underlines our high level of expertise in special plant engineering for radioactive materials. We are pleased to contribute to this exciting project with our expertise in the fields of radiopharmacy, technology and process development," explains Felix Husmann, Managing Director of the Eckert & Ziegler subsidiary Isotope Technologies Dresden GmbH (ITD), which specializes in plant engineering. "In view of the high global demand for radiopharmaceuticals, special plant engineering is becoming increasingly important. With our many years of experience, we are ideally positioned as a competent partner for the pharmaceutical industry.”
"What convinced us about ITD were the perfect package of their many years of experience, their price and their customer-oriented approach to solutions”, stated Vinod Ramnandanlal, Commercial Director of NRG. “With ITD, we have found a strong partner with whom we can jointly build up the technical infrastructure of our FIELD-LAB and thus accelerate the development of radiopharmaceuticals to fight cancer.”
About Eckert & Ziegler.
Eckert & Ziegler Strahlen- und Medizintechnik AG with more than 800 employees, is one of the world's largest providers of isotope-related components for nuclear medicine and radiation therapy. The company offers services for radiopharmaceuticals at various locations, from early development to commercialization. Eckert & Ziegler shares (ISIN DE0005659700) are listed in the TecDAX index of Deutsche Börse.
Contributing to saving lives.
About Isotope Technologies Dresden
Isotope Technologies Dresden GmbH (ITD) is a subsidiary of Eckert & Ziegler AG and one of the leading international specialists for the development, design and manufacture of hot cells for production, material testing, research & development and other applications in the radiopharmaceutical and industrial sectors. ITD has many years of experience in the development, manufacture and installation of customer-specific special equipment.
About Nuclear Research and Consultancy Group (NRG)
NRG is an internationally operating nuclear service provider. The company produces isotopes, conducts nuclear technological research, is a consultant on the safety and reliability of nuclear installations and provides services related to radiation protection.
FIELD-LAB is an initiative of the Advancing Nuclear Medicine consortium and is a unique breeding ground for the development of new nuclear medicine, which are expected to take an increasing role in the personalized treatment of life-threatening diseases like cancer.
Research / 02.02.2021
Four new groups use single-cell methods to advance medicine
A year ago, BIH, MDC and Charité launched the joint research focus "Single Cell Approaches for Personalised Medicine". Its aim is to use innovative single cell technologies to answer clinical questions. This aspiration will be put into practice by four new junior research groups, which have now started.
They were declared the “2018 Breakthrough of the Year”: new single cell technologies that let researchers analyze the genetic activity of individual cells was chosen as that year’s top scientific achievement by the eminent journal Science. “These revolutionary technologies can play a major role in personalized medicine,” says Professor Christopher Baum, Chair of the BIH Board of Directors and Chief Translational Research Officer of Charité – Universitätsmedizin Berlin. “We have therefore decided to promote the translation of single-cell analysis. We want to expedite the transfer of research findings into clinical practice and vice versa, using clinical observations to explore new avenues of single-cell research.” To this end, the Berlin Institute of Health (BIH), the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) and Charité – Universitätsmedizin Berlin have jointly established the focus area “Single-Cell Approaches to Personalized Medicine.”
State-of-the-art technologies for clinical use
At the core of the new focus area are four new junior research groups, whose leaders were selected in a competitive international recruitment process. Dr. Leif Ludwig, who comes to Berlin from the Broad Institute in Cambridge, Massachusetts, will study with his group how the development and function of stem cells is linked to the DNA of their “cellular power plants,” the mitochondria. Dr. Simon Haas comes from the German Cancer Research Center in Heidelberg and will use cancer stem cell analysis to investigate the origin of leukemia diseases in a targeted way. Dr. Stefanie Grosswendt from Berlin’s Max Planck Institute for Molecular Genetics wants to find out how individual cells know what task they have to perform in the overall network. Dr. Ashley Sanders is Canadian and comes from the European Molecular Biology Laboratory in Heidelberg and will research how new mutations arise in individual cells and drive different characteristics within an organ or tumor.
The junior research groups will be located at the MDC’s Berlin Institute for Medical Systems Biology (BIMSB) in Mitte. Here, they will have access to the latest single-cell methods and can collaborate with excellent systems biologists. BIMSB’s Scientific Director, Professor Nikolaus Rajewsky, has himself played a major role in the development of single-cell technologies. “It was as if we had invented a super microscope with which we could suddenly look inside every cell in a tissue, all the cells at once, and see what was going on at the molecular level inside the cell – for example, when and why it gets sick,” he explains. Rajewsky and Professor Angelika Eggert, Director of the Charité’s Department of Pediatrics, Division of Oncology and Hematology, are the spokespersons for the BIH’s new focus area.
Collaborating with clinicians
BIMSB is located in Berlin’s Mitte district, and thus in close proximity to Campus Charité Mitte (CCM). This will prove to be a big plus for their translational work because each junior research group will also work closely with a clinician at Charité, helping to develop single-cell technologies for real-world medical issues and clinical applications. Ashley Sanders will collaborate with Britta Siegmund, the Director of Charité’s Medical Department, Division of Gastroenterology, Infectiology and Rheumatology. Angelika Eggert will be the clinical partner of Stefanie Grosswendt. Simon Haas and Leif Ludwig will team up with the directors of Charité’s Medical Department, Division of Hematology, Oncology and Tumor Immunology, Lars Bullinger at Campus Virchow-Klinikum (CVK) and Ulrich Keller at Campus Benjamin Franklin (CBF).
“I believe that cancer research in particular will benefit from the new single-cell technologies,” says Eggert. “That’s because tumors are by no means made up wholly of the same kind of cells , but are often a very heterogeneous mixture of distinctly differentiated cancer cells, connective tissue cells, blood vessel cells and immune cells. The more precisely you know the cellular composition of a tumor, the more specifically you can target your strategies to combat it.”
The beginning of a “Cell Hospital”
“I am very pleased and also a little proud that we were able to bring these amazing young people to Berlin,” says Rajewsky. At the same time, they could hardly pass up such a unique opportunity. While the researchers can gain an in-depth understanding of the molecular details, the partnering physicians assess the clinical relevance of the findings and provide the researchers with insights into pathologies that single-cell technologies could potentially elucidate.
“I therefore consider this initiative to be the beginning of a ‘Cell Hospital,’ in which the basic research of the MDC/BIMSB, the clinical research of Charité and the translational research of the BIH are brought together,” explains Rajewsky. “The idea is not only to understand the mechanisms that cause cells to become diseased, but also to discover these cells early enough to restore them to health. I am sure that we will make significant progress for at least some diseases.”
Press release of BIH and Charité together with the MDC
Research / 29.01.2021
Singles or pairs in cancer cells
An important receptor on the surface of cancer and immune cells prefers to remain noncommittal; sometimes it is present as a single, sometimes as a pair. This was first shown by an MDC team in the journal PNAS, and will decisively advance the development of new medications.
It all sounds similar to a dance event – but are singles or couples dancing here? This was the question Ali Isbilir and Dr. Paolo Annibale at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) were trying to answer. However, their investigation did not involve a ballroom, but the cell membrane. The question behind their investigation: does a particular protein receptor on the surface of cancer and immune cells appear alone or connect in pairs?
The receptor is called “CXCR4” – the subject of heated debate among experts in recent years due to its mysterious relationship status. Does it appear in singles or pairs on the cell membrane? And what makes the difference? The research team of the Receptor Signaling Lab at the MDC, has now solved the puzzle of its relationship status for the first time. Their findings were recently published in the journal “Proceedings of the National Academy of Sciences” (PNAS).
CXCR4 is an important receptor on immune and cancer cells
“When CXCR4 is found in large numbers on cancer cells, it also ensures that they can migrate, thereby laying the foundation for metastases,” says lead author Isbilir. Metastases are known to be difficult to treat; some patients die as a result of these secondary tumors.
CXCR4 is also involved in inflammations. The center of inflammation releases messenger substances from the chemokine class. In lymph nodes, chemokines ensure that immune cells form many CXCR4 receptors on their membrane. With the help of these receptors, immune cells can locate the center of inflammation and migrate to it. The name CXCR, which stands for “chemokine receptor,” also refers to this ability. “Such receptors are the most important target structures in pharmaceutical research,” emphasizes Professor Martin Lohse, the last author of the study. “Approximately one-third of all drugs address this class of receptors.”
Whether such receptors are present as pairs or singles is therefore not only central to basic research, but also to the pharmaceutical industry. Using new methods of optical microscopy, the team has now been able to answer this question for the first time. Apparently, CXCR4 wants to remain noncommittal – it occurs temporarily in pairs (as a transient dimer), but also alone (as a monomer). The team found that the relationship status depends largely on how many CXCR4 receptors are located on a cell. If the cell surface is densely occupied, more pairs are formed. If only a few receptors are present, they more often appear singly. At the same time, the researchers could show that certain drugs acting as CXCR4 blockers can suppress pair formation. “It is assumed that CXCR4 pairs negatively affect one’s health. We can use our new microscopic methods to test whether this is really the case,” explains Lohse.
Fluorescent pairs and singles
The scientists combined two recent optical microscopy methods: Using single-molecule microscopy, they were then able to determine the relationship status of individual CXCR4 receptors on the surface of living cells. Fluorescence fluctuation spectroscopy also made it possible to measure the relationship status in cells that had a large number of receptors. The special feature here: to do this, the researchers had to develop a method to efficiently mark all receptors. They also had to develop a highly sensitive microscopy strategy with which they could see individual molecules and their oligomerization. The team presents the new methods in a report in the journal “Nature Protocols”.
“The exciting thing is that we can now use these fluorescence methods to study living cancer cells. We can find out whether CXCR4 is present in pairs or alone,” says Annibale, who is co-head of the Receptor Signaling Lab and also last author of the study in “Nature Protocols”. “And then we can apply CXCR4 blockers to singles and pairs and test which are more effective against tumors. This will hopefully lead to more specific cancer drugs with fewer side effects.”
Pathologists today are also examining the properties of patients’ cancer cells in detail. This allows cancer therapies to be designed in the most personalized and effective way possible. Annibale hopes that the approach could be now used for screening the effects of different drugs on the function of this and similar receptors. This could be helpful in devising new therapies for breast, or lung cancer, for example.
Text: Susanne Donner
Research / 29.01.2021
Naked mole-rats speak in dialect
Some converse in Creole, while others speak Scots, but it’s not only humans who can be identified by the diversity of language they speak. Naked mole-rats have their own dialects, too. Shared dialect also strengthens cohesion within a colony, a team led by MDC researcher Gary Lewin reports in the current "Science" cover story.
In the wild, naked mole-rats live exclusively in underground burrows and tunnels in semi-arid regions of Eastern Africa. The rodents obtain all the water they need through their food such as the underground tubers of plants. Credit: Felix Petermann, MDC
Some converse in Creole, while others speak Scots, but it’s not only humans who can be identified by the diversity of language they speak. Naked mole-rats have their own dialects, too. Shared dialect also strengthens cohesion within a colony, a team led by MDC researcher Gary Lewin reports in the current "Science" cover story.
The computer program, which uses AI, didn’t only identify the animals on the basis of their individual voices: “It also detected similarities in the types of sounds made within a single colony,” says Lewin. The program was therefore also able to identify which colony a specific individual came from. “That meant that each colony probably had its own distinct dialect,” says Barker. But at that point, the research team did not yet know whether the animals were aware of that, and whether they could recognize their own dialect and distinguish it from others.
A preference for kith and kin
In order to find out both those things, Barker performed several experiments. In the first, she repeatedly placed one naked mole-rat in two chambers, connected via a tube. In one chamber the chirping of another naked mole-rat could be heard, while the other chamber was silent. “We observed that the animals always immediately headed for the chamber where the chirps could be heard,” says Barker. If the sounds were made by an individual from the test subject’s own colony, it would give an immediate vocal response, but if they were made by an individual from a foreign colony, the mole-rat would remain silent. “That enabled us to infer that naked mole-rats can recognize their own dialect and will selectively respond to that.”
To ensure that the test subjects were responding to the dialect and not to the voice of an individual known to them, the researchers deliberately created artificial sounds. These contained characteristics of each dialect but did not resemble the voice of a specific individual. “The naked mole-rats produced vocal response to the chirps developed by the computer,” reports Barker. And the experiment worked even when the chamber where the familiar and trusted dialect could be heard was given the scent of a foreign colony. “That demonstrated that the naked mole-rats were responding specifically to dialect rather than scent, and that they have a positive reaction to hearing their own dialect,” says Lewin.
Foster pups learn the dialect of their new colony
In further experiments, the researchers placed three orphaned naked mole-rat pups in foreign colonies where the queen – the only female in naked mole-rat colonies that reproduces – had also recently had a litter. “That ensured that the new arrivals would not be attacked,” explains Barker. “Six months later, our computer program showed that the foster pups had acquired the dialect of their new home.”
It was rather more by chance that the team discovered another interesting fact: a naked mole-rat queen isn’t only responsible for reproduction in her colony, she also plays a decisive role in controlling and preserving dialect integrity. “During the course of the study, one of our colonies lost two queens within relatively quick succession,” says Lewin. “In the anarchy that ensued, we observed that the vocalizations of the other naked mole-rats in the colony began to vary much more widely than usual. Dialect cohesiveness was thus greatly reduced and didn’t return until a few months later, with the ascendance of another high-ranking female as the new queen.”
Insight into the basic workings of human culture
“Human beings and naked mole-rats seem to have much more in common that anyone might have previously thought,” concludes Lewin. “Naked mole-rats have a linguistic culture that developed long before human beings even existed. The next step is to find out what mechanisms in the animals’ brains support this culture, because that could give us important insight into how human culture evolved.”
Text: Anke Brodmerkel
Audio examples. Credit: Alison Barker, Lewin Lab, MDC
Innovation, Patient care / 12.01.2021
Eckert & Ziegler: Seed Implantation for Prostate Cancer Receives Reimbursement for Outpatient Care
Seed implantation for prostate cancer is now to be reimbursed as an outpatient treatment by public health insurances in Germany. This was decided by the Federal Joint Committee (G-BA) with effect from January 8, 2021.
Seed implantation or so called LDR brachytherapy is an organ-preserving, minimally invasive radiation procedure. In this procedure, millimeter-sized, low-level radioactive titanium tubes are inserted into the prostate while protecting the surrounding tissue. Compared to other treatment options, such as removal of the prostate or external radiation therapy, brachytherapy has a different side effect profile that is often more beneficial for the patient.
"We are pleased that the treatment costs of seed brachytherapy for prostate cancer are now to be covered by the public health insurance funds, both on an inpatient and outpatient basis," explains Dr. Harald Hasselmann, member of the Executive Board of Eckert & Ziegler AG and responsible for the Medical segment. "In its summary assessment, the G-BA recognizes the benefit of the method as sufficiently proven and its medical necessity as given."
"As a result of the consideration of benefit and medical necessity, brachytherapy for localized prostate cancer can achieve a PSA-based recurrence-free survival comparable to other curative therapies (radical prostatectomy, percutaneous radiotherapy). The side effect profile of LDR brachytherapy shows advantages in terms of preservation of continence and sexual function as well as bowel function," summarizes the G-BA in its overall assessment of interstitial brachytherapy for localized prostate cancer with a low risk profile.
There are approximately 473,000 new cases of prostate cancer in Europe each year (Globocan, 2020). In Germany, inpatient seed brachytherapy has been included in the reimbursement catalog of health insurance companies since 2004. Eckert & Ziegler BEBIG is the European market leader for seeds and produces them at its Berlin site.
About Eckert & Ziegler.
Eckert & Ziegler Strahlen- und Medizintechnik AG with more than 800 employees, is one of the world's largest providers of isotope-related components for radiation therapy and nuclear medicine. Eckert & Ziegler shares (ISIN DE0005659700) are listed in the TecDAX index of Deutsche Börse.
Research / 12.01.2021
Enhanced speed, contrast, and information: New contrast mechanism improves xenon MRI
Xenon magnetic resonance imaging offers deep insights into the human body and opens up new possibilities in the diagnosis and treatment of diseases. Physicists from the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) in Berlin have now achieved a considerable improvement of the method of detection involving the noble gas xenon. Applying a number of new technical tricks and testing two molecules, the scientists managed, within seconds, to gain more image information from single-shot data acquisition than was previously possible. Moreover, the new contrast mechanism requires less contrast agent and no gadolinium, the subject of continued debate with regard to potential intolerance. The method is around 850 times more sensitive than comparable contrast agents in conventional MRI involving water molecules. The results of the study have now been published in the journal “Chemical Science”.
The ability to detect pathological processes in the body that would otherwise remain hidden using conventional imaging techniques – this is the potential promised by xenon magnetic resonance imaging. In contrast to conventional MRI, this method involves detecting the non-toxic noble gas xenon rather than water molecules. Thanks to the special magnetization of xenon, it has an extremely high signal strength in MRI. In addition, xenon imaging also has analytical potential because molecules that interact with xenon can be used as drug carriers that can now be localized and characterized using MRI.
Physicists at the FMP have been working for years to further perfect xenon MRI so that it can be used, for example, in the diagnosis and treatment of cancer. Following the discovery of several molecules that are able to bind the noble gas xenon very well to deliver high-contrast images from inside the body, Dr. Leif Schröder’s team has now achieved another success.
“We have made accessible another contrast mechanism that is capable of generating significantly more image information than the previous method in a shorter space of time,” explained Leif Schröder. “The so-called relaxivity is much higher, which means that we need much less contrast agent than required by conventional methods to generate image contrast, which is extremely beneficial, particularly for medical applications.”
T2 contrast needs only short contact time
The work now published in “Chemical Science” focused on the T2 contrast – one of the two contrast parameters in magnetic resonance imaging alongside T1 – and how it can be influenced by the two molecules cryptophane-A monoacid (CrA-ma) and cucurbituril (CB6). Although these two metal-free molecules are considered highly potent candidates for xenon MRI, this question had not been investigated previously.
Leif Schröder and his colleague Martin Kunth were able to demonstrate that even short contact times between xenon and the molecule resulted in a signal change. A single shot involving elaborate, continuous observation of the signal suffices to be able to display the T2 contrast for an entire series of images. Previously, at least two measurements were required for a single image – one with an “on” signal and the other with an “off” signal – and it took at least 30 or seconds for an image to be encoded. The new contrast mechanism manages this in around 7 seconds from just a single shot.
“It results in extreme time savings compared to the old method,” remarked Martin Kunth. Another advantage of the new mechanism is that no additional reference images or controversial metal complexes are needed to create the T2 contrast. In addition, more than 1,000 images with progressive contrast can now be reconstructed from a single continuous signal. The conventional method was only able to generate a maximum of 30 images, each of which had to be taken separately, involving far greater effort. “Essentially, it is a very simple measurement; we need just one data set to obtain an information-rich series of images with a much better spatial resolution,” emphasized the physicist.
Data with a high informative value
The simple measurement is coupled with complex data processing, which is also innovative. The software, programmed by the FMP researchers, is able to compute more than just relative signal comparisons – where is it lighter, and where darker. In fact, it is able for the first time to calculate absolute numbers for certain physical parameters. The numbers describe the exact exchange rate between xenon and the molecules, enabling conclusions to be drawn on aspects such as the stability of a molecule as a drug carrier.
“Drug transporters must possess a certain degree of stability to ensure that they do not release the drug too early or too late. We are now able to measure this property, as well as the activation energy needed for entering the drug carrier,” stated Martin Kunth, describing one of the many new potential applications.
“In a nutshell, our new method enables us not only to improve clinical imaging, but also to provide answers to pharmacological or chemical-analytical questions,” added Leif Schröder. “As such, we have taken xenon MRI a crucial step forward, which will now benefit all researchers and clinics that work with it.”
Kunth M., Schröder L.; Binding Site Exchange Kinetics revealed through Efficient Spin-Spin Dephasing of Hyperpolarized 129Xe, Chemical Science 2021, 12, 158-169, DOI: 10.1039/D0SC04835F
Text press release: Beatrice Hamberger, Translation: Teresa Gehrs
Research, Patient care / 11.01.2021
A potent weapon against lymphomas
MDC researchers have developed a new approach to CAR T-cell therapy. The team has shown in Nature Communications that the procedure is very effective, especially when it comes to fighting follicular lymphomas and chronic lymphocytic leukemia, the most common type of blood cancer in adults.
The body’s defense system generally does not recognize cancer cells as dangerous. To correct this sometimes fatal error, researchers are investigating a clever new idea, one that involves taking a handful of immune cells from cancer patients and “upgrading” them in the laboratory so that they recognize certain surface proteins in the malignant cells. The researchers then multiply the immune cells and inject them back into the patients’ blood – setting them off on a journey through the body to detect and attack all cancer cells in a targeted way.
In fact, the first treatments based on this idea have already been approved: So-called CAR T cells have been used in Europe since 2018, particularly in patients with B-cell lymphomas for whom conventional cancer therapies have not worked.
T cells are like the immune system’s police force. The abbreviation CAR stands for “chimeric antigen receptor“ – meaning that the cellular police force is equipped with a new, laboratory-designed special antenna that targets a surface protein on the cancer cells. Thanks to this antenna, a small number of T cells can round up a large number of cancer cells and destroy them. Ideally, the CAR T cells patrol the body for weeks, months or even years and thus prevent tumor relapse.
A kind of signpost for B cells
Until now, the antenna on the CAR T cells was primarily directed against the protein CD19, which B cells – a type of immune cells – carry on their surface. Yet this form of therapy is by no means effective in all patients. A team led by Dr. Uta Höpken, head of the Microenvironmental Regulation in Autoimmunity and Cancer Lab at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), has now developed a new twist on this therapy that sensitizes the T cells in the laboratory to a different identifying feature: the B-cell homing protein CXCR5.
“CXCR5 was first described at the MDC more than 20 years ago, and I have been studying this protein myself for almost as long,” says Höpken. “I am therefore very pleased that we have now succeeded in using CXCR5 to effectively combat non-Hodgkin's lymphomas, such as follicular and mantle cell lymphoma as well as chronic lymphocytic leukemias, in the laboratory.” This protein is a receptor that helps mature B cells move from the bone marrow – where they are produced – to immune system organs such as the lymph nodes and spleen. “Without the receptor, the B cells would not find their way to their target site, the B-cell follicles of these lymphoid organs,” Höpken explains.
A well-suited target
“All mature B cells, including malignant ones, carry this receptor on their surface. So it seemed to us to be well suited to detect B-cell tumors – thereby enabling CAR-T cells directed against CXCR5 to attack the cancer,” says Janina Pfeilschifter, a PhD student in Höpken’s team. She and Dr. Mario Bunse from the same research group are the lead authors of the paper, which appeared in the journal Nature Communications. “In our study, we have shown through experiments with human cancer cells and two mouse models that this immunotherapy is most likely safe and very effective,” says Pfeilschifter.
The new approach may be particularly well suited for patients with a follicular lymphoma or chronic lymphocytic leukemia (CLL). “Both types of cancer involve not only B cells but also follicular T helper cells, which also carry CXCR5 on their surface,” Bunse explains. The special antenna for the identifying feature, the CXCR5-CAR, was generated by Dr. Julia Bluhm during her time as a PhD student in the MDC’s Translational Tumorimmunology Lab, which is headed by physician Dr. Armin Rehm. He and Höpken are the corresponding authors of the study.
First successes in the petri dish
Pfeilschifter and Bunse first showed that various human cells, for example, from blood vessels, the gut and the brain, do not carry the CXCR5 receptor on their surface and are therefore not attacked in the petri dish by T cells equipped with CXCR5-CAR. “This is important to prevent unexpected organ damage from occurring during therapy,” Pfeilschifter explains. In contrast, experiments with human tumor cell lines showed that malignant B cells from very different forms of B-non-Hodgkin’s lymphoma all display the receptor.
Professor Jörg Westermann, from the Division of Hematology, Oncology and Tumor Immunology in the Medical Department of Charité – Universitätsmedizin Berlin at the Campus Virchow Clinic, also provided the team with tumor cells from patients with CLL or B-non-Hodgkin’s lymphomas. “There, too, we were able to detect CXCR5 on all B-lymphoma cells and follicular T helper cells,” Pfeilschifter says. When she and Bunse placed the tumor cells in the petri dish together with the CXCR5-targeted CAR T cells, almost all of the malignant B and T helper cells disappeared from the tissue sample after 48 hours.
Mice with leukemia were cured
The researchers also tested the new procedure on two mouse models. “The CAR T cells are infused into the blood of cancer patients,” Höpken says. “So animal research is needed to show that the cells home to the niches where the cancer resides, multiply there and then do their job effectively.”
One model consisted of animals with a severely suppressed immune system, which could therefore be treated with human CAR T cells without causing rejection reactions. “We also developed a pure mouse model for CLL specifically for the current study,” Bunse reports. “We administered mouse CAR T cells against CXCR5 to these animals by infusion and were able to eliminate mature B cells and T helper cells, including malignant ones, from the B-cell follicles of the lymphoid organs.”
The researchers discovered no serious side effects in the mice. “We know from experience with cancer patients that CAR T-cell therapy increases the risk of infection for a few months,” Rehm says. But in practice this side effect is almost always easily managed.
A clinical trial is in the works
”No laboratory can tackle such a study on its own,” Höpken emphasizes. “It has only come about thanks to a successful collaboration between many colleagues at the MDC and Charité.” For her, the study is the first step toward creating a “living drug” – similar to other cellular immunotherapies being developed at MDC. “We are already cooperating with two cancer specialists at Charité and are currently working with them to prepare a phase 1/2 clinical trial,” adds Höpken’s colleague Rehm. Both hope that the first patients will begin to benefit from their new CAR-T cell therapy in the near future.
Text: Anke Brodmerkel
The German José Carreras Leukemia Foundation has funded the research with around 240,000 euros over a period of three years. The non-profit organization supports forward-looking research projects and infrastructure projects that investigate the causes of leukemia and improve treatment, as well as social projects.
Mario Bunse, Janina Pfeilschifter et al. (2021): “CXCR5 CAR-T cells simultaneously target B cell non-Hodgkin’s lymphoma and tumor-supportive follicular T helper cells”. Nature Communications, DOI: 10.1038/s41467-020-20488-3.
Innovation / 05.01.2021
Single Mouse Trials: mimicking clinical phase II trials in PDX models with manageable costs and efforts
The long and successful collaboration of EPO with the Charité University Hospital in Berlin recently led to the following publication:
Combination of copanlisib with cetuximab improves tumor response in cetuximab-resistant patient-derived xenografts of head and neck cancer
The article has been published in the peer-reviewed journal Oncotarget (Oncotarget, 2020, Vol. 11, (No. 41), pp: 3688-3697).
Head and neck squamous cell carcinoma (HNSCC) represents the 6th most common type of cancer and despite recent advances remains an area of high unmet medical need. Around 66% of HNSCCs harbor genomic alterations in one of the major components of the phosphoinositide 3-kinase (PI3K) signaling pathway, making PI3K an attractive target.
EPO has established a thoroughly characterized panel of more than 70 HNSCC patient-derived xenograft (PDX) models (HPV +/-). To explore the activity of the PI3K inhibitor copanlisib in monotherapy and in combination with the EGFR inhibitor cetuximab, 33 PDX models were selected out of this panel for a mouse clinical trial together with Bayer AG.
How YOUR projects could benefit from it
We successfully applied the one mouse, one tumor, one treatment trial design on our HNSCC PDX panel to establish a sound preclinical rational for the evaluation of copanlisib in combination with cetuximab in a clinical setting. This demonstrates that a large number of heterogeneous tumors can be evaluated and a clinical phase II trial can be mimicked in PDX models with manageable costs and efforts.
Mouse clinical trials in oncology drug development
Around 85% of preclinical agents entering oncology clinical trials fail to demonstrate sufficient safety or efficacy to gain regulatory approval. This high failure rate highlights the continued limitations of the predictive value of existing preclinical models and clearly shows an urgent need for experimental systems that better replicate the diversity of human tumor biology in a preclinical setting. While PDX models faithfully recapitulate human tumor biology and predict patient drug response, studies with small numbers of models have limited value in predicting potential clinical-trial response at the population level. Mouse clinical trials (MCTs) are population-based efficacy studies mimicking human trials. For these, the single mouse study design is a feasible and very cost-effective approach to reliably screen a large numbers of models with diverse genetic characteristics.
Important considerations for your study
Similar to clinical trials, rational design of MCTs requires statistical power calculation and sample size determination, thus the number of mouse models as well as the number of mice per model needs to be carefully considered. In general, the study design depends on factors such as the study aims, the efficacy of the applied drugs and the available resources. For example, when there is only a limited number of suitable PDXs, e.g., PDXs carrying a particular mutation or PDXs of a specific subtype, the number of mice per PDX could be increased to boost statistical power. Our scientific and bioinformatics team will actively support you to tailor a study design specifically for your needs based on detailed statistical and bioinformatics analyses.
There is a broad variety of possible applications for single mouse trials. These include exploration of new drug combinations as demonstrated by our new publication, comprehensive analysis of one tumor entity, identification of biomarkers for predicting treatment responses, screening of a large number of compounds in diverse tumor populations and many more. Please reach out to learn more!
Source: EPO Gmbh Newsletter December 2020: Single Mouse Trialsepo-berlin.com
Research, Patient care / 30.12.2020
Integration of BIH into Charité and the privileged partnership with the MDC
Joint press release of the Berlin Institute of Health and Charité – Universitätsmedizin Berlin
On January 1, 2021, the Berlin Institute of Health (BIH) will become the translational research unit of Charité – Universitätsmedizin Berlin and will then form – alongside the hospital and the medical faculty – Charité’s third pillar. The Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) will become the Privileged Partner of the BIH. The three institutions are completing the final stage of implementing the administrative agreement between the federal government and the State of Berlin that was signed by German Research Minister Anja Karliczek and Governing Mayor of Berlin and Senator for Science and Research Michael Müller in July 2019. Through this novel science policy initiative, the federal government will be structurally involved for the first time in an institution of a university medical center and will have a seat on Charité’s Supervisory Board.
German Research Minister Anja Karliczek explains: “The integration of the BIH into Charité will finally become reality at the turn of the year. We are placing great hope in this new structure, which closely links together medical research and clinical practice. I would like to thank all those involved for their commitment and dedication to implementing the integration over the past months. We are all very excited about the research activities. I wish the BIH, Charité and the Max Delbrück Center much success with their joint cooperation. I am convinced that this alliance will become a national and international beacon for translational biomedical research.”
Governing Mayor of Berlin and Senator for Science and Research Michael Müller says: “The integration of the BIH into Charité will greatly benefit medical research and the healthcare hub of Berlin, but above all patients all across Germany. The path was not always easy, but it was always right to pursue this goal. I would therefore like to warmly thank everyone who in the past months has helped bring this process to a successful conclusion. The fact that the federal government is so strongly committed to a state institution on a permanent basis and that we are all working in unison is not something that can be taken for granted and is a sign of confidence in the outstanding work that is being done at Charité, the BIH and the MDC.”
Professor Christopher Baum will in the future represent the BIH in Charité’s Board of Directors as Board Member responsible for the translational research unit. He welcomes the integration for he is convinced that translational medicine depends on close interaction between research and clinical care. “We belong together, but at the same time we will maintain our special identity and purpose. We are working together for the benefit of patients who urgently need new medical approaches. Both perspectives – that of today’s clinical care practices and that of tomorrow’s medicines – stimulate our scientific work.”
Professor Heyo K. Kroemer,Chief Executive Officer of Charité, welcomes the BIH as the third pillar for translational research within Charité: “I look forward to working with the BIH to further advance the translation of research findings into clinical care for our patients and to fruitfully use the synergies between Charité and the BIH. Yet the integration is not only important for us, but has the potential to serve as a blueprint for future federal-state cooperation in supporting research. Special thanks are especially due to Axel Pries, who over the past years has not only been deeply committed to this project, but has also played a key role in driving it forward.”
Professor Axel Radlach Pries, Dean of Charité, served for two years, until early October 2020, as interim Chief Executive Officer of the BIH. He looks with satisfaction on what has been achieved and with much anticipation to the next phase: “Integrating the BIH into Charité and establishing the Privileged Partnership with the MDC has required very extensive coordination between our three institutions. The implementation of the administrative agreement can now be concluded as planned and without any notable problems. Parallel to this process, the BIH has established new structures, made dynamic scientific progress and attracted outstanding researchers to Berlin. I therefore have no doubt that going forward the BIH will be successful as the Charité’s third pillar.”
Professor Thomas Sommer, interim Scientific Director of the MDC, says: “I very much look forward to the close collaboration. As a bridge between basic research and clinical practice, the BIH is the ideal partner for us in Berlin. Our scientists provide innovative capabilities in vascular biomedicine and single cell analysis and help advance technology facilities. The MDC, the BIH and Charité want to further develop the idea of a translational research commons focused on improving the well-being of patients. Our close links will give the healthcare hub of Berlin a boost.”
Turning research into health
The mission of the BIH, which was founded in 2013, is to transfer basic research findings to the patient’s bedside and, vice versa, to use clinical observations to develop new research ideas. In the past this has already required close collaboration between the BIH, Charité and the MDC. For example, Charité and the BIH jointly run the Clinical Study Center (CSC) in order to significantly improve the quality of all clinical studies and together with other partners have launched the BIH Charité Clinician Scientist Program to train a new generation of scientists with translational training. The technology transfer unit BIH Innovations is also a joint undertaking by the two institutions. During the coronavirus pandemic, BIH researchers have teamed up with Charité scientists and physicians to make valuable discoveries in the fight against the SARS-CoV-2 virus and the COVID-19 disease. Their findings have been published in leading scientific journals.
“The trusting collaboration between Charité and the BIH, as well as the MDC, is not only tried and tested, but also works excellently,” says Professor Kroemer. “The successful application of our three institutions to be a location of the National Center for Tumor Diseases in Berlin is an expression of this. Now it’s a matter of optimizing the framework conditions even further to create the best environment for translational research.”
Promoting translation nationwide
With its integration into Charité, the BIH has also received a mandate from the federal government to support promising translational projects throughout Germany. “We are delighted to take on this mandate,” says Christopher Baum. “And here, in particular, I see us playing a role in rare and complex diseases, for which we want to specifically expand the possibilities of university medicine.” Baum also wants to further develop translation into an exact science whose results can not only be measured quantitatively and objectively but also reproduced. “That will be necessary in order to identify those projects that are most promising and take the best possible next steps in each case,” he explains. Here the BIH Quest Center has already done crucial groundwork to raise the quality of biomedical research.
Single cells, blood vessels and regenerative medicine
The BIH has established three focus areas in collaboration with Charité and the MDC, selecting areas that link up excellent research approaches with clinical expertise. The focus area “Single Cell Technologies for Personalized Medicine” aims to use innovative single cell technologies to answer clinical research questions, while the focus area “Translational Vascular Biomedicine” seeks to gain a better understanding of how malfunctions in the smallest of blood vessels are responsible for many common diseases. Through the full takeover of the BCRT, the BIH Center for Regenerative Therapies, from 2021 and the cooperation with the German Stem Cell Network (GSCN), the BIH will conduct research in particular in the field of stem cell research and advanced therapy medicinal products (ATMPs) and translate its findings into practice.
Multiple locations for the BIH
The integration of the BIH into Charité will increase the number of scientific teams belonging to the BIH from 43 at present to 58; by the end of 2021 this number will be 71. The BIH will then have around 400 employees, who will be spread across multiple locations: Starting in March, the scientific teams working on vascular biomedicine will move into the Käthe Beutler Building in Berlin-Buch, in the immediate vicinity of the Privileged Partner, the MDC. In this building, named after a Jewish pediatrician and researcher, BIH and MDC teams will work together under one roof. In the Outpatient, Translation and Innovation Center (Ambulanz-, Translations- und Innovationszentrum – ATIZ) in Berlin-Mitte, which celebrated its topping-out ceremony in July 2020 and is scheduled for completion in early 2022, teams involved in digital medicine, such as the BIH Digital Health Center, and other research groups will work together with experts from Charité. ATIZ will also house the joint Clinical Study Center. The single cells focus area will be based at the MDC’s Berlin Institute for Medical Systems Biology (BIMSB), which is also located in Berlin-Mitte. The scientific teams working in the field of regenerative medicine will primarily carry out research at the Charité Campus Virchow Clinic in Berlin-Wedding, on the premises of the BCRT. The BIH Digital Health Accelerator will move into new offices at Zirkus in Berlin-Mitte at the beginning of 2021.
Research / 21.12.2020
The Achilles’ heel of cancer stem cells
Colon cancer stem cells have one weak spot: the enzyme Mll1. An MDC team led by Walter Birchmeier has now shown in Nature Communications that blocking this protein prevents the development of new tumors in the body.
Since colonoscopies were introduced in Germany for early cancer detection, the number of diagnoses of advanced cancer every year has decreased, as precancerous lesions can now be detected and immediately removed as part of the examination. As a result, the death rate from colon cancer has also gone down – by 26 percent in women and 21 percent in men. Nevertheless, it remains the fourth deadliest cancer in the Western world – just behind lung, prostate and breast cancer. This is because the slow-growing tumors only become noticeable in the advanced stages of the disease and are therefore often diagnosed too late. Survival rate for advanced colorectal cancer is just five percent.
“Treatment options are very limited – not least because the cancer can return even after successful chemotherapy,” explains Johanna Grinat, the study’s lead author and a doctoral student in the Signal Transduction in Development and Cancer Lab. “The recurrent cancer is often more aggressive than the original tumor, which is thought to be caused by cancer stem cells. So we took a closer look at these cells.”
Molecular switch found in cancer stem cells
The researchers led by Professor Walter Birchmeier identified Mll1, a protein that regulates stem cell genes in mice and in human colon cancer cells. In mice, the team was able to genetically trigger the formation of intestinal tumors. However, if the mice lacked the gene for Mll1, no tumors were able to be induced. And this seems to be the case in humans as well: Human colon cancer cell cultures that the team enriched with cancer stem cells lost some of their stem cell properties and behaved less aggressively when Mll1 was blocked. Together with Professor Eduard Batlle and bioinformaticians at the IRB in Barcelona, the MDC group used clinical data to show that colon cancer patients whose tumors have a large amount of this protein have a worse prognosis than patients with tumors that contain little Mll1.
Mll1 is an enzyme that sits on the DNA and controls the expression of certain genes “epigenetically,” as the researchers say. “It primarily does this in cancer stem cells, where the Wnt signaling pathway is strongly activated,” Grinat explains. “This means that, by deactivating it, we can specifically treat cancer stem cells.”
The Wnt signaling pathway regulates the self-renewal and division of stem cells. If mutations occur that trigger a more active Wnt signaling cascade, the affected stem cells become more resistant than healthy stem cells. They then multiply uncontrollably and form tumors. Although chemotherapy slows down the cell division, it can also increase the selection pressure on cancer stem cells: “They become resistant to the treatment and form new tumors that, due to the mutation, grow more rapidly and are even more aggressive,” says Dr. Julian Heuberger. This is why it is so important, he explains, to understand the regulatory mechanisms of cancer stem cells in particular. The postdoctoral researcher is also lead author and head of the study and now works in the Division of Hepatology and Gastroenterology in Charité’s Medical Department. “With Mll1,” he adds, “we have found a molecular switch that primarily controls the self-renewal and division of cancer stem cells in colon cancer”
Hope and more effective therapies
Genetically “knocking out” a gene, as the scientists did with mice, is not possible in humans. In mice, the formation of cancer stem cells can be followed over time and there are always enough stem cells available for experiments. However, MII1 could be blocked with a chemical drug. Small molecules have already been developed for this research, for example, the inhibitors MI-2 and MM-401, which bind to essential Mll1 complexes and thereby inactivate its function. “Understanding the way these molecules work will enable us to develop and test these and even more clinically effective Mll1 inhibitors,” says Birchmeier, who is the study’s last author.
Healthy stem cells in the intestine are apparently not blocked in the process. “We were able to use another system in mice, salivary gland cancer cells, to show that Mll1 only affects cancer cells and not healthy stem cells,” says Birchmeier. This also provides hope for the treatment of other types of cancer, as animal models have shown that head and neck tumors have the same Achilles’ heel. “On the basis of our mouse studies, clinical trials are currently being conducted at the University Hospital of Düsseldorf to evaluate the use of Mll1 inhibitors in the treatment of head and neck tumors.“
If they are successful, patients with colon cancer could be treated in the future with both chemotherapy and Mll1 inhibitors, i.e., therapeutics that specifically impede cancer stem cells. This increases the chances of a successful treatment – even with advanced colon cancer.
Text: Catarina Pietschmann
Research, Innovation, Patient care, Education / 21.12.2020
Calling all young STEM talent
The 57th edition of the “Jugend forscht” competition will soon kick off under the theme “Lass Zukunft da.” The MDC is once again co-sponsoring the search for tomorrow’s scientists – this year to be held fully virtual. The young researchers apparently don’t mind the new format: almost 9,000 children and young people have signed up for the competition so far.
During extraordinary times like this pandemic, it is particularly important to promote young talent in the fields of science, technology, engineering and mathematics (STEM) through special initiatives. The Germany-wide young researcher competition “Jugend forscht” is therefore going virtual this year, with the regional round starting in February.
For the first time, Buch campus is one of the three locations in Berlin. The competition’s sponsors include the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Campus Berlin-Buch GmbH and – as an associate sponsor – the Experimental and Clinical Research Center (ECRC) of the MDC and Charité – Universitätsmedizin Berlin.
“Let there be a future”
Despite facing difficult circumstances at school and in their free time, almost 9,000 children and young people have signed up and submitted a project idea. This year, they will present their research projects under the theme “Lass Zukunft da” (Let there be a future) at over 120 competitions across Germany.
A total of 64 projects by schoolchildren and students between the ages of 10 and 21 will compete in the regional round hosted by the Buch campus. The sponsoring institutions are in charge of organizing a program for the regional rounds – from the introductory event to the presentations and their evaluation by the jury to the award ceremony.
“As a science and biotech campus, we’re excited about being able to support the ‘Jugend forscht’ competition,” says Dr. Ulrich Scheller, managing director of Campus Berlin-Buch GmbH. “Promoting young talent in the STEM fields is one of our key aims, which we also pursue through other activities such as the Life Science Learning Lab (Gläsernes Labor) for schoolchildren.”
About the competition
“Jugend forscht” is Germany’s biggest and best-known competition for the next generation of researchers. It is a joint initiative of the federal government, the magazine Stern, the business and scientific communities, and schools. The aim is to support talented achievers in the areas of science, technology, engineering and mathematics (STEM). Young researchers compete each year in seven subject areas. Gifted children up to the age of 14 can take part in the junior segment “Schüler experimentieren,” while “Jugend forscht” is open to young people from the age of 15 onwards. The non-profit association Stiftung Jugend forscht e.V. organizes the competition. (https://www.jugend-forscht.de/information-in-english.html)