Research / 25.09.2020
An in-depth atlas of the heart
Researchers from three continents have produced a first extensive draft of a cell atlas of the human heart to understand how this vital organ functions and to shed light on what goes wrong in cardiovascular disease. As the team reports in Nature, it reveals a huge cellular and molecular diversity.
Each day, the human heart beats around 100,000 times. It keeps blood flowing in one direction through the four different chambers, varying speed with rest, exercise or stress. This is extremely complex and needs the cells in each part of the heart to coordinate with each other for every heartbeat. Researchers have, until now, known amazingly little about how the organ manages to pull off this daunting feat, which ensures that the body is supplied with oxygen and nutrients and carbon dioxide and waste products are carried away from other vital organs and tissues.
In order to change this, 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), teamed up with Dr Sarah Teichmann from Wellcome Sanger Institute in Cambridge, UK; Professors Jonathan Seidman and Christine Seidman, both from Harvard Medical School in Boston; and Dr Michela Noseda from Imperial College London. Together they launched the Human Heart Cell Atlas, a project dedicated to probing and understanding the human heart, cell by cell. The Human Heart Cell Atlas is part of the international Human Cell Atlas and has received a grant of nearly four million US dollars from the Chan Zuckerberg Initiative as well as 2.5 million euros from the German Center for Cardiovascular Research (DZHK ) and the British Heart Foundation (BHF).
Insights from around half a million cells and cell nuclei
The teams involved in this project, comprised of 33 scientists from 19 institutions in Germany, the United Kingdom, the United States, Canada, China and Japan, analysed around half a million individual cells and cell nuclei of the human heart. Now, they are releasing their first extensive draft of the human heart cell atlas in the journal Nature. It shows the huge diversity of cells and reveals previously unknown subtypes of heart muscle cells and supporting cardiac cells as well as certain types of protective immune cells in the heart and an intricate network of blood vessel cells. It also predicts how the cells communicate to keep the heart working.
“This is the first time anyone has looked at the single cells of the human heart at this scale, which has only become possible with large-scale single cell sequencing,” says Professor Norbert Hübner, senior author from the MDC, Charité – Universitätsmedizin Berlin, the Berlin Institute of Health (BIH ) and the DZHK. “This study shows the power of single cell genomics and international collaboration. Knowledge of the full range of cardiac cells and their gene activity is fundamental to understanding how the heart functions and to unravel how it responds to stress and disease.”
Professor Christine Seidman, a senior author from Brigham and Women’s Hospital, Harvard Medical School and Howard Hughes Medical Institute, says: “Millions of people are undergoing treatments for cardiovascular diseases. Understanding the healthy heart will help us understand interactions between cell types and cell states that can allow lifelong function and how these differ in diseases. Ultimately these fundamental insights may suggest specific targets that can lead to individualized therapies in the future, creating personalized medicines for heart disease and improving the effectiveness of treatments for each patient.” Cardiovascular disease is the leading cause of death worldwide, killing an estimated 17.9 million people each year, with heart attacks and strokes causing the majority of these.
A heterogenous organ
For their work, the researchers used seven female and seven male hearts from brain-dead donors between 40 and 75 years of age from Europe and the United States whose hearts were healthy but not suitable for transplantation for various reasons. In order to characterize the heart cells as precisely as possible, the scientists examined which genes are switched on in the individual cells and cell nuclei from six different regions of the heart. These regions included the left and right atria and ventricles; the lower tip of the heart, called the apex; and the ventricular septum, the partition that separates the two ventricles. After all, the heart is a rather heterogeneous organ. For example, the differences in blood pressure between the left and right ventricles are quite large.
Using single cell sequencing methods, which the scientists adapted beforehand to the particular properties of heart tissue, and with the aid of machine learning and imaging techniques, the team discovered that there were major differences in the cells in these areas of the heart. Each area had specific sets of cells, highlighting different developmental origins and potentially different responses to treatments.
All known cell types in the heart also contain numerous subtypes. There is, for instance, not one heart muscle cell, but many different cardiomyocytes with, in some cases, different functions. The gene expression profiles indicate that of some of them are equipped to handle a much higher metabolic rate than others. The researchers don’t yet know why this is so. They also found very different patterns of gene expression in the fibroblasts that form the heart’s connective tissue.
Too much scaffolding
After a heart attack, or myocardial infarction, the fibroblasts attempt to replace damaged cardiac tissue with new scaffolding to provide support to withstand the forces associated with a normal heartbeat. Sometimes, they overbuild this scaffolding, or extracellular matrix (ECM). This excess scar tissue is often responsible for arrythmias and heart failure.
“We saw various subtypes of fibroblasts. Some produce extracellular matrix via different processes. Some remodel this scaffolding. And some communicate with immune cells that are physically next to them. This could also influence how much scarring occurs,” says MDC researcher Dr Henrike Maatz, a member of Hübner’s lab and one of the four first authors of the paper. “With the Human Heart Cell Atlas, we created a basis to really understand fibrotic processes: Why are they different in the ventricles and atria? How can we control them?”
Another unexpected finding was that the ventricles of the female hearts had higher numbers of muscle cells and fewer connective tissue cells than those of the male hearts – even though they are typically smaller. This finding may be a clue to why women are less vulnerable than men to cardiovascular diseases. “It’s intriguing but it’s based on just seven hearts of each gender. We’ll have to see whether this result holds up to further investigation,” says Maatz.
Zooming in to investigate small areas
As part of this study, the researchers also investigated the blood vessels running through the heart in unprecedented detail. The atlas showed how the cells in these veins and arteries are adapted to the different pressures and locations, and could help understand what goes wrong in the blood vessels during coronary heart disease.
Dr Michela Noseda, a senior author from the National Heart and Lung Institute, Imperial College London, says: “Our international effort provides an invaluable set of information to the scientific community by illuminating the cellular and molecular details of cardiac cells that work together to pump blood around the body. We mapped the cardiac cells that can be potentially infected by SARS-CoV-2 and found that specialized cells of the small blood vessels are also virus targets. Our data sets are a goldmine of information for understanding the subtleties of heart disease.”
For a long time scientists only had a bird’s eye view of the heart, which was like looking at a map from above. With the help of single-cell sequencing technology, researchers can now, for the first time, zoom in to investigate small areas.
Dr Sarah Teichmann, a senior author from the Wellcome Sanger Institute and co-chair of the Human Cell Atlas Organising Committee, says: “This great collaborative effort is part of the global Human Cell Atlas initiative to create a ‘Google map’ of the human body. Openly available to researchers worldwide, the Heart Cell Atlas is a fantastic resource, which will lead to new understanding of heart health and disease, new treatments and potentially even finding ways of regenerating damaged heart tissue.”
This study was supported by the British Heart Foundation (BHF), European Research Council, the Federal Ministry of Education and Research of Germany, the German Center for Cardiovascular Research (DZHK), the Leducq Fondation, the German Research Foundation (DFG ), the Chinese Scholarship Council (CSC), the Alexander von Humboldt Foundation, the European Molecular Biology Organization (EMBO ), the Canadian Institutes for Health Research (CIHR), the Heart and Stroke Foundation (HSF), Alberta Innovates (AI), the Chan Zuckerberg Initiative (CZI), the Wellcome Sanger Institute, Wellcome, the US National Institutes of Health (NIH) and the Howard Hughes Medical Institute.
- All data from this study can be explored online.
- WHO statistics on cardiovascular disease
- How the heart works (website of the British Heart Foundation)
- Press release: “Straight to the heart”
- Press release: “Unlocking the secrets of heart cells”
Monika Litviňuková, Carlos Talavera-López, Henrike Maatz, Daniel Reichart et al. (2020): “Cells of the adult human heart”. Nature, DOI: 10.1038/s41586-020-2797-4.
Professor Norbert Hübner
Head of the Genetics and Genomics of Cardiovascular Diseases Group
Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
Dr Henrike Maatz
Postdoc in the Genetics and Genomics of Cardiovascular Diseases Group
Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
The Max Delbrück Center for Molecular Medicine
The Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) was founded in Berlin in 1992. It is named for the German-American physicist Max Delbrück, who was awarded the 1969 Nobel Prize in Physiology and Medicine. The MDC’s mission is to study molecular mechanisms in order to understand the origins of disease and thus be able to diagnose, prevent, and fight it better and more effectively. In these efforts the MDC cooperates with Charité – Universitätsmedizin Berlin and the Berlin Institute of Health (BIH) as well as with national partners such as the German Center for Cardiovascular Research (DZHK) and numerous international research institutions. More than 1,600 staff and guests from nearly 60 countries work at the MDC, just under 1,300 of them in scientific research. The MDC is funded by the German Federal Ministry of Education and Research (90 percent) and the State of Berlin (10 percent), and is a member of the Helmholtz Association of German Research Centers. www.mdc-berlin.de
The Wellcome Sanger Institute
The Wellcome Sanger Institute is a world leading genomics research centre. We undertake large-scale research that forms the foundations of knowledge in biology and medicine. We are open and collaborative; our data, results, tools and technologies are shared across the globe to advance science. Our ambition is vast – we take on projects that are not possible anywhere else. We use the power of genome sequencing to understand and harness the information in DNA. Funded by Wellcome, we have the freedom and support to push the boundaries of genomics. Our findings are used to improve health and to understand life on Earth. Find out more at www.sanger.ac.uk
Wellcome exists to improve health by helping great ideas to thrive. We support researchers, we take on big health challenges, we campaign for better science, and we help everyone get involved with science and health research. We are a politically and financially independent foundation. www.wellcome.ac.uk
The Imperial College London
Imperial College London is one of the world's leading universities. The College's 17,000 students and 8,000 staff are expanding the frontiers of knowledge in science, medicine, engineering and business, and translating their discoveries into benefits for our society.
Imperial is the UK’s most international university, according to Times Higher Education, with academic ties to more than 150 countries. Reuters named the College as the UK's most innovative university because of its exceptional entrepreneurial culture and ties to industry. www.imperial.ac.uk
The Harvard Medical School
Harvard Medical School has more than 11,000 faculty working in the 11 basic and social science departments comprising the Blavatnik Institute and at the 15 Harvard-affiliated teaching hospitals and research institutes: Beth Israel Deaconess Medical Center, Boston Children’s Hospital, Brigham and Women’s Hospital, Cambridge Health Alliance, Dana-Farber Cancer Institute, Harvard Pilgrim Health Care Institute, Hebrew SeniorLife, Joslin Diabetes Center, Judge Baker Children’s Center, Massachusetts Eye and Ear/Schepens Eye Research Institute, Massachusetts General Hospital, McLean Hospital, Mount Auburn Hospital, Spaulding Rehabilitation Network and VA Boston Healthcare System. www.hms.harvard.eduwww.mdc-berlin.de
Innovation / 21.09.2020
DCprime and Glycotope Sign Licensing Agreement to Advance Program Combining Cancer Vaccination and Therapeutic Antibody Platforms
21.09.2020 / DCprime, the front-runner in the field of relapse vaccines, and Glycotope GmbH, a clinical-stage oncology/immuno-oncology company built on world-leading glycobiology expertise, today announced an expansion of their existing partnership through a new research collaboration and licensing agreement.
Originally initiated in July 2018, the partnership combines DCprime’s proprietary DCOne® relapse vaccine platform and Glycotope’s highly specific anti-tumor antibody platform with the aim of developing novel immunotherapeutic approaches in oncology. Under the expanded agreement a therapeutic antibody program has been selected from Glycotope’s portfolio which will be further evaluated in preclinical studies to potentially treat a broad range of solid tumors.
“Today’s agreement further exemplifies our commitment to develop novel cancer immunotherapies based on partnerships, in addition to pioneering the relapse vaccine paradigm. Our relationship with Glycotope has matured and brought forward a very promising program, potentially leading to a highly differentiated novel combination therapy towards solid tumors,” commented Erik Manting, CEO of DCprime.
“We are delighted to expand our collaboration with DCprime and to see one of our antibody programs move forward in a novel combination therapy approach with a cancer vaccine based on the DCOne® platform,” said Henner Kollenberg, Managing Director of Glycotope GmbH. “Glycotope has developed a growing pipeline of high-value cancer therapies and today’s announcement further highlights the promising product opportunities for monotherapeutic or combinational approaches offered by our portfolio.”
DCprime is the front-runner in the field of relapse vaccines, a new class of oncology vaccines administered after or in conjunction with standard of care therapy to delay or prevent disease recurrence. Our lead product is a whole-cell-based vaccine addressing blood cancers with a high risk of relapse. We are pursuing similar vaccination approaches for solid tumors. We believe relapse vaccines will improve survival by putting the patient’s immune system back in control. For more information, please visit: https://dcprime.com.
Glycotope, founded in 2000 in Berlin, focuses on the development of antibodies with an increased tumor-specificity by binding to proteins carrying tumor-specific carbohydrate structures. These “GlycoBodies” are developed in different highly potent formats such as ADCs, bispecifics or in combination with cell and gene therapy approaches in-house or by license partners. The Company’s further pipeline includes biopharmaceuticals for various oncological indications. Visit https://www.glycotope.com.
Research / 08.09.2020
Towards a cell-based interceptive medicine in Europe
Hundreds of researchers, clinicians, industry leaders and policy makers from all around Europe are united by a vision of how to revolutionize healthcare. In a perspective in Nature and the LifeTime Strategic Research Agenda they now present a roadmap of how to leverage the latest scientific breakthroughs and technologies over the next decade, to track, understand and treat human cells throughout an individual’s lifetime.
The LifeTime initiative, co-coordinated by the Max Delbrück Center of Molecular Medicine in the Helmholtz Association (MDC) in Berlin and the Institut Curie in Paris, has developed a strategy to advance personalized treatment for five major disease classes: cancer, neurological, infectious, chronic inflammatory and cardiovascular diseases. The aim is a new age of personalized, cell-based interceptive medicine for Europe with the potential of improved health outcomes and more cost-effective treatment, resulting in profoundly changing a person’s healthcare experience.
Earlier detection and more effective treatment of diseases
To form a functioning, healthy body, our cells follow developmental paths during which they acquire specific roles in tissues and organs. But when they deviate from their healthy course, they accumulate changes leading to disease which remain undetected until symptoms appear. At this point, medical treatment is often invasive, expensive and inefficient. However, now we have the technologies to capture the molecular makeup of individual cells and to detect the emergence of disease or therapy resistance much earlier.
Using breakthrough single-cell and imaging technologies in combination with artificial intelligence and personalized disease models will allow us to not only predict disease onset earlier, but also to select the most effective therapies for individual patients. Targeting disease-causing cells to intercept disorders before irreparable damage occurs will substantially improve the outlook for many patients and has the potential of saving billions of Euros of disease-related costs in Europe.
A detailed roadmap for implementing LifeTime
The perspective article “The LifeTime initiative and the future of cell-based interceptive medicine in Europe” and the LifeTime Strategic Research Agenda (SRA) explain how these technologies should be rapidly co-developed, transitioned into clinical settings and applied to the five major disease areas. Close interactions between European infrastructures, research institutions, hospitals and industry will be essential to generate, share and analyze LifeTime’s big medical data across European borders. The initiative’s vision advocates ethically responsible research to benefit citizens all across Europe.
According to Professor Nikolaus Rajewsky, scientific director of the Berlin Institute for Medical System Biology at the Max Delbrück Center for Molecular Medicine and coordinator of the LifeTime Initiative, the LifeTime approach is the way into the future: "LifeTime has brought together scientists across fields – from biologists, to clinicians, data scientists, engineers, mathematicians, and physicists – to enable a much improved understanding of molecular mechanisms driving health and disease. Cell-based medicine will allow doctors to diagnose diseases earlier and intercept disorders before irreparable damage has occurred. LifeTime has a unique value proposition that promises to improve the European patient’s health.”
Dr. Geneviève Almouzni, director of research at CNRS, honorary director of the research center from Institut Curie in Paris and co-coordinator of the LifeTime Initiative believes that the future with LifeTime offers major social and economic impact: “By implementing interceptive, cell-based medicine we will be able to considerably improve treatment across many diseases. Patients all over the world will be able to lead longer, healthier lives. The economic impact could be tremendous with billions of Euros saved from productivity gains simply for cancer, and significantly shortened ICU stays for Covid-19. We hope EU leaders will realize we have to invest in the necessary research now."
- The LifeTime Initiative
- Focus area ”Single cell technologie for personalized medicine” at the MDC and BIH
- Single cell analysis at the MDC
- Rajewsky, Nikolaus et al. (2020): “The LifeTime initiative and the future of cell-based interceptive medicine in Europe”. Nature, DOI: 10.1038/s41586-020-2715-9.
- LifeTime Strategic Research Agenda
- Torres-Padilla, Maria Elena et al. (2020): “Thinking ‘ethical’ when designing a new biomedical research consortium”. EMBO J, DOI: 10.15252/embj.2020105725
Prof. Dr. Nikolaus Rajewsky
Co-coordinator of the LifeTime Initiative
Director of the Berlin Institute of Medical Systems Biology (BIMSB)
Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
+49 (0)30 9406-2999 (office)
Communication manager for the LifeTime Initiative
Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
+49 176 6563 9465
The LifeTime Initiative is a growing community of more than 100 leading European research institutions and hospitals, together with international advisers and over 80 supporting companies. LifeTime includes the preeminent European laboratories developing multi-omic strategies, scientific infrastructures, bioimaging and computational technologies, as well as world-renowned laboratories in the area of personalized disease models, bioethicists and a core group of leading clinician scientists. Many of the involved institutions include or are linked to translational/clinical research facilities and hospitals, ensuring that LifeTime discoveries can be rapidly translated into clinical practice.
Research / 03.09.2020
ERC funding for pioneering research
Two MDC scientists – Kathrin de Rosa and Ilaria Piazza – have earned ERC Starting Grants to fuel their pioneering research. They are seeking answers to questions that may one day change the way we approach vaccines and think about how small molecules influence gene expression and disease.
Dr. Kathrin de la Rosa and Dr. Ilaria Piazza, who are both junior group leaders at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), have each won European Research Council (ERC) Starting Grants. The prestigious grants provide about €1.5 million over five years to early-career scientists and scholars to build their own teams and conduct “high risk, high reward” research. The researchers must have completed their Ph.D. within the last two to seven years and have a scientific track record showing great promise. This year, 436 European scientists from diverse research fields will receive the funding.
“The ERC Starting Grants tend to fund projects that would perhaps fail in other contexts, because the ideas are, to simply put it, too crazy,” says Piazza, who heads the Allosteric Proteomics Lab. De la Rosa, who heads the Immune Mechanisms and Human Antibodies Lab, agrees: “It enables us to address more risky hypotheses.”
Small interactions, big impact?
Piazza investigates the interactions between proteins and small molecules, which can be either natural metabolites, or manmade drugs. “We know quite a lot about how proteins interact with each other, or interact with nuclei acids like DNA or RNA, but exploring how they interact with metabolites or drugs on a global scale, that is new,” Piazza says.
She has developed an innovative approach to analyze these interactions: a combination of protease, a protein that chops up or “cleaves” proteins, and mass spectrometry, a machine that detects and reads all the different segments of proteins, called peptides. Piazza compares peptide chains of a protein exposed to a small molecule versus not exposed. If the chains are different, it indicates the protein was cut differently because it was bound to the small molecule.
The power of the approach is she can study thousands of proteins at the same time, to see which ones bind to a particular small molecule of interest. The “crazy” part of her hypothesis is that the interactions between proteins and small molecules that occur inside the cell nucleus can directly affect gene expression. She suspects these interactions – which reflect the influences of the outside world, versus predetermined genetics – hold the key to explaining why diseases develop.
“Why is it that twins, which have the same genetic code, can have different personalities and diseases?” Piazza asks. “How we live and the environment we live in affect how DNA is translated into proteins, and I believe the interactions between proteins and small molecules plays a huge role that is totally unexplored.”
It might be that the effect is much smaller than she suspects, but receiving the ERC Starting Grant is validation the idea is worth pursing, Piazza says. The grant of about €1.7 million for her project proteoRAGE will enable her to hire additional team members for her lab, which started earlier this year. “I need brave people who aren’t afraid to think out of the box,” she says.
Exploiting nature’s successful tricks
Kathrin de la Rosa, who started her immunology research lab at MDC in 2018, could hardly believe she had won the grant. “But when congratulations came from others who helped me through the submission process, then I could celebrate,” she says. She was awarded about €1.5 million for her project AutoEngineering.
It is focused on tweaking the body’s own B cells in the laboratory so that they produce antibodies that are even more powerful than their natural counterparts. But de la Rosa will not use genetic scissors such as CRISPR-Cas9 to alter their DNA. “If these scissors cut in the wrong place, there can be unintended side effects. The cells can even turn cancerous,” she says. Instead, de la Rosa wants to harness the natural ability of B cells.
B cells are a type of white blood cell. They produce highly specialized antibodies that recognize and bind to intruders in the body. In this way, they attract defensive cells that destroy pathogens such as viruses, bacteria and parasites. When B cells encounter such pathogens, they get activated – they multiply and their DNA strands break especially often at sites where antibodies are encoded. This randomly modifies the antibodies, creating versions with a better fit. In rare cases during malaria infection, antibodies “steal” a segment of another gene: A whole new pathogen receptor is inserted that leads to broadly reactive antibodies. “Pathogens have a harder time escaping from these antibodies, even when the intruder mutates and changes its surface,” de la Rosa says.
De la Rosa wants to uncover the process of natural “segment stealing” step by step, which she and colleagues observed for the first time in 2016. Her lab will seek to understand the underlying mechanisms to induce the process in the petri dish. “First, we have to find efficient ways of exploiting this cell’s own mechanism, test whether it is safer than CRISPR-Cas9 and then use it to create new types of antibodies,” she says. “Just imagine if we could copy the most successful tricks from nature and thereby help the immune system keep pathogens such as HIV in check!” For her and her team it is very exciting to work on something that could one day be a completely new approach to vaccines. “It’s going to be an interesting journey,” de la Rosa says.
Text: Laura Petersen
Research, Patient care / 03.09.2020
In pursuit of the origin and role of ecDNA
How does cancer develop and how does it progress? Dr. Anton Henssen from the Experimental and Clinical Research Center (ECRC) wants to find out more about circular DNA in order to use its cancer cell-specific characteristics for therapy, diagnosis or clinical prognosis. He has now been awarded an ERC Starting Grant.
The research community is increasingly turning its attention to the role of extrachromosomal DNA in cancer development. According to the latest research, cancer cells appear to have the ability to produce small, ring-shaped sections of extrachromosomal DNA known as ecDNA, which they can then reintegrate into existing chromosomal DNA. If the original order of DNA segments is disrupted, this can lead to the dysregulation of cell growth and cancer.
“We have already shown that this phenomenon occurs more frequently than previously thought in primary neuroblastoma, a type of cancer found primarily in children,” confirms Dr. Anton Henssen, scientist at the Experimental and Clinical Reseach Center (ECRC ), a facility jointly operated by the Charité – Universitätsmedizin Berlin and the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC). Henssen also works as a physician at Charité’s Department of Pediatrics, Division of Oncology and Hematology. He adds: “This observation suggests that the circularization of DNA is an important driver behind the remodeling of cancer cell DNA”.
The intention of CancerCirculome
The launch of the CancerCirculome project will see the pediatric oncologist and Emmy Noether Independent Junior Research Group leader work alongside his research team to unravel the principles governing DNA modifications in pediatric cancers. Over the next five years, the researchers will focus on the mechanisms and effects of DNA circularization and the reintegration of DNA fragments into chromosomes. “The details of how ecDNA is made and how it replicates remain unknown. To get closer to identifying the origin of these tiny ring-shaped fragments, we will reconstruct the exact DNA sequences they contain,” explains Henssen. He adds: “To do this we will identify the molecular factors responsible for the generation and replication of ecDNA at the single-cell level.”
The team hope to discover previously unknown mechanisms which cause cells to lose control over cell growth and proliferation. “These mechanisms could be used as new diagnostic and treatment targets – not just in pediatric cancers, but as a fundamental principle governing all cancers,” says Henssen, who is also a BIH Charité Clinician Scientist and a researcher at the German Cancer Consortium (DKTK). Using single-cell CRISPR-based methods (which enable researchers to alter and disrupt ecDNA in a targeted manner), the researchers will attempt to demonstrate the biological effects of DNA circularization and reintegration. The researchers plan to target and manipulate the genetic information contained in ecDNA fragments inside human cells in order to evaluate their effects on cancer cell fitness and function. The researchers also plan to study the behavior, presence and genomic integration of these fragments at the single-cell level during cancer treatment. The aim is to uncover the oncogenic role of ecDNA and determine the mechanisms responsible for the reintegration of ecDNA into chromosomes.
The researchers hope to translate this knowledge into clinical benefits for patients. “We hope to use our understanding of the underlying principles to define novel diagnostic and predictive markers which could then be used for the personalized diagnosis, risk assessment and treatment of cancers,” concludes Henssen. The researchers’ long-term aim is to contribute to and inform our understanding of different cancers, and to support clinical trials involving personalized treatments for children with difficult-to-treat cancers.
Research / 27.08.2020
A team at the MDC has answered a question that has puzzled scientists for some 40 years. In the journal Cell, the group explains how cells are able to switch on completely different signaling pathways using only one signaling molecule: the nucleotide cAMP. To achieve this, the molecule is virtually imprisoned in nanometer-sized spaces.
There are up to a hundred different receptors on the surface of each cell in the human body. The cell uses these receptors to receive extracellular signals, which it then transmits to its interior. Such signals arrive at the cell in various forms, including as sensory perceptions, neurotransmitters like dopamine, or hormones like insulin.
One of the most important signaling molecules the cell uses to transmit such stimuli to its interior, which then triggers the corresponding signaling pathways, is a small molecule called cAMP. This so-called second messenger was discovered in the 1950s. Until now, experimental observations have assumed that cAMP diffuses freely – i.e., that its concentration is basically the same throughout the cell – and that one signal should therefore encompass the entire cell.
“But since the early 1980s we have known, for example, that two different heart cell receptors release exactly the same amount of cAMP when they receive an external signal, yet completely different effects are produced inside the cell,” reports Dr. Andreas Bock. Together with Dr. Paolo Annibale, Bock is temporarily heading the Receptor Signaling Lab at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) in Berlin.
Like holes in a Swiss cheese
Bock and Annibale, who are the study’s two lead authors, have now solved this apparent contradiction – which has preoccupied scientists for almost forty years. The team now reports in Cell that, contrary to previous assumptions, the majority of cAMP molecules cannot move around freely in the cell, but are actually bound to certain proteins – particularly protein kinases. In addition to the three scientists and Professor Martin Falcke from the MDC, the research project involved other Berlin researchers as well as scientists from Würzburg and Minneapolis.
“Due to this protein binding, the concentration of free cAMP in the cell is actually very low,” says Professor Martin Lohse, who is last author of the study and former head of the group. “This gives the rather slow cAMP-degrading enzymes, the phosphodiesterases (PDEs), enough time to form nanometer-sized compartments around themselves that are almost free of cAMP.” The signaling molecule is then regulated separately in each of these tiny compartments. “This enables cells to process different receptor signals simultaneously in many such compartments,” explains Lohse. The researchers were able to demonstrate this using the example of the cAMP-dependent protein kinase A (PKA), the activation of which in different compartments required different amounts of cAMP.
“You can imagine these cleared-out compartments rather like the holes in a Swiss cheese – or like tiny prisons in which the actually rather slow-working PDE keeps watch over the much faster cAMP to make sure it does not break out and trigger unintended effects in the cell,” explains Annibale. “Once the perpetrator is locked up, the police no longer have to chase after it.”
The team identified the movements of the signaling molecule in the cell using fluorescent cAMP molecules and special methods of fluorescence spectroscopy – including fluctuation spectroscopy and anisotropy – which Annibale developed even further for the study. So-called nanorulers helped the group to measure the size of the holes in which cAMP switches on specific signaling pathways. “These are elongated proteins that we were able to use like a tiny ruler,” explains Bock, who invented this particular nanoruler.
The team’s measurements showed that most compartments are actually smaller than 10 nanometers – i.e., 10 millionths of a millimeter. This way, the cell is able to create thousands of distinct cellular domains in which it can regulate cAMP separately and thus protect itself from the signaling molecule’s unintended effects. “We were able to show that a specific signaling pathway was initially interrupted in a hole that was virtually cAMP-free,” said Annibale. “But when we inhibited the PDEs that create these holes, the pathway continued on unobstructed.”
A chip rather than a switch
“This means the cell does not act like a single on/off switch, but rather like an entire chip containing thousands of such switches,” explains Lohse, summarizing the findings of the research. “The mistake made in past experiments was to use cAMP concentrations that were far too high, thus enabling a large amount of the signaling molecule to diffuse freely in the cell because all binding sites were occupied.”
As a next step, the researchers want to further investigate the architecture of the cAMP “prisons” and find out which PDEs protect which signaling proteins. In the future, medical research could also benefit from their findings. “Many drugs work by altering signaling pathways within the cell,” explains Lohse. “Thanks to the discovery of this cell compartmentalization, we now know there are a great many more potential targets that can be searched for.”
“A study from San Diego, which was published at the same time as our article in Cell, shows that cells begin to proliferate when their individual signaling pathways are no longer regulated by spatial separation,” says Bock. In addition, he adds, it is already known that the distribution of cAMP concentration levels in heart cells changes in heart failure, for example. Their work could therefore open up new avenues for both cancer and cardiovascular research.
Text: Anke Brodmerkelwww.mdc-berlin.de
Research / 25.08.2020
Eckert & Ziegler: Gallium-68-Generator erhält Zulassung für Kanada
Die Eckert & Ziegler Radiopharma GmbH hat von der kanadischen Gesundheitsbehörde Health Canada die Marktzulassung für ihren pharmazeutischen 68Ge/68Ga-Generator GalliaPharm® erhalten.
„Wir freuen uns, GalliaPharm® nun in Kanada anbieten zu können. Mittlerweile sind die Generatoren von Eckert & Ziegler in immer mehr Ländern erhältlich. Wenn sich in den kommenden Jahren Gallium-basierte Diagnosen auf breiter Front durchsetzen, sind wir als Lieferant dafür bestens gerüstet“, erklärt Dr. Lutz Helmke, Vorstandsmitglied der Eckert & Ziegler AG und verantwortlich für das Segment Medical. „Da es weltweit momentan viele klinische Studien mit sogenannten Theranostika gibt, erwarten wir eine steigende Nachfrage sowohl nach dem diagnostischen Radioisotop Gallium-68 als auch dem therapeutischen Radioisotop Lutetium-177.“
GalliaPharm® wird bereits erfolgreich für die Diagnose von neuroendokrinen Tumoren und demnächst auch für Prostatakrebs (Ga-68-PSMA) verwendet.
Galliumgeneratoren bieten eine preiswerte Alternative zur radioaktiven Markierung von Biomolekülen mit Gallium-68 im Rahmen der PET, einer bildgebenden Untersuchungsmethode, mit denen die An- oder Abwesenheit von krankem Gewebe nachgewiesen wird. Das Verfahren kommt vor allem bei der Diagnostik von Krebs, Herzinfarkten oder neurologischen Erkrankungen zum Einsatz. Bisher werden zur Markierung der Biomoleküle meist die Radioisotope Fluor-18 oder Kohlenstoff-11 benutzt. Hierfür sind Millioneninvestitionen für Großgeräte (Zyklotrone) erforderlich. Der 68Ge/68Ga-Generator dagegen hat in etwa die Größe einer Thermoskanne und kann wesentlich preiswerter bezogen werden, was in den nuklearmedizinischen Kliniken und Praxen Kosten senkt und Flexibilität erhöht.
Über Eckert & Ziegler.
Die Eckert & Ziegler Strahlen- und Medizintechnik AG gehört mit über 800 Mitarbeitern zu den weltweit größten Anbietern von isotopentechnischen Komponenten für Strahlentherapie und Nuklearmedizin. Die Eckert & Ziegler Aktie (ISIN DE0005659700) ist im TecDAX der Deutschen Börse gelistet.
Research / 14.08.2020
Targeting a Chronic Pain Gateway Could Bring Relief
A new approach to chronic pain treatment targets a molecule that moves pain messages into nerve cell nuclei. For this study recently published in Science, researchers at the Weizmann Institute of Science worked together with MDC scientists.
Something like a quarter of the world’s population suffers from chronic pain at some point in their lives. As opposed to acute pain – for example, the feeling after hitting your finger with a hammer -- chronic pain may not even have a clear cause, and it can linger for years or lifetimes. The burden of chronic pain includes damage to mental and physical health, lower productivity and drug addiction.
A new study led by scientists at the Weizmann Institute of Science (WIS) in Rehovot (Israel) suggests an original approach to treating this affliction, by targeting a key gateway leading to the activation of genes in the peripheral nerve cells that play a role in many forms of chronic pain. The findings of this study were published today in Science.
Pain starts in the sensory neurons – those that pass information from the skin to the central nervous system. Damage to these neurons, chronic injury or disease can cause the neurons to “short circuit,” sending continuous pain messages. Professor Mike Fainzilber of the Biomolecular Sciences Department at WIS investigates molecules that regulate the biomolecular messaging activities taking place within these nerve cells. These molecules – importins – are found in every cell, acting as conduits between the cell nucleus and its cytoplasm, shuttling molecules in and out of the nucleus and thus controlling access to the genes. This role takes on special significance in the peripheral nerve cells, with their long, thin bodies in which molecular messages can take hours to get from nerve endings to cell nuclei. Some of the importins Fainzilber and his team have identified, for example, relay messages about injury to the body of the nerve cell, initiating repair mechanisms.
A protein that controls a pain pathway
Already for years Professor Michael Bader as head of the lab “Molecular Biology of Peptide Hormones” at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) investigated the importance of importins in a long-term project together with the Institute of Biology at the University of Lübeck. “For this purpose we genetically modified mice so that in each line one of these importins was missing,” Bader explains. To ask which importin is involved in chronic neuropathic pain, the researchers, led by Dr. Letizia Marvaldi in Fainzilber’s group, first set out to screen several importin-mutant mouse lines from Bader’s lab. The research was supported by the European Research Council.
Behavioral screens on these different lines revealed importin alpha-3 as the only importin implicated in controlling pain pathways. The team then sought to identify the gene expression pattern associated with long-lasting pain in peripheral nerve cells, and see how it tied into importin alpha-3 activity. Analyses of differences in the expression patterns between normal neurons and neurons lacking importin alpha-3 directed Marvaldi’s attention to c-Fos, a protein that importin alpha-3 brings into the nucleus. c-Fos is a transcription factor – a molecule that raises or lowers the expression of numerous genes. Further experiments in mice showed that c-Fos accumulates in the nucleus in peripheral nerve cells of mice suffering from chronic pain.
They then used specialized viruses as tools to reduce or disable importin alpha-3 or c-Fos in mouse peripheral nerve cells. These mice had much reduced responses to chronic pain situations than those of regular mice. Further research showed that importin alpha-3 is critical in late and chronic pain. c-Fos is also involved in earlier pain responses, but it seems to enter the nucleus by other means at those earlier stages. This suggests that blocking importin alpha-3 activity might be especially well-suited to preventing lasting, chronic pain.
A potential drug target
The research team then took their findings to the next level, asking how easily they can be translated to clinical application. They took advantage of a specialized database, the Connectivity Map (CMap) from the Broad Institute in Massachusetts, which reveals connections between drugs and gene expression patterns. This database enabled them to identify around 30 existing drugs that might target the importin alpha-3—c-Fos pathway. Almost two thirds of compounds they identified were not previously known to be associated with pain relief. The team chose two – one a cardiotonic drug and the other an antibiotic – and tested them again in mice. Indeed, injection with these compounds provides relief of neuropathic pain symptoms in mice.
“The compounds we identified in this database search are a kind of fast track – proof that drugs already approved for other uses in patients can probably be repurposed to treat chronic pain,” says Marvaldi. “Clinical trials could be conducted in the near future, as these compounds have already been shown to be safe in humans.”
“We are now in a position to conduct screens for new and better drug molecules that can precisely target this chain of events in the sensory neurons,” says Fainzilber. “Such targeted molecules might have fewer side effects and be less addictive than current treatments, and they could provide new options for reducing the burden of chronic pain.” Also participating in this research were Dr. Nicolas Panayotis, Dr. Stefanie Alber, Dr. Shachar Y. Dagan, Dr. Nataliya Okladnikov, Dr. Indrek Koppel, Agostina Di Pizio, Didi-Andreas Song, Yarden Tzur, Dr. Marco Terenzio, Dr. Ida Rishal and Dr. Dalia Gordon, all of the Weizmann Institute of Sciences Biomolecular Sciences Department; Dr. Franziska Rother of the MDC and the University of Lübeck; and Professor Enno Hartmann of the University of Lübeck.
Professor Michael Fainzilber’s research is supported by the Moross Integrated Cancer Center; the David Barton Center for Research on the Chemistry of Life; the Nella and Leon Benoziyo Center for Neurological Diseases; the Laraine and Alan A. Fischer Laboratory for Biological Mass Spectrometry; the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; the Rising Tide Foundation; Lawrence Feis; the estate of Florence and Charles Cuevas; the estate of Lilly Fulop; the estate of Lola Asseof; and the European Research Council. Professor Fainzilber is the incumbent of the Chaya Professorial Chair in Molecular Neuroscience.
The original version of this press release was distributed by WIS.
Picture: Confocal micrograph of a peripheral sensory neuron in culture. Marker stains and antibodies are used to identify neurons (red), c-Fos protein (green) and nuclei (blue). Note the nuclear localization of c-Fos. (© Fainzilber, WIS)www.mdc-berlin.de
Research / 14.08.2020
€66 million for the Berlin spin-off T-knife
The Berlin biotech start-up T-knife, a spin-off from the MDC and Charité, has secured investments totaling €66 million. Four venture capital funds committed to the financing in early August. T-knife develops new cancer treatments using modified immune system T cells.
It is usually a long path from the initial idea in the biomedical laboratory to a new therapy for patients. This takes time – and above all, lots of money. For about 20 years, scientists at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) and Charité – Universitätsmedizin Berlin headed by Professor Thomas Blankenstein have been working on developing new cancer treatments using the body’s own immune cells whose receptors have been genetically modified in the laboratory. Blankenstein is investigating whether these modified T cells can stop cancer from developing. Two years ago, the scientist founded the company T-knife together with Elisa Kieback and Holger Specht and with support from Ascenion GmbH. The biotech start-up, which now has 18 employees, plans to develop new and highly sophisticated cancer therapeutics to treat tumors based on T-cell receptors.
T-knife will now receive €66 million in capital funding from four venture capital firms: Versant Ventures and RA Capital Management from the U.S. and the company’s seed investors Andera Partners and Boehringer Ingelheim Venture Fund. This was agreed by the V.C. firms on August 6 in a Series A round of financing. Series A refers to large capital injections following the initial start-up financing. T-knife’s Series A round is the largest so far for a German company this year.
Professor Thomas Sommer, interim Scientific Director of the MDC, congratulated Blankenstein and his T-knife colleagues: “This is an outstanding success, which underlines how research by MDC teams finds its way into practical application, into clinics and to the patients. It also shows how important our cooperation with the Charité is in ensuring benefits for patients.” Blankenstein commented: “We are looking forward to the study results and hope that this gene therapy will provide us with a new and promising opportunity to better fight cancer in the future.”
Treating solid tumors
T-knife is developing next-generation adoptive T-cell therapies for solid tumors by using its proprietary humanized T-cell receptor (HuTCR) mouse platform – mouse strains whose T cells express only human T-cell receptors (TCRs) – to bring highly effective and safe T-cell receptor-based therapeutics to market.
“Having worked in stealth mode to create a powerful humanized mouse platform bearing the human TCR loci, it is especially gratifying to now receive the validation from esteemed healthcare dedicated funds like Versant Ventures and RA Capital Management,” said Elisa Kieback, chief executive officer and scientific co-founder of T-knife. “We are equally grateful for the continued support of our founding shareholders, Andera Partners and Boehringer Ingelheim Venture Fund, two top-tier healthcare investors who have been our true partners since inception. Going forward, our goal is to become a transatlantic company by establishing a U.S. presence and expanding our management team accordingly.”
The company has demonstrated preclinical proof-of-concept and its lead TCR candidate has entered clinical development. In addition, T-knife has validated the platform for over 90 cancer targets, with several follow-on drug candidates already in preclinical development. The company expects to bring three additional TCRs into the clinic by 2022.
A long and winding road – The journey from basic research to a new therapy. A film about Thomas Blankenstein
Research / 13.08.2020
Michael Potente to strengthen vascular research
With the appointment of BIH Professor Michael Potente, the Berlin Institute of Health (BIH), Charité – Universitätsmedizin Berlin and the Max Delbrück Center (MDC) are strengthening their joint focus area “Translational Vascular Biomedicine.” Potente, a trained cardiologist, is particularly interested in the innermost cell layer that lines our blood vessels, the endothelium.
“Cardiovascular diseases are still one of the most frequent causes of illness and death,” says Prof. Axel Radlach Pries, Dean of Charité and interim Chairman of the BIH Executive Board. “Since changes in vascular function are a factor in many diseases, the BIH decided some time ago to establish a Translational Vascular Biomedicine focus area in order to achieve significant progress and translational success in this field. We are delighted to be able to complement and expand upon this research in such an outstanding way with the appointment of Michael Potente.”
Michael Potente has visited Berlin regularly since 2017 as a BIH Visiting Professor, funded by Stiftung Charité. He was invited by BIH Professor Holger Gerhardt, who heads the Integrative Vascular Biology Lab at the MDC and is also spokesperson for the Translational Vascular Biomedicine focus area at the BIH. “I know very few scientists like Michael Potente who carry out innovative research at the highest level with such enthusiasm, curiosity, and a keen sense of the most important issues,” says Gerhardt. “His work is constantly uncovering new connections and has a lasting impact on our understanding of the fascinating biology of blood vessels. I am hugely looking forward to working with him to further advance the translation of these findings into clinical practice.” The 43-year-old Michael Potente will conduct research at the BIH and MDC’s Käthe Beutler Building on the Berlin-Buch campus.
Understanding the growth and function of blood vessels
Michael Potente is mainly interested in the influence of metabolism on blood vessels. “We want to understand how metabolic processes control the growth, remodeling and function of blood vessels,” explains Potente, who currently heads the Angiogenesis and Metabolism Laboratory at the Max Planck Institute for Heart and Lung Research in Bad Nauheim. For example, a lack of oxygen and nutrients can lead to the formation of new blood vessels (a process known as angiogenesis) in tumors. Angiogenesis also plays a central role in eye diseases like wet macular degeneration, which leads to blindness if left untreated. “In this case, therapeutic interventions are already possible thanks to the use of inhibitors that suppress the abnormal growth of the blood vessels,” reports Potente.
However, in other diseases, such as chronic ischemic heart disease or peripheral artery disease in the legs, blocked blood vessels still cause a lack of oxygen and nutrients to reach the tissue, but unfortunately this often does not lead to the sufficient formation of new blood vessels. “We would hope for new, functional vessels to grow that would restore the supply – but here, the underlying disease prevents that from happening,” explains Potente. “If it were possible to specifically promote the growth of new blood vessels, this would have great therapeutic value.” Unfortunately, previous attempts to do so have not achieved long-term success, and have instead resulted in side effects.
Differing endothelia in different organs
Potente and his colleagues therefore hope to understand how the organ-specific environment affects blood vessels – particularly the endothelium. Endothelial cells are responsible for the formation of new blood vessels. "Endothelial cells have a completely different configuration in different organs," said Potente. "In the brain, for example, they are particularly closely connected to each other and form the blood-brain barrier; in the liver, the endothelium is permeable and thus enables the organ's filtering function.” In diabetics whose blood sugar levels are constantly above normal, endothelial cells change over time and lose specific properties, which leads to the frequent vascular problems associated with this disease.
In order to discover the molecular and cellular mechanisms behind these differences, Potente was awarded a €2 million ERC Consolidator Grant from the European Research Council in 2017. It was also at this time that he came to Berlin regularly as a BIH Visiting Professor. The Stiftung Charité has promoted this collaboration, which has been fundamental for the appointment, in the course of its Private Excellence Initiative Johanna Quandt.
The aesthetics of blood vessels
As a cardiology specialist, Michael Potente is also active on the clinical side. In Berlin, he hopes to contribute his experience working at the interface between basic research and patient care – and thus strengthen the focus on translational vascular biomedicine. “I am fascinated by the aesthetics of blood vessels, the advancement of scientific knowledge and, ultimately, the possibility of one day making basic research applicable in the diagnosis and treatment of disease.” This is a sentiment fully in line with the BIH’s mission of turning research into health. Michael Potente was born in Aachen in 1976 and studied medicine at Goethe University Frankfurt and the University of Toronto. Already in the course of his experimental doctoral thesis at Goethe University Frankfurt, which he completed in 2003, he conducted research into blood vessels. He then worked both as a postdoctoral research at the Institute of Cardiovascular Regeneration and as a physician in the Department of Cardiology of Goethe University Frankfurt, where he qualified as a professor in the field of internal medicine in 2013. In 2012 he established his own research group at the Max Planck Institute for Heart and Lung Research in Bad Nauheim. Potente has already received numerous awards and grants, including an ERC Starting Grant, an ERC Consolidator Grant and the distinction as a European Molecular Biology Organization (EMBO ) Young Investigator. He has published his research in distinguished journals and serves as an expert reviewer for numerous international scientific journals.
Joint press release from BIH, Charité and MDC
Text: Stefanie Seltmann, BIH
Innovation / 13.08.2020
Eckert & Ziegler Records Solid Half-Year Results
Growth Trend for Radiopharmaceuticals Remains Intact
Despite heavy burdens from corona and the drop in oil price, Eckert & Ziegler Strahlen- und Medizintechnik AG (ISIN DE0005659700, TecDAX), a specialist for isotope applications in medicine, science and industry, closed the first half of 2020 with a net income of 12.7 million EUR, almost reaching the record level of the previous year (13.1 million EUR). Revenues amounted to EUR 83.6 million and were thus 6% below the previous year's level.
The main reason for the relatively steady performance was the continued strong growth, compared to the previous year, in sales and earnings from radiopharmaceutical products and services in the Medical segment. While laboratory equipment and brachytherapy sources, including iodine implants, suffered considerably from reduced orders from hospitals due to the coronavirus crisis, half-year sales of pharmaceutical radioisotopes increased by more than € 4 million, or almost 30%, to just under € 20 million.
In contrast, the Isotope Products segment, due to Corona, could not maintain the high sales level of the same period of the previous year and achieved sales of EUR 47.1 million, which is EUR 8.3 million or about 15% lower than in the first half of 2019. Declining revenues particularly affected the lucrative components for industrial measurement technology, the Brazilian business and waste management services. Slight increases were only recorded in medical devices components and raw materials trading.
With the figures for the first half of the year, the Eckert & Ziegler Group has largely met, and in the case of net profit for the period, even exceeded the budget targets for the current financial year, as revised due to the coronavirus crisis.
Taking into account one-off effects and the expectation that the impact of the corona pandemic will not change dramatically, the Executive Board expects revenues of EUR 170 million and a net income of at least EUR 20 million to be achieved in the FY 2020.
The complete financial statements can be viewed here:
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.
Contributing to saving lives.
Eckert & Ziegler AG, Karolin Riehle, Investor Relations
Robert-Rössle-Str. 10, 13125 Berlin
Tel.: +49 (0) 30 / 94 10 84-138, firstname.lastname@example.org, www.ezag.com
Research / 06.08.2020
COVID-19: Immune system derails
A severe course of COVID-19 does not solely result in a strong immune reaction – rather, the immune response is caught in a continuous loop of activation and inhibition. This is reported in Cell by experts of the nationwide deCOI research network, including colleagues at the MDC.
Most patients infected with the coronavirus SARS-CoV-2 show mild or even no symptoms. However, 10 to 20 percent of those affected develop pneumonia during the course of COVID-19 disease, some of them with life-threatening effects. "There is still not very much known about the causes of these severe courses of the disease. The high inflammation levels measured in those affected actually indicate a strong immune response. Clinical findings, however, rather tend to indicate an ineffective immune response. This is a contradiction," says Joachim Schultze, professor at the University of Bonn and research group leader at the DZNE. "We therefore assume that although immune cells are produced in large quantities, their function is defective. That is why we examined the blood of patients with varying degrees of COVID-19 severity," explains Leif Erik Sander, Professor of Infection Immunology and Senior Physician at Charité’s Medical Department, Division of Infectious Diseases and Respiratory Medicine.
The study was carried out within the framework of a nationwide consortium - the "German COVID-19 OMICS Initiative" (DeCOI) - resulting in the analysis and interpretation of the data being spread across various teams and sites. Among the DeCOI members there are several researchers from the Max Delbrück Center for Molecular Medicine in the Helmholtz Association: Professor Markus Landthaler and Dr. Emanuel Wyler from the Berlin Institute for Medical Systems Biology (BIMSB) of the MDC contributed to the current publication in Cell.
Joachim Schultze was significantly involved in coordinating the project. The blood samples came from a total of 53 men and women with COVID-19 from Berlin and Bonn, whose course of disease was classified as mild or severe according to the World Health Organization classification. Blood samples from patients with other viral respiratory tract infections as well as from healthy individuals served as important controls.
The investigations involved the use of single-cell OMICs technologies, a collective term for modern laboratory methods that can be used to determine, for example, the gene activity and the amount of proteins on the level of single, individual cells - thus with very high resolution. Using this data, the scientists characterized the properties of immune cells circulating in the blood - so-called white blood cells. "By applying bioinformatics methods on this extremely comprehensive data collection of the gene activity of each individual cell, we could gain a comprehensive insight of the ongoing processes in the white blood cells," explains Yang Li, Professor at the Centre for Individualised Infection Medicine (CiiM) and Helmholtz Centre for Infection Research (HZI) in Hannover. "In combination with the observation of important proteins on the surface of immune cells, we were able to decipher the changes in the immune system of patients with COVID-19," adds Birgit Sawitzki, Professor at the Institute of Medical Immunology on Campus Virchow-Klinikum.
The human immune system comprises a broad arsenal of cells and other defense mechanisms that interact with each other. In the current study, the focus was on so-called myeloid cells, which include neutrophils and monocytes. These are immune cells that are at the very front of the immune response chain, i.e. they are mobilized at a very early stage to defend against infections. They also influence the later formation of antibodies and other cells that contribute to immunity. This gives the myeloid cells a key position.
"With the so-called neutrophils and the monocytes we have found that these immune cells are activated, i.e. ready to defend the patient against COVID-19 in the case of mild disease courses. They are also programmed to activate the rest of the immune system. This ultimately leads to an effective immune response against the virus," explains Antoine-Emmanuel Saliba, head of a research group at the Helmholtz Institute for RNA-based Infection Research (HIRI) in Würzburg.
But the situation is different in severe cases of COVID-19, explains Sawitzki: "Here, neutrophils and monocytes are only partially activated and they do not function properly. We find considerably more immature cells that have a rather inhibitory effect on the immune response." Sander adds: "The phenomenon can also be observed in other severe infections, although the reason for this is unclear. Many indications suggest that the immune system stands in its own way during severe courses of COVID-19. This could possibly lead to an insufficient immune response against the corona virus, with a simultaneous severe inflammation in the lung tissue.“
Approaches to therapy?
The current findings could point to new therapeutic options, says Anna Aschenbrenner from the LIMES Institute at the University of Bonn: "Our data suggest that in severe cases of COVID-19, strategies should be considered that go beyond the treatment of other viral diseases." The Bonn researcher says that in the case of viral infections one does not actually want to suppress the immune system. "If, however, there are too many dysfunctional immune cells, as our study shows, then one would very much like to suppress or reprogram such cells." Jacob Nattermann, Professor at the Medical Clinic I of the University Hospital Bonn and head of a research group at the DZIF, further explains: "Drugs that act on the immune system might be able to help. But this is a delicate balancing act. After all, it's not a matter of shutting down the immune system completely, but only those cells that slow down themselves, so to speak. In this case these are the immature cells. Possibly we can learn from cancer research. There is experience with therapies that target these cells."
Nationwide team effort
In view of the many people involved, Schultze emphasizes the cooperation within the research consortium: "As far as we know, this study is one of the most comprehensive studies to date on the immune response in COVID-19 based on single cell data. The parallel analysis of two independent patient cohorts is one of the strengths of our study. We analyzed patient cohorts from two different sites using different methods and were thus able to validate our findings directly. This is only possible if research data is openly shared and cooperation is based on trust. This is extremely important, especially in the current crisis situation. “
The original version of this press release was sent out on August 6, 2020 by Charité - Universitätsmedizin Berlin, the University of Bonn, the German Centre for Neurodegenerative Diseases (DZNE), the Helmholtz Centre for Infection Research (HZI) and the German Centre for Infection Research (DZIF) and colleagues from the nationwide research association DeCOI.
Innovation / 06.08.2020
T-knife Completes € 66 Million Series A Financing to Develop Next-Generation T-Cell Therapies
T-knife’s proprietary humanized mouse platform (HuTCR) T-cell receptors expected to provide superior affinity/specificity properties
T-knife GmbH, a next-generation adoptive T-cell company using its proprietary humanized T-cell receptor (HuTCR) mouse platform to treat solid tumors, announced today the closing of a €66 million Series A round of financing. The round was led by Versant Ventures and RA Capital Management, with significant participation from existing investors Andera Partners and Boehringer Ingelheim Venture Fund (BIVF).
The Company was spun out of Max-Delbruck Center for Molecular Medicine with support of Charité University Hospital in Berlin in 2018, where its proprietary HuTCR transgenic mouse platform carrying the entire human TCRαβ gene loci was established by the pioneering work of Prof. Thomas Blankenstein, T-knife’s co-founder. Due to its natural in vivo selection of high- affinity TCRs, T-knife’s TCR-T-cell platform has the potential to be a marked improvement over existing TCR technologies in treating solid tumors.
“Having worked in stealth mode to create a powerful humanized mouse platform bearing the human TCR loci, it is especially gratifying to now receive the validation from esteemed healthcare dedicated funds like Versant Ventures and RA Capital,” commented Elisa Kieback, Chief Executive Officer and scientific co-founder of T-knife. “We are equally grateful for the continued support of our founding shareholders, Andera Partners and Boehringer Ingelheim Venture Fund, two top- tier healthcare investors who have been our true partners since inception. Going forward, our goal is to become a transatlantic company by establishing a U.S. presence and expanding our management team accordingly.”
T-knife’s proprietary HuTCR mouse expresses only human TCRs that are restricted to human HLA. Due to their natural generation in mice without negative thymic selection, these TCRs are of high specificity and high affinity. The Company has generated a pipeline of patented, unique TCR candidates for clinical development. Proceeds from the Series A round will be allocated to advancing at least four programs into the clinic, ramping-up preclinical work for additional selected proprietary pipeline candidates and discovering TCRs against novel targets.
Moving forward, T-knife’s Board of Directors will be comprised of Josh Resnick (RA Capital), Alex Mayweg (Versant Ventures), Olivier Litzka (Andera Partners), Frank Kalkbrenner (BIVF), Thomas Blankenstein and Elisa Kieback. The Company was advised by Blueprint Life Science Group on the fundraising and by CMS on all legal aspects of the transaction. The new investors were advised by Goodwin Procter. The transaction will close upon governmental and anti-trust clearance.
Alex Mayweg of Versant Ventures commented, “While CAR-T-based therapies have already demonstrated their power in the treatment of hematological cancers, their foray into solid tumors has proven to be less successful. T-knife has developed an exciting technology as its TCR- T cell therapy targets tumor antigens in an MHC-restricted manner, allowing it to be one of the few platforms that is able to target solid tumors. We are consequently thrilled to co-lead this round with RA Capital, a preeminent healthcare dedicated fund, as their investment mandate mirrors our own mission to identify and support game-changing therapies with curative intent.”
“We are delighted that T-knife is now an RA Capital portfolio company and are especially pleased to partner with Versant Ventures on leading this financing round,” commented Josh Resnick of RA Capital Management. “With the Company’s financial and strategic support now in place, we look forward to working alongside management and fellow investors bring T-knife’s potentially transformative T-cell therapies to solid tumor patients.”
Olivier Litzka of Andera Partners added, “Together with our seed round co-investor BIVF and their representative Detlev Mennerich, who also served as the Company’s Chairman over the past two years, we are extremely proud of T-knife’s progress, culminating in this transformational, top quality Series A round. We commend Elisa, Thomas and the team for their accomplishments, and welcome our new partners who share the vision of making T-knife the premier leader in the cell therapy field.”
About T-Knife GmbH
T-knife is a next-generation adoptive T-cell company utilizing its proprietary humanized T-cell receptor (HuTCR) mouse platform technology to treat solid tumors. It was founded as a spin-off from Max-Delbruck Center for Molecular Medicine with support of Charité University Hospital in Berlin in 2018. Ascenion GmbH, technology transfer partner of MDC and Charité, accompanied the scientists from the beginning, continuously expanded the patent base, supported the acquisition of pre-seed funding and the negotiation of collaboration and license agreements in coordination with MDC and Charité.
T-knife ́s mission is to use its unique technology to bring highly effective and safe T-cell receptor- based therapeutics to market. Based on the unparalleled T-cell immunology expertise of its founders and the unique and proprietary HuTCR platform, the Company develops fully human TCRs which are expected to set new technology standards and to provide superior safety and efficacy.
The Company has demonstrated pre-clinical proof-of-concept and its lead TCR has entered clinical development. In addition, T-knife has validated the platform for over 90 undisclosed cancer targets, with several follow-on drug candidates being already in preclinical development. The Company expects to bring three additional TCRs into the clinic by 2022. T-knife is executing a two-pronged corporate growth strategy: developing an internal pipeline of best- in-class therapeutics and in parallel, establishing external partnerships by out-licensing already patented TCRs and/or providing the Company’s HuTCR mouse for unbiased discovery of new epitopes. T-knife is backed by top tier investors Versant Ventures, RA Capital, Andera Partners, and Boehringer Ingelheim Venture Fund.
Elisa Kieback, CEO
Tel.: +49 30 94892433
Dr. Ludger Wess / Ines-Regina Buth Managing Partners
Tel. +49 40 88 16 59 64
Tel. +49 30 23 63 27 68
Blueprint Life Science Group
Tel.: +1.415.375.3340 Ext. 4
Research, Innovation, Patient care / 05.08.2020
Christopher Baum chosen to head the BIH
On August 5, 2020, the Supervisory Board of the Berlin Institute of Health (BIH), chaired by BMBF State Secretary Christian Luft, unanimously appointed Professor Christopher Baum as Chief Executive Officer of the BIH. The distinguished scientific manager and recognized expert in translation, molecular medicine and gene therapy will take office in Berlin on October 1, 2020. Baum is currently Vice President for Medicine at the Universität zu Lübeck as well as a member of the Board of Directors of the University Hospital of Schleswig-Holstein (UKSH). He succeeds Professor Axel R. Pries, who for the past two years has served as interim Chief Executive Officer of the BIH and who will now be able to devote himself full-time to his role as Dean of Charité – Universitätsmedizin.
“As Chairman of the Supervisory Board, I am delighted that Professor Baum is joining the Berlin Institute of Health as its Chief Executive Officer,” said Christian Luft, State Secretary at the Federal Ministry of Education and Research (BMBF). “Professor Baum is the right person to usher in the BIH’s integration into Charité, given his strong strategic planning skills and wealth of leadership experience. He will also sustainably advance the BIH’s focus on medical translation, in Berlin as well as in Germany and internationally. I am very much looking forward to working together.”
Steffen Krach, State Secretary at the Berlin Senate Chancellery – Higher Education and Research, concurred, saying: “Christopher Baum is the ideal candidate for the BIH and a valuable addition to our healthcare hub. Berlin has big plans as a scientific and medical location, and I very much look forward to working with him going forward.”
Baum takes over a well-run organization
Professor Axel R. Pries, interim Chief Executive Officer of the BIH and Dean of Charité – Universitätsmedizin Berlin, is handing over a well-run organization to his successor: “In recent years, the BIH has grown into one of the top translational medicine locations in Germany. We are moving forward with our mission of turning research into health, and we already have a number of successes to show for it, from research findings published in high-ranking journals – including and especially on the current coronavirus pandemic – to national and international collaborations, and the launching of spin-off companies in digital medicine. I am delighted that, with Professor Baum, we have found a Chief Executive Officer who is well versed in all these areas and will continue to drive them forward.”
Professor Heyo K. Kroemer, Chief Executive Officer at Charité – Universitätsmedizin Berlin, welcomed BIH’s new CEO, who will also sit on Charité’s Executive Board from 2021 following the integration of the BIH into Charité. “Christopher Baum has a great deal of management experience of his own in university hospitals. At the independent BIH, he will strongly promote the transfer of research results into clinical practice, making maximum use of the synergies that exist with Charité.”
Expert in molecular medicine and gene therapy
Professor Thomas Sommer, interim Scientific Director of the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), also expressed delight at the appointment of Christopher Baum: “As an expert in molecular medicine and an acclaimed scientific manager, Christopher Baum will be an excellent partner for us. With him at the helm of the BIH, we will continue to extend the close collaboration between the MDC, Charité and the BIH. I warmly congratulate Christopher Baum and wish him great success in his new role.” The MDC, along with Charité, is a founding institution of the BIH and will be a privileged partner of the BIH after the BIH is integrated into Charité.
Professor Christopher Baum was born in 1962 in Marburg. He studied philosophy for two semesters in Mainz, and medicine in Essen, Freiburg and Hamburg. He obtained his doctorate in 1991, and qualified as a professor in the field of molecular medicine in 1999 at the University of Hamburg. In 2000, he joined the Hannover Medical School (MHH) as a professor for stem cell biology, and was also an associate professor of pediatrics at the Cincinnati Children’s Hospital in the United States from 2002. In Hanover, he led the Institute of Experimental Hematology from 2006 and served as both the Ombudsperson for Good Scientific Practice and the Dean of Research. He was elected President of the MHH in 2013. At the beginning of 2019, Baum moved to the University of Lübeck as its first full-time Vice President for Medicine and a member of the Board of Directors of UKSH – Germany’s second largest university hospital after Charité.
Molecular biologist, doctor and scientific manager
“I would like to thank all those involved for putting their trust in me, and I am greatly looking forward to this new role,” said Baum after learning of his appointment. “Translation is a core concern of mine: turning research into health means turning scientific findings into concrete applications that help people. The BIH is an outstanding institution involved in shaping the transition from basic research to medicine. I will do my utmost to accomplish this special mission together with the first-class team at the BIH.” Baum is interested in both promoting research and intensive cooperating with clinicians. “With Charité, we have an excellent clinical and scientific partner at our side – this partnership is enhanced and expanded in various areas by the MDC. The synergy that exists between these outstanding partner institutions provides the foundation for the BIH’s success.”
Christopher Baum’s interest in gene therapy began early on in his scientific career. He developed genetic vectors for planting genes in blood stem cells and uncovered the basics of so-called insertional mutagenesis, which can cause blood cancer in patients undergoing gene therapy. Based on these findings, he developed test procedures that enabled this dangerous side effect to be eliminated before the genetically modified blood stem cells are transferred. In his scientific management roles, he has designed national and international networks for translational research in stem cell and gene therapy. In Hanover, he introduced the voluntary scientific year as a new form of Germany’s voluntary social year, the Regenerative Sciences PhD program of the Cluster of Excellence REBIRTH (From REgenerative BIology to Reconstructive THerapy), the clinician scientist Young Academy Program, and the further education program TRAIN Academy for translational sciences. He was also responsible for the overall coordination of the MHH’s proposals for the German Universities Excellence Initiative. At UKSH and the Universität zu Lübeck, a center for artificial intelligence, he dedicated himself primarily to linking computer science and medicine, cooperating between the Lübeck and Kiel locations, and expanding interprofessional teaching. He also introduced a PhD program in medical informatics with dual supervision by experts from computer science and medicine.
Baum has received numerous awards for his scientific work, including the Ursula M. Händel Animal Welfare Prize of the German Research Foundation (DFG) and the Eva Luise Köhler Research Award for research on rare diseases. He is a member of the Executive Board of the German Association of Medical Faculties (MFT), where he chairs the Science Working Groupwww.bihealth.org
Innovation / 30.07.2020
Eckert & Ziegler: Implementation of the share split by issuing bonus shares to be effective on 4 August 2020
Eckert & Ziegler AG (ISIN DE0005659700, TecDAX) announces that the increase in share capital approved by the Annual General Meeting on 10 June 2020 has been registered in the commercial register and that the share split can now be implemented.
The Annual General Meeting on 10 June 2020 resolved to increase the share capital from currently EUR 5,292,983.00 by EUR 15,878,949.00 to EUR 21,171,932.00 from company funds. The capital increase was carried out by converting a partial amount of EUR 15,878,949.00 of the other revenue reserves reported under revenue reserves in the Company's annual balance sheet as of 31 December 2019 into share capital in return for the issue of 15,878,949 new no-par value bearer shares ("bonus shares"). The bonus shares are entitled to dividends from 1 January 2020. The Company's shareholders are entitled to the bonus shares on the basis of their shareholdings at a ratio of 1:3, so that for every one (1) existing share, the shareholders receive an additional three (3) bonus shares.
As all shares of the Company are held in collective giro accounts, the shareholders of the Company will receive co-ownership of the global certificate deposited with Clearstream Banking AG in the amount of the bonus shares attributable to them by means of a deposit credit and will not have to take any action in respect of the acceptance of these shares.
The bonus shares will be allocated to the entitled shareholders on the basis of their holdings of old shares according to the status as of 3 August 2020 after the close of the stock exchange by means of a deposit credit. The bonus shares will receive the same ISIN / WKN as the existing shares and will be included for trading on the regulated market of the Frankfurt Stock Exchange (Prime Standard).www.ezag.com
Innovation / 24.07.2020
Eckert & Ziegler Increases Profit Forecast to 4 Euro per Share
Based on initial, un-audited assessments, revenues and earnings of Berlin-based isotope specialists Eckert & Ziegler Strahlen- und Medizintechnik AG (ISIN DE0005659700) for the half year ending 30 June 2020 are significantly higher than expected.
The consolidated result in the first half of the year should reach EUR 2.47 per share (Q2 previous year: EUR 2.59). At the same time sales should run to about EUR 84 million (Q2 previous year: EUR 89 million).
On the basis of this evaluation, and despite Corona, the Executive Board expects the consolidated result for the financial year 2020 to exceed the forecast published at the beginning of the year. It therefore rescinds the previous guidance and increases the target of EUR 3.50 to EUR 4.00 per share. The Executive Board keeps the revenue forecast at EUR 170 million.
The figures are based on the share capital as of 30 June 2020. Converted to the increased share capital of EUR 21,171,932, the forecast is EUR 1.00 per share.
The complete figures for the first half year 2020 will be published on 13 August 2020.
Insider information pursuant to Article 17 MARwww.ezag.com
Research, economic development, Innovation / 21.07.2020
FMP spin-off Tubulis acquires €10.7 million for the development of novel antibody drug conjugates (ADCs)
The young company Tubulis announced today the closure of a Series A funding round totaling €10.7 million to advance the development of a novel class of highly stable and efficient antibody drug conjugates (ADCs) for treating cancer and other serious diseases, and to promote the further growth of the company. Tubulis was founded as a spin-off of the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) in Berlin and the Ludwig-Maximilians-Universität (LMU) München in 2019.
Tubulis has proprietary unique technologies for producing novel and particularly stable antibody drug conjugates (ADCs). In the process, a wide range of drugs can be linked to an antibody specific to the relevant indication by way of stable coupling (conjugation). One positive aspect of this is that adverse side effects in healthy tissue can be minimized, since the drug is prevented from separating from the antibody prematurely. In addition, the company’s proprietary technologies offer the potential to generate previously impossible protein-drug combinations, enabling the therapeutic spectrum of this approach to be broadened to other indications.
“Our group, which helped develop the scientific basis for Tubulis’ innovative technology by advancing new chemical methods to generate stable ADCs, is very proud of the company’s tremendous development and achievement. Today’s Series A funding is further proof of this,” remarked Professor Dr. Christian Hackenberger, Head of Chemical Biology at the FMP and Leibniz-Humboldt Professor at the Humboldt-Universität zu Berlin. The chemist looks forward to the years ahead and to continued cooperation with the start-up company. “One of the key factors of this success is the great team, which was able to build on the long-standing fruitful collaboration with colleagues from LMU headed by Prof. Dr. Heinrich Leonhardt. With this very successful funding round behind it, the company now has the perfect basis for continuing to revolutionize ADC therapy.”
Professor Dr. Volker Haucke, Director of the FMP, added: “Tubulis’ successful acquisition of funding is further proof of the FMP’s successful strategy to transfer results from basic research to biomedical application.”
The funding round was co-led by BioMedPartners and the High-Tech Gründerfonds (HTGF), with the support of Seventure, Coparion, Bayern Kapital and Occident and significant contributions by private individuals and the founders themselves.
“The aim of Tubulis is to use our dual platform approach to generate uniquely matched and disease-specific ADCs that combine selective antibodies with effective drugs,” stated Dr. Dominik Schumacher, CEO and co-founder of Tubulis, who completed his doctoral thesis at the FMP in Professor Christian Hackenberger’s research group. “The funding committed by this experienced consortium is a validation of our technology, and reflects the latest renaissance of ADC development in our sector. These financial resources will enable us to continue validating our platforms and to transfer our first two selected ADC candidates to the hospital setting.”
Prof. Dr. Christian Hackenberger
Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP)
Leibniz-Humboldt-Professur für Chemische Biologie, Humboldt-Universität zu Berlin
Phone +49 (0)30 / 94793 - 181
Dr. Dominik Schumacher, CEO
Phone +49 89 218074233
Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP)
Phone +49 (0)30 94793 104
Tubulis generates uniquely matched protein-drug conjugates by combining proprietary novel technologies with disease-specific biology. Our goal is to expand the therapeutic potential of antibody drug conjugates (ADCs) ushering in a new era and delivering better outcomes for patients. Employing the company’s proprietary ADC development approach, Tubulis will advance a variety of conjugates, unlimited by indication. For more information visit www.tubulis.com.
About Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) im Forschungsverbund Berlin e.V.
The Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) conducts basic research in Molecular Pharmacology with the aim to identify novel bioactive molecules and to characterize their interactions with their biological targets in cells or organisms. These compounds are useful tools in basic biomedical research and may be further developed for the treatment, prevention, or diagnosis of disease.
The FMP is part of the Forschungsverbund Berlin e.V. (FVB), who legally represents eight non-university research institutes - members of the Leibniz Association - in Berlin. The institutions pursue common interests within the framework of a single legal entity while maintaining their scientific autonomy. More than 1,900 employees work within the research association. The eight institutes were founded in 1992 and emerged from former institutes of the GDR Academy of Sciences.
Research / 15.07.2020
Janggu makes deep learning a breeze
Researchers from the MDC have developed a new tool that makes it easier to maximize the power of deep learning for studying genomics. They describe the new approach, Janggu, in the journal Nature Communications.
Imagine that before you could make dinner, you first had to rebuild the kitchen, specifically designed for each recipe. You’d spend way more time on preparation, than actually cooking. For computational biologists, it’s been a similar time-consuming process for analyzing genomics data. Before they can even begin their analysis, they spend a lot of valuable time formatting and preparing huge data sets to feed into deep learning models.
To streamline this process, researchers from the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) developed a universal programming tool that converts a wide variety of genomics data into the required format for analysis by deep learning models. “Before, you ended up wasting a lot of time on the technical aspect, rather than focusing on the biological question you were trying to answer,” says Dr. Wolfgang Kopp, a scientist in the Bioinformatics and Omics Data Science research group at MDC’s Berlin Institute of Medical Systems Biology (BIMSB), and first author of the paper. “With Janggu, we are aiming to relieve some of that technical burden and make it accessible to as many people as possible.”
Unique name, universal solution
Janggu is named after a traditional Korean drum shaped like an hourglass turned on its side. The two large sections of the hourglass represent the areas Janggu is focused: pre-processing of genomics data, results visualization and model evaluation. The narrow connector in the middle represents a placeholder for any type of deep learning model researchers wish to use.
Deep learning models involve algorithms sorting through massive amounts data and finding relevant features or patterns. While deep learning is a very powerful tool, its use in genomics has been limited. Most published models tend to only work with fixed types of data, able to answer only one specific question. Swapping out or adding new data often requires starting over from scratch and extensive programming efforts.
Janggu converts different genomics data types into a universal format that can be plugged into any machine learning or deep learning model that uses python, a widely-used programming language.
“What makes our approach special is that you can easily use any genomic data set for your deep learning problem, anything goes in any format,” Dr. Altuna Akalin, who heads the Bioinformatics and Omics Data Science research group.
Separation is key
Akalin's research group has a dual mission: developing new machine learning tools, and using them to investigate questions in biology and medicine. During their own research efforts, they were continually frustrated by how much time was spent formatting data. They realized part of the problem was each deep learning model included its own data pre-processing. By separating the data extraction and formatting from the analysis, it provides a much easier way to interchange, combine or reuse sections of data. It’s kind of like having all the kitchen tools and ingredients at your fingertips ready to try out a new recipe.
“The difficulty was finding the right balance between flexibility and usability,” Kopp says. “If it is too flexible, people will be drowned in different options and it will be difficult to get started.”
Kopp has prepared several tutorials to help others begin using Janggu, along with example datasets and case studies. The Nature Communications paper demonstrates Janggu’s versatility in handling very large volumes of data, combining data streams, and answering different types of questions, such as predicting binding sites from DNA sequences and/or chromatin accessibility, as well as for classification and regression tasks.
While most of Janggu’s benefit is on the front end, the researchers wanted to provide a complete solution for deep learning. Janggu also includes visualization of results after the deep learning analysis, and evaluates what the model has learned. Notably, the team incorporated “higher-order sequence encoding” into the package, which allows to capture correlations between neighboring nucleotides. This helped to increase accuracy of some analyses. By making deep learning easier and more user-friendly, Janggu helps throw open the door to answering all kinds of biological questions.
“One of the most interesting applications is predicting the effect of mutations on gene regulation,” Akalin says. “This is exciting because now we can start understanding individual genomes, for instance, we can pinpoint genetic variants that cause regulatory changes, or we can interpret regulatory mutations occurring in tumors.”
Text: Laura Petersen
Research / 02.07.2020
A research group at the MDC has discovered a protein that protects mature B lymphocytes from stress-induced cell death. It also helps immune cells produce effective antibodies, which can stop the pathogen at different points in the infection.
Whenever a germ gets into the human body, the immune system usually responds immediately to fight off the enemy attacker. One of our defense system’s most important strategies involves B lymphocytes, also known as B cells, which produce antibodies that target and neutralize pathogens. B cells play a central role in adaptive immunity and, together with T cells and components of the innate system, they protect the body against foreign pathogens, allergens and toxins.
Many Berlin researchers involved in the study
A team led by Dr. Michela Di Virgilio, head of the Genome Diversification & Integrity Lab at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), has now identified a protein called Pdap1 that supports B cells in this important task while simultaneously protecting them from stress-induced cell death.
The lead authors of the study, which was published in the Journal of Experimental Medicine, are the two doctoral students Verónica Delgado-Benito and Maria Berruezo-Llacuna – both members of Di Virgilio’s lab. Researchers from the MDC’s Berlin Institute of Medical Systems Biology (BIMSB) and the Experimental and Clinical Research Center (ECRC ) were also involved. The ECRC is a joint institution of the MDC and Charité – Universitätsmedizin Berlin.
B cells must continuously adapt
“A successful humoral immune response, which is mediated by antibodies, is dependent on several factors,” explains Di Virgilio. Mature B cells have to modify their genes (i.e., building instructions) in order to create antibodies that better match the distinguishing features on the surface of the invading pathogen. This is known as the lock-and-key principle and is achieved by somatic hypermutation, which mutates the pathogen-recognizing portion of the antibody molecule after the encounter and B cell activation.
Over the course of the humoral immune response, another part of the antibodies is transformed in a process known as class-switch recombination (CSR). Here, B cells change the isotype of the antibodies they produce. Instead of immunoglobulins of the isotype IgM, which are predominantly produced at the start of an infection, they may produce, for example, IgG antibodies, which have a different effector function. This process potentiates the ability of antibodies to effectively dispose of the pathogen.
The protein was found with the help of “gene scissors”
“In the beginning, we primarily wanted to understand how class switching works,” says Delgado-Benito. “So we genetically modified a mouse B cell line using the CRISPR-Cas9 gene scissors to prevent them from producing certain proteins.” In this way, she and the team discovered that without PDGFA associated protein 1 (Pdap1), less class switching occurs.
“In the next step, we generated mice where the gene for Pdap1 was switched off specifically in B cells,” reports Berruezo-Llacuna. “This showed us that the protein is also crucial for somatic hypermutation.” Without the protein, fewer such mutations occurred in the pathogen-recognizing part of the antibody, thus reducing the possibility to generate highly-specific variants.
B cells die more easily without Pdap1
“A particularly surprising finding to come out of our in vivo experiments, however, was that mouse B cells that are unable to produce Pdap1 die far more easily than is normally the case,” adds Di Virgilio. Her team discovered that the protein protects B lymphocytes from stress-induced cell death. “Mature B cells experience cellular stressors particularly when they begin to grow and proliferate rapidly after contact with the pathogen,” explains the researcher.
It seems that in unmodified animals, Pdap1 helps B cells to cope with this stress. Without the protein, however, a program is started that ultimately leads to cell death. “So Pdap1 not only helps the B lymphocytes to consistently produce the effective antibodies,” says Di Virgilio. “It can also be seen as their protector.”
Text: Anke Brodmerkelwww.mdc-berlin.de
Research / 30.06.2020
Osmotic stress identified as stimulator of cellular waste disposal
Cellular waste disposal, where autophagy and lysosomes interact, performs elementary functions, such as degrading damaged protein molecules, which impair cellular function, and reintroducing the resulting building blocks such as amino acids into the metabolic system. This recycling process is known to keep cells young and, for instance, protects against protein aggregation, which occurs in neurodegenerative diseases. But what, apart from starvation, actually gets this important system going? Researchers from the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) in Berlin have now discovered a previously unknown mechanism: osmotic stress, i.e. a change in water and ionic balance, triggers a response within hours, resulting in the increased formation and activity of autophagosomes and lysosomes. The work, now published in “Nature Cell Biology”, describes the new signaling pathway in detail, and provides a crucial basis for improving our understanding of the impact environmental influences have on our cellular recycling and degradation system, and how this knowledge can be used for therapeutic purposes.
Image of mouse astrocytes showing the actin cytoskeleton (red) and lysosomes (green). (Image: Tania Lopez-Hernandez)
Our cells are occasionally in need of a “spring clean” so that incorrectly folded protein molecules or damaged cell organelles can be removed, preventing the aggregation of protein molecules. The mechanisms responsible for this removal are so-called “autophagy” and the closely related lysosomal system, the discovery of which earned the Nobel Prize for Medicine in 2016.
Quite a number of studies suggest that autophagy and lysosomes play a central role in aging and in neurodegenerative diseases. It is also generally agreed that fasting or food deprivation can kickstart this cellular degradation and recycling process. Other than that, little is known about how cells and organs control the quality of their protein molecules, and which environmental influences give the decisive signal to start cleaning up.
Water loss induces the formation of lysosomes and autophagy
A new trigger has now been identified by scientists from the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) in Berlin: it is osmotic stress, i.e. the state in which cells lose water, that starts the system of autophagy and of lysosomal degradation. The study has just been published in the prestigious journal “Nature Cell Biology”.
“When dehydration occurs, we suddenly see more lysosomes in the cells, i.e. more organelles where aggregated protein molecules are degraded,” explained co-last author PD Dr. Tanja Maritzen. “It’s a clever adaptation because cellular water loss simultaneously fosters the aggregation of proteins. These aggregates must be removed quickly to ensure the continued function of cells, and this works better when cells have more lysosomes.”
Ion transporter NHE7 switches on newly discovered pathway
The researchers were able to observe what happens at the molecular level in dehydrated cells using astrocytes, star-shaped cells in the brain that assist the work of our nerve cells: in the event of dehydration, the ion transporter NHE7 translocates from the cell’s interior, where it is normally positioned, to the cell's limiting plasma membrane that shields the cell from the outside. This leads to an influx of sodium ions into the cell, indirectly increasing the level of calcium – a key messenger – in the cytosol. The elevated level of calcium in turn activates a transcription factor called TFEB, which finally switches on autophagy and lysosomal genes. In other words, the system is initiated by the ion transporter NHE7, triggered by osmotic stress.
“This pathway was completely unknown,” stated group leader and last author of the study, Professor Dr. Volker Haucke. “It is a new mechanism that responds to a completely different type of physiological challenge to those previously known.”
Discovery of aggregated proteins in brain cells
Counter experiments revealed the importance of this pathway for human health: when the researchers removed a component of the signaling pathway, such as the transporter NHE7 or the transcription factor TFEB, aggregated protein molecules accumulated in astrocytes under osmotic stress conditions; they could not be broken down. In the study, this phenomenon was demonstrated for components such as synuclein – a protein that plays a role in Parkinson’s disease.
“Neurodegenerative diseases in particular are a possible consequence of this pathway being switched on incorrectly,” stated Tania López-Hernández, post-doc in Professor Haucke’s and Dr. Maritzen’s respective groups, and lead author of the study. “In addition, NHE7 is a so-called Alzheimer’s risk gene. We now have new insights into why this gene could play such a critical role.”
Another interesting point is that an intellectual disability in boys, passed on via the X chromosome, is due to a mutation in the NHE7 gene. The researchers suspect that the disease mechanism is linked to the degradation mechanism that has now been described. If only the switch, i.e. the NHE7 protein, were defective, an attempt could be made to turn on the pathway in another way. “It is very difficult in practice, and extremely expensive, to repair a genetic defect, but it would be conceivable to pharmacologically influence the NHE7 protein or to use other stimuli such as spermidine as a food supplement to switch on the autophagy system in these patients,” explained cell biologist and neurocure researcher Volker Haucke.
Medical relevance of basic research
In order to carry out such interventions, however, the foundations need to be researched more thoroughly. For example, it is not yet clear how osmotic stress affects the translocation of NHE7 to the cell surface. It is also not known whether the entire degradation system is initiated or whether just individual genes are switched on, or which specific responses to osmotic stress are needed to activate the lysosomal system. Nor is it known which other stimuli may be triggered by this physiological process. The researchers now seek to answer all these questions in subsequent projects.
“Our work has shown us the fundamental impact that our water and ionic balance has on the capability of our cells and tissue to break down defective protein molecules,” remarked Volker Haucke. “Now we want to gain a better understanding of this mechanism – also because it plays a major role in aging, neurodegeneration and the prevention of several other diseases.”
Text: Beatrice Hamberger
Translation: Teresa Gehrs
Lopez-Hernandez, T., Puchkov, D., Krause, E., Maritzen, T., Haucke, V. Endocytic regulation of cellular ion homeostasis controls lysosome biogenesis. In: Nature Cell Biology July 2020 issue. DOI10.1038/s41556-020-0535-7
Research / 18.06.2020
Jan Philipp Junker receives Helmholtz AI grant
MDC researcher Jan Philipp Junker and his collaborator Maria Colomé-Tatché at Helmholtz Center Munich have received a €200,000 grant to improve big data processing to better understand how gene networks are wired together during development and disease.
Scientists generally understand how stem cells transform into a specialized heart, brain or muscle cell. But now they want more specifics: the precise, step-by-step instructions that drive cell fate and function. Understanding the exact flow of genes turning on or off other genes, called “gene regulatory networks,” throughout the normal cell differentiation process could also help clarify what goes wrong in diseases such as cancer and heart disease.
Researchers at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) and Helmholtz Center Munich will use a Helmholtz Artificial Intelligence Grant to try to decode these complex networks by combining advanced experimental, sequencing and machine learning tools. “Suddenly, with recent technological developments, this goal that seemed to be almost unreachable, is within reach,” says Dr. Jan Philipp Junker, who heads the Quantitative Developmental Biology Lab at MDC’s Berlin Institute for Medical Systems Biology.
The Helmholtz AI Grant program supports “high-risk, high-reward” research over a relatively short timeframe of three years, encouraging investigators to try out novel ideas and “fail fast” if need be and continue innovating. “This doesn’t mean this should be completely reckless research and that we are ready to burn the money entirely,” Junker says. “It’s a calculated risk.”
The €200,000 grant will be shared equally by Junker and his collaborator, Dr. Maria Colomé-Tatché, a group leader at the Institute of Computational Biology at Helmholtz Center Munich, to support a post doc and a Ph.D. student conducting experiments, developing computational tools and analyzing data. The two centers are required to provide matching funds.
Really big data
With the recent advent of single-cell sequencing, scientists are able to see which genes are active in individual cells as they progress from undifferentiated cells into specific cell types, such as a muscle cell or brain cell. But so far, computational tools have not successfully pieced together how genes specifically influence each other.
“In principle, we can see what happens, what genes go on and what genes go off as a cell differentiates, but understanding which gene turns on which other genes, how these activation networks work in different cell types, that is still basically an open question,” Junker explains. Attacking this question requires colossal amounts of data – sequencing tens of thousands of active genes, in tens of thousands of individual cells. One data set includes at least 20,000 dimensions. That’s where AI and machine learning can help, sifting through all that data and finding meaningful patterns, which in this case, are the gene regulatory networks.
It also requires aligning the time scales of multiple data streams so they can be effectively analyzed and yield accurate insights. The team is working to improve this alignment. Notably, they have adapted a method called SLAM-seq to label freshly transcribed RNA molecules, which indicate newly activated genes. Identifying old RNA present in a cell versus new RNA will help clarify the order of gene activations. Combining this information with data on DNA accessibility should help make network reconstructions more accurate.
Junker and his team will initially seek to reconstruct gene networks in normal embryonic development of zebrafish, a model organism for vertebrates, including humans. Once the computational approach is verified, they can use it to study disease development in humans, which can open doors to new treatments.
“In the more distant future,” Junker says, “when we have a complete network for cell differentiation for an organ, then we could go to the drawing board and decide which arrow or node we want to attack with a therapy.”
Text: Laura Petersen
Research / 11.06.2020
Overactive enzyme causes hereditary hypertension
After more than 40 years, several teams at the MDC and ECRC have now made a breakthrough discovery with the help of two animal models: they have proven that an altered gene encoding the enzyme PDE3A causes an inherited form of high blood pressure. This could lead to new concepts for the treatment of hypertension.
A Turkish family from a village near the Black Sea first caught the attention of medical researchers in the early 1970s. A physician discovered that many members of this large family had both unusually short fingers and astronomically high blood pressure, sometimes twice as high as that of healthy people. Those affected die around the age of 50, usually due to a stroke.
Some twenty years later a group of researchers at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), led by Professor Friedrich Luft and Dr. Sylvia Bähring, began to study this mysterious phenomenon. It proved to be no easy task. Not until May 2015 were the researchers able to report in the journal Nature Genetics that they had found an altered gene in all patients who were affected by the hypertension and brachydactyly (HTNB) syndrome – i.e., high blood pressure and abnormally short digits. The genetic disorder is also known as Bilginturan syndrome, after its Turkish discoverer.
The genetic makeup encodes an enzyme called phosphodiesterase 3A, or PDE3A for short, that regulates both blood pressure and bone growth. The gene mutation that Luft and his team had discovered causes the enzyme to be more active than usual.
Researchers provide the missing evidence
Yet so far there has been no evidence that definitely shows that the mutated PDE3A causes Bilginturan syndrome, which has since been discovered in other families around the world. An international group of 40 researchers from Berlin, Bochum, Limburg, Toronto (Canada) and Auckland (New Zealand) has now supplied this evidence in the journal Circulation. Participating in the study were research groups from the MDC and Charité – Universitätsmedizin Berlin, including teams led by Professors Luft, Michael Bader, Maik Gollasch and Dominik N. Müller as well as Dr. Arndt Heuser and Dr. Sofia Forslund. The last author of the paper is Dr. Enno Klußmann, head of the MDC’s Anchored Signaling Lab.
“We mainly worked with two animal models,” reports Dr. Lajos Markó, the paper’s co-lead author along with Maria Ercu. One of the models consisted of genetically modified mice in which the human enzyme PDE3A in the smooth muscle cells of the vessel walls was overactive due to the gene alteration. “These animals exhibited extremely high blood pressure as compared to the control animals,” Markó says.
Genetically modified rats recapitulate the genetic disorder
But what proved more interesting to the scientists was a rat model created by the Bader Lab using CRISPR-Cas9 technology. With the help of the gene-editing tool, the team had altered nine base pairs in a region of the PDE3A gene that is mutated in the syndrome, a so-called mutation hot spot. The resulting enzyme differed from the normal variants with respect to three amino acids. “And just as in the patients, this tiny change increased the activity of the enzyme,” Ercu says.
“The rats resembled human patients to a truly extraordinary degree,” Ercu adds. “They not only suffered from high blood pressure, but the toes on their forefeet were significantly shortened – similar to the fingers of people with the syndrome.” And using micro-computed tomography, the researchers discovered a prominent loop in the brain vessels of the rats that is also found in people with the syndrome. “Our rat model provides, in my view, definitive proof that the syndrome is caused by a mutation in the PDE3A gene,” Klußmann says.
The goal is to treat hypertension more effectively
The researchers have even developed an approach for treating this inherited form of high blood pressure. “There is a drug called riociguat that is already approved as a therapeutic for pulmonary hypertension,” Klußmann says. We know, he says, that it activates an enzyme that produces a signaling molecule, which in turn dampens down an overactive PDE3A. “The blood pressure of rats to which we administered a derivative of riociguat dropped to a normal level,” Klußmann reports. There are already other PDE3A inhibitors on the market, according to him, but they are not suitable for long-term therapy due to their side effects.
Klußmann now wants to take a closer look at how the mutated PDE3A interacts with other protein molecules. Stronger interaction with certain adaptor proteins, he says, could cause cells of the vessel walls to replicate at an increased rate.
In fact, Klußmann has a big goal in his sights: “By learning more about the effects of the PDE3A’s interactions with other proteins and understanding how they are involved in the regulation of blood pressure, we will hopefully find new and more effective therapeutic approaches for one of the most widespread diseases of all, hypertension.”
Text: Anke Brodmerkelwww.mdc-berlin.de
Discovery of important molecular mechanism of Charcot-Marie-Tooth disease
Charcot-Marie-Tooth (CMT) disease is the most common form of inherited neuropathies. A genetic mutation causes the insulating myelin layer of peripheral nerves to become progressively damaged, resulting in severe disabilities in the case of CMT type 4B, for instance. Since the molecular basis is largely unknown, this type of CMT is untreatable and incurable to this day. Now researchers from the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) in Berlin, in collaboration with colleagues from Milan, Paris and Mexico, have been able to highlight a new molecular mechanism: According to their discovery, the protein Rab35 and the mTOR signaling pathway it regulates play a central role in the formation of myelin sheaths in the peripheral nervous system. First in-vivo experiments show that new therapies can be derived from the findings. The work has now been published in the prestigious journal “Nature Communications”.
Many of our nerve cords (axons) are enveloped by a myelin sheath, which ensures that signals can be sent near instantaneously from the brain to muscles and organs. However, genetically programmed defects in myelination occur among the broad group of inherited neuropathies, disrupting this signaling process. This results in the onset of a variety of neurological deficits occurring in peripheral nerves and the degeneration of the nerve cords. This is the case with Charcot-Marie-Tooth disease (CMT), the most common inherited neuropathy. CMT type 4B is characterized by a very early onset of the disease; sufferers are often already confined to a wheelchair in their teens. In the worst case, neurodegeneration spreads to the respiratory tract, which can lead to death by respiratory failure. At present, there is no prospect of a cure.
Unexpected interaction partners
It is therefore all the more important to explore the largely unknown molecular mechanisms of the disease. This is exactly what scientists from the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) in Berlin have done, in collaboration with teams of researchers led by Professor Alessandra Bolino (IRCCS Ospedale San Raffaele University, Milan), Professor Arnaud Echard (Sorbonne Université / Institut Pasteur, Paris) and Professor Genaro Patiño-López (Hospital Infantil, Mexico).
Researching the protein Rab35, the Berlin team led by Linda Sawade and Professor Volker Haucke discovered more or less by chance that this small GTPase, which is involved in the regulation of intracellular membrane transport, interacts with three proteins associated with CMT 4B: Owing to a gene mutation, MTMR2, MTMR5 and MTMR13 do not function properly in CMT 4B patients, or they are completely lacking.
These three critical proteins belong to the group of myotubularin-related (MTMR) phosphatidylinositol (PI) phosphatases that specifically hydrolyze the endosomal signaling lipids PI(3)P and PI(3,5)P2 at the 3’-phosphate group, i.e. they remove phosphates from lipids.
Rab35 regulates myelin sheath formation
“Our study revealed that the protein Rab35 regulates the longitudinal growth of the myelin sheath by binding and recruiting the two pseudophosphatases MTMR13 and MTMR5, and hence, also the active phosphatase MTMR2 bound to it in a complex,” reported Linda Sawade, lead author of the study.
The new finding was that Rab35 binds this lipid phosphatase complex, and therefore plays a key role in regulating myelin sheath formation. The detection was confirmed in knock-out micethat specifically lack the Rab35 protein in Schwann cells – the cells in the peripheral nervous system that form myelin sheaths. Loss of the Rab35 protein led to the abnormalities and, eventually, the degenerative destruction (demyelination) of myelin sheaths in the sciatic nerve.
Inhibition of mTORC1 proves effective
Coincidentally, the researchers observed an abnormally elevated activity of the mTORC1 signaling pathway– one of the central signaling complexes for regulating myelin sheath formation in nerve tissue. Pharmacological inhibition of the hyperactive mTORC1 signaling complex using the drug Rapamycin partially rescued nerve damage in knock-out mice. Further experiments on cultured cells in which Rab35 expression had been suppressed confirmed the positive effects of mTORC1 inhibition on defective myelin sheaths.
The researchers were also able to draw an important conclusion from the absence of the Rab35 protein: mTORC1 is hyperactive because PI 3-phosphates are no longer regulated, causing the accumulation of PI(3)P and PI(3,5)P2 lipids. “We assume that this pathological process results from an impaired recruitment of MTMR complexes,” explained biochemist and cell biologist Linda Sawade. “Conversely, this would mean that Rab35 normally suppresses the activity of mTORC1 by recruiting MTMR phosphatases to lysosomes.”
Findings have an impact beyond basic research
In a nutshell, the results have a great impact for basic research: Rab35 is a previously unidentified regulator of myelin sheath formation in the peripheral nervous system and a repressor of mTORC1.
The results also offer a glimmer of hope to CMT4B patients: Therapeutic treatment using mTORC1-inhibiting drugs such as Rapamycin could improve disease progression. It would be the first treatment option for this serious condition.
Group leader Professor Dr. Volker Haucke: “Our work has led to the discovery of a new molecular mechanism in a particularly severe form of inherited neuropathy that is highly clinically relevant and that we now want to explore in greater depth with the Milan team led by Alessandra Bolino.
Linda Sawade, Federica Grandi, Marianna Mignanelli, Genaro Patiño-López , Kerstin Klinkert, Francina Langa Vives, Roberta Di Guardo, Arnaud Echard, Alessandra Bolino, Volker Haucke. Rab35-regulated lipid turnover by myotubularins represses mTORC1 activity and controls myelin. Nature communications. June 2020; https://doi.org/10.1038/s41467-020-16696-6
Text: Beatrice Hamberger, Translation: Theresa Gehrs
Image: Sciatic nerves from 3-month-old mice in cross section: In contrast to control animals (on the far left), animals with loss of the Rab35 protein in Schwann cells exhibit demyelination of nerve fibers: myelin outfoldings (yellow arrow); myelin degeneration (green arrow); ‘tomacula’ – focal thickening of the myelin sheath (red star). (Image: Alessandra Bolino, IRCCS Ospedale San Raffaele)www.leibniz-fmp.de
Research / 28.05.2020
Clarifying a culprit in inflammatory bowel disease
It’s been a bit of a mystery: is a particular family of proteins responsible for cell survival or cell death in the intestinal lining? A new mouse model developed at the Max Delbrück Centre for Molecular Medicine (MDC) provides clear evidence and a potential treatment target for inflammatory bowel disease.
A common protein found throughout the body, NF-kB, promotes harmful inflammation, cell proliferation and cell death in the intestinal lining, the key features of inflammatory bowel disease (IBD), according to research recently published in The Journal of Pathology.
“This was surprising because usually NF-kB helps protect cells from death,” says Dr. Marina Kolesnichenko. The scientist from the Signal Transduction in Tumour Cells Lab spearheaded the research at Max Delbrück Centre for Molecular Medicine in the Helmholtz Association (MDC).
Good or bad?
NF-kB is a family of transcription factor proteins, which transcribe parts of DNA inside cells to carry out various cellular processes, from cell replication and survival, to inflammation and cell death, which is called apoptosis.
NF-kB’s role in apoptosis in the intestine has been up for debate, with some studies suggesting it plays a protective or “anti-apoptotic” role, while others found hints it might be “pro-apoptotic,” contributing to cell death. One reason for the lack of clarity: previous studies mostly disrupted the signaling pathway several steps “upstream”, this means before NF-kB gets activated, rather than targeting NF-kB directly.
A specific target
Normally, NF-kB can’t begin its work until it is released by an inhibiting molecule. Kolesnichenko and her collaborators developed a mouse model that blocks the inhibitor specifically in the epithelium, which are the cells lining the gut. This unleashed persistent NF-kB activation only in that tissue. Extended activation in the intestinal lining was distinctly harmful, leading to increased inflammation in both the intestine and colon, as well as dangerous stem cell hyperproliferation and cell death in the intestine.
“The study demonstrates that activation of NF-kB alone, without any contribution of upstream components, is sufficient to trigger an IBD-like pathology,” says Prof. Claus Scheidereit, who heads the Signal Transduction in Tumour Cells Lab.
The team further investigated the results in epithelial organoids, which are miniature guts cultured from the intestinal linings of the modified mice. The researchers found that without immune cells present, activated NF-kB boosted abnormal signaling of the Wnt pathway. Aberrant Wnt signaling is detected in the majority of cases of colorectal cancer.
Given that IBD patients are at higher risk of developing colorectal cancer later in life, Kolesnichenko is curious to investigate if NF-kB is a key driver of that transition towards cancer. Further investigations might reveal that blocking NF-kB in the intestinal lining could help treat IBD or colorectal cancer.
A unique position
Kolesnichenko initiated and led the study, collaborating with several women from other units at MDC and at Charité – Universitätsmedizin Berlin. Notably, she published the results as the senior paper author, which is unusual for MDC post docs. Kolesnichenko notes it is important for post docs to be able to show independence and initiative, particularly when seeking funding from agencies that consider the number of “last author” papers they have published.
“The most rewarding part was working together with truly inspiring scientists, each of whom contributed something unique and essential to the story,” Kolesnichenko says.www.mdc-berlin.de
Research / 19.05.2020
Cells sound the alarm on chlamydia
A chlamydia infection triggers an inflammatory response at the cellular level. MDC researchers conducted experiments in cell cultures to examine the role that the enzyme GBP1 plays in this response. They have now published their findings in Cell Reports.
Chlamydia is one of the most common sexually transmitted diseases in Germany. Chlamydia bacteria need host cells to survive and reproduce. They often use mucous membrane cells in the human reproductive and urinary organs for this purpose, effectively “hijacking” the host’s cellular metabolism. These intruders either go undetected or signaling molecules alert the innate immune system of their presence. In the latter case, the body’s own defense system recognizes the bacteria as foreign and provokes an inflammatory response to destroy the bacteria.
The human guanylate-binding protein 1 (GBP1) plays a key role in the defense mechanisms against chlamydia or other pathogens. Researchers already know that this enzyme is not only capable of slowing down the reproduction of the chlamydia bacteria, but can also set off an inflammatory response by turning on certain signaling pathways. Yet exactly how these processes work is still a mystery. Now, a team led by Professor Oliver Daumke at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) has learned more about the role of specific metabolites of the enzyme in question. Working with the Max Planck Institute for Infection Biology, the researchers discovered which signaling pathways and protein complexes are activated by the metabolites.
GMP is important for the immune defense
The enzyme being studied – GBP1 – can act as a catalyst to speed up the cleavage of bioactive compounds. “It converts GTP to GMP in two steps through a reaction with water,” Daumke says. “GTP is a widely distributed cellular molecule that serves as a building block of RNA and is required for signaling processes.”
To understand what effect this cleavage has on the cell, Audrey Xavier, a PhD student in Daumke’s lab and the lead author of the study, modified the catalyzing enzyme. The enzyme either no longer functioned or it could only carry out the first step of the cleavage. She then introduced the different variants of the enzyme into human immune cells and infected them with chlamydia. The researcher was only able to measure typical inflammatory responses in those cells where the cleavage was fully possible. “That shows that GMP is crucial for this process,” Xavier says. But GMP does not appear to be responsible for slowing the growth of chlamydia. “Unfortunately, we still don’t exactly know how GBP1 inhibits the growth of the bacteria,” she says.
Blocking the signaling pathway
Xavier was even able to determine which signaling pathway GMP turns on in infected cells. According to the researcher, there are various protein complexes that can provoke an inflammatory response in cells, and the most well-known of these – the NLRP3 inflammasome – is activated when GMP is broken down to uric acid.
She managed to shut down this uric acid signaling pathway with an already approved drug that is normally used to treat gout. This disease is characterized by especially severe inflammatory responses. The research team observed that the agent allopurinol attenuates the inflammatory symptoms in cells infected with chlamydia. “Allopurinol helps reduce inflammation – and possibly also in people who have chlamydia,” Xavier says, adding: “But first clinical trials will need to test whether this might have potential as a supplemental therapy in combination with an antibiotic.”
Research / 14.05.2020
Support for SARS-CoV-2 diagnostics
The LabHive digital platform aims to provide necessary resources to diagnostic centres to enable more tests for SARS-CoV-2. Tobias Opialla from the MDC is one of 15 volunteers who has been involved in the project since the #WirvsVirus Hackathon organized by the German government.
An interdisciplinary team of 15 scientists, physicians, web developers, and security experts will use the digital platform LabHive to bundle testing capacities for SARS-CoV-2 and to compensate for bottlenecks in diagnostic centers. On LabHive qualified volunteers can provide their manpower, and research laboratories can offer reagents and equipment. Diagnostic centres have access to these services and can call on support if needed.
"In many university or non-university research labs, the corona crisis has restricted scientific operations," says Dr. Tobias Opialla from the Berlin Institute for Medical Systems Biology (BIMSB), an institution of the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC). "LabHive provides resources such as personnel, reagents or equipment that might otherwise remain unused." Like all participants, Opialla works voluntarily on the development and implementation of the platform.
The idea for this project was born during the #WirVsVirus-Hackathon of the German government and the project is currently funded by the German Federal Ministry of Education and Research. Their partner is the Björn Steiger Foundation.
Dr. Tobias Opialla
Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
Berlin Institute for Medical Systems Biology (BIMSB)
Scientist at the Proteomics and Metabolomics Platform
+49 30 9406 1330
Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
Editor, Communication Department
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Innovation / 12.05.2020
Q1 Performance Stable despite Oil Price Slump and Corona Expenses. Strong Growth in Radiopharmaceutical Products
Despite heavy burdens from corona and the drop in oil prices, Eckert & Ziegler Strahlen- und Medizintechnik AG (ISIN DE0005659700, TecDAX), a specialist for isotope applications in medicine, science and industry, completed the first quarter of 2020 roughly at the same level as last year. While sales increased by around 2% to 44 mm EUR million, net income came in at 0.98 EUR per share, some 14% or 16 Cent down from previous year’s quarter.
The main reason for the relatively steady performance was the continued strong growth, compared to the previous year, in sales and earnings from radiopharmaceutical products and services in the Medical segment. While sales revenues here increased by 26% or EUR 4.2 million to just under EUR 21 million, the segment's net profit even rose by 28% to EUR 3.5 million or EUR 0.62 per share.
In contrast, sales and earnings in the industrial components business retrenched as expected. While in the previous year the Isotope Products segment was able to contribute EUR 0.59 per share to earnings, it only achieved a net income of EUR 1.3 million or EUR 0.26 per share in the first quarter of 2020. The most significant factor for the decrease were currency losses of about EUR 1 million or minus EUR 0.19 per share, which had to be posted at the end of March due to the devaluation of the Brazilian real. In February, the exchange rate of the Latin American country had collapsed by around 20% against the euro in the course of the Corona pandemic. The quarterly result of the Isotope Products segment was also negatively impacted by a 12% year-on-year decline in sales to EUR 24 million, reflecting the recent drop in oil prices and, as expected, a related slump in demand for measurement technology components.
The Executive Board expects the results of the first quarter to mark a bottom, which should roughly characterize the second quarter. It therefore confirms its earnings forecast of EUR 3.50 per share for the full year 2020 and the dividend recommendation of EUR 1.70 per share, which will be submitted to the Annual General Meeting on June 10, 2020.
The complete financial statements can be viewed here:
About Eckert & Ziegler.
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.
Innovation / 11.05.2020
US health authorities to provide USD 6 million in funding for MYELO radiation protection pill
Berlin-based MYELO Therapeutics, an affiliated company of Eckert & Ziegler Strahlen- und Medizintechnik AG, will receive USD 6 million from the National Institutes of Health (NIH) over the next three years for the further development of its radiation protection pill MYELO001. The company is one of the few European applicants to successfully compete for funds from the relatively generous US catastrophe prevention program.
The money will be used to finance further tests and proof of concept and to investigate the functional mechanism of the new orally applicable drug. If the multi-year trials are successful, MYELO has the opportunity to win valuable contracts from civil protection agencies in America and elsewhere to build up emergency stocks.
"MYELO Therapeutics is one of a series of strategic investments that Eckert & Ziegler is using to push its growth into new dimensions in the mid term," explained Dr. Andreas Eckert, CEO of the TecDAX company Eckert & Ziegler. "The Executive Board has been able to continuously increase the financial resources for this purpose over the past few years. Although it would still be years too early to make concrete statements on sales or earnings potential, the award of the contract by the American health authorities shows that Eckert & Ziegler is on the right track when it comes to selecting its financing projects".
For details of the radiation protection pill and the funding commitment of the American health authorities, see the detailed press release of MYELO Therapeutics: http://www.myelotherapeutics.com/news.html
About Eckert & Ziegler.
Eckert & Ziegler Eckert & Ziegler Strahlen- und Medizintechnik AG with more 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.
Innovation / 07.05.2020
Eckert & Ziegler Enters TecDAX
The Berlin-based Eckert & Ziegler Strahlen- und Medizintechnik AG (ISIN DE0005659700, S-DAX) a specialist in isotope-related applications in medicine, science and industry, will enter the TecDAX effective as of 8 May 2020.
This index, which is measured in terms of market capitalisation of the free float and trading volume in the shares, comprises the 30 largest technology stocks in Germany.
"We are pleased about the admission to the TecDAX and expect that this will give our company and our share additional attention on the international capital market. Thanks to its strong growth, Eckert & Ziegler is now officially one of the largest listed technology companies in Germany," said Dr. Andreas Eckert, Chief Executive Officer of Eckert & Ziegler AG.
About Eckert & Ziegler.
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 radiation therapy and nuclear medicine.
Research / 06.05.2020
Phage capsid against influenza: perfectly fitting inhibitor prevents viral infection
A new approach brings the hope of new therapeutic options for suppressing seasonal influenza and avian flu: On the basis of an empty – and therefore non-infectious – shell of a phage virus, researchers from Berlin have developed a chemically modified phage capsid that “stifles” influenza viruses. Perfectly fitting binding sites cause influenza viruses to be enveloped by the phage capsids in such a way that it is practically impossible for them to infect lung cells any longer. This phenomenon has been proven in pre-clinical trials, also involving human lung tissue. Researchers from the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Freie Universität Berlin, Technische Universität Berlin (TU), Humboldt-Universität (HU), the Robert Koch Institute (RKI) and Charité-Universitätsmedizin Berlin were involved in this groundbreaking work. The results are also being used for the immediate investigation of the coronavirus. The findings have now been published in Nature Nanotechnology.
Influenza viruses are still highly dangerous: The World Health Organization (WHO) estimates that flu is responsible for up to 650,000 deaths per year worldwide. Current antiviral drugs are only partially effective because they attack the influenza virus after lung cells have been infected. It would be desirable – and much more effective – to prevent infection in the first place.
This is exactly what the new approach from Berlin promises. The phage capsid, developed by a multidisciplinary team of researchers, envelops flu viruses so perfectly that they can no longer infect cells. “Pre-clinical trials show that we are able to render harmless both seasonal influenza viruses and avian flu viruses with our chemically modified phage shell,” explained Professor Dr. Christian Hackenberger, Head of the Department Chemical Biology at the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) and Leibniz-Humboldt Professor for Chemical Biology at HU Berlin. “It is a major success that offers entirely new perspectives for the development of innovative antiviral drugs.”
Multiple bonds fit like hook-and-loop tape
The new inhibitor makes use of a feature that all influenza viruses have: There are trivalent receptors on the surface of the virus, referred to as hemagglutinin protein, that attach to sugar molecules (sialic acids) on the cell surface of lung tissue. In the case of infection, viruses hook into their victim – in this case, lung cells – like a hook-and-loop fastener. The core principle is that these interactions occur due to multiple bonds, rather than single bonds.
It was the surface structure of flu viruses that inspired the researchers to ask the following initial question more than six years ago: Would it not be possible to develop an inhibitor that binds to trivalent receptors with a perfect fit, simulating the surface of lung tissue cells?
We now know that this is indeed possible – with the help of a harmless intestinal inhabitant: The Q-beta phage has the ideal surface properties and is excellently suited to equip it with ligands – in this case sugar molecules – as “bait”. An empty phage shell does the job perfectly. “Our multivalent scaffold molecule is not infectious, and comprises 180 identical proteins that are spaced out exactly as the trivalent receptors of the hemagglutinin on the surface of the virus,” explained Dr. Daniel Lauster, a former PhD student in the Group of Molecular Biophysics (HU) and now a postdoc at Freie Universität Berlin. “It therefore has the ideal starting conditions to deceive the influenza virus – or, to be more precise, to attach to it with a perfect spatial fit. In other words, we use a phage virus to disable the influenza virus!”
To enable the Q-beta scaffold to fulfill the desired function, it must first be chemically modified. Produced from E. coli bacteria at TU Berlin, Professor Hackenberger’s research group at FMP and HU Berlin use synthetic chemistry to attach sugar molecules to the defined positions of the virus shell.
Virus is deceived and enveloped
Several studies using animal models and cell cultures have proven that the suitably modified spherical structure possesses considerable bond strength and inhibiting potential. The study also enabled the Robert Koch Institute to examine the antiviral potential of phage capsids against many current influenza virus strains, and even against avian flu viruses. Its therapeutic potential has even been proven on human lung tissue, as fellow researchers from the Medical Department, Division of Infectiology and Pneumology, of Charité were able to show: When tissue infected with flu viruses was treated with the phage capsid, the influenza viruses were practically no longer able to reproduce.
The results are supported by structural proof furnished by scientists at Freie Universität Berlin from the Research Center of Electron Microscopy (FZEM): High-resolution cryo-electron microscopy and cryo-electron microscopy show directly and, above all, spatially, that the inhibitor completely encapsulates the virus. In addition, mathematical-physical models were used to simulate the interaction between influenza viruses and the phage capsid on the computer. “Our computer-assisted calculations show that the rationally designed inhibitor does indeed attach to the hemagglutinin, and completely envelops the influenza virus,” confirmed Dr. Susanne Liese from the AG Netz of Freie Universität Berlin. “It was therefore also possible to describe and explain the high bond strength mathematically.”
Therapeutic potential requires further research
These findings must now be followed up by more preclinical studies. It is not yet known, for example, whether the phage capsid provokes an immune response in mammals. Ideally, this response could even enhance the effect of the inhibitor. However, it could also be the case that an immune response reduces the efficacy of phage capsids in the case of repeated-dose exposure, or that flu viruses develop resistances. And, of course, it has yet to be proven that the inhibitor is also effective in humans.
Nonetheless, the alliance of Berlin researchers is certain that the approach has great potential. “Our rationally developed, three-dimensional, multivalent inhibitor points to a new direction in the development of structurally adaptable influenza virus binders. This is the first achievement of its kind in multivalency research,” emphasized Professor Hackenberger. The chemist believes that this approach, which is biodegradable, non-toxic and non-immunogenic in cell culture studies, can in principle also be applied to other viruses, and possibly also to bacteria. It is evident that the authors regard the application of their approach to the current coronavirus as one of their new challenges. The idea is to develop a drug that prevents coronaviruses from binding to host cells located in the throat and subsequent airways, thus preventing infection.
Berlin university alliance at its best
Cooperation between scientists from different disciplines played a major role in the discovery of the new influenza inhibitor. Biologists, chemists, physicists, virologists, medical scientists and imaging specialists from three Berlin universities HU, Freie Universität Berlin and TU, the Robert Koch Institute, Charité and, last but not least, FMP were all involved in the project. “In my opinion, such a complex project could only have been undertaken in Berlin, where there truly are experts for every issue,” stated Professor Dr. Andreas Herrmann, Head of Molecular Biophysics at HU Berlin. “It was the Berlin university alliance at its best,” he added, “and I hope that the follow-up studies will be equally successful.”
The project was funded within Collaborative Research Center 765 (Speaker Professor Dr. Rainer Haag, Freie Universität Berlin) of the German Research Foundation (DFG).
Daniel Lauster, Simon Klenk, Kai Ludwig, Saba Nojoumi, Sandra Behren, Lutz Adam, Marlena Stadtmüller, Sandra Saenger, Stephanie Franz, Katja Hönzke, Ling Yao, Ute Hoffmann, Markus Bardua, Alf Hamann, Martin Witzenrath, Leif E. Sander, Thorsten Wolff, Andreas C. Hocke, Stefan Hippenstiel, Sacha De Carlo, Jens Neudecker, Klaus Osterrieder, Nediljko Budisa, Roland R. Netz, Christoph Böttcher, Susanne Liese, Andreas Herrmann, Christian P. R. Hackenberger. Phage capsid nanoparticles with defined ligand arrangement block influenza virus entry. Nature Nanotechnology DOI 10.1038/s41565-020-0660-2