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Aktuelle Pressemitteilungen von www.charite.de In diesem Feed haben wir die aktuellsten Pressemitteilungen der Charité – Universitätsmedizin Berlin zusammengestellt. © Charité – Universitätsmedizin Berlin https://www.charite.de:443/en/service/press_reports/feed/pressfeed/atomfeed.xml 2021-06-06T21:27:11+02:00 Charité - Webmaster IT webmaster@charite.de SARS-CoV-2: Estimating infectiousness 2021-05-25T16:00:00+02:00 2021-05-25T16:00:00+02:00 https://www.charite.de/en/service/press_reports/artikel/detail/sars_cov_2_estimating_infectiousness/ Charité-Redaktion webteam@charite.de © Charité – Universitätsmedizin Berlin

What started as the preliminary analysis of routine laboratory data has since evolved into the largest-ever study of viral load levels in patients with SARS-CoV-2. A team of researchers from Charité – Universitätsmedizin Berlin have now analyzed the PCR samples of more than 25,000 persons with COVID-19. Working under the leadership of Prof. Dr. Christian Drosten, the team determined the viral loads of each individual sample and used their results to estimate levels of infectiousness. The research, which has been published in Science*, provides a clear idea of the infectiousness of the disease in different age groups and at different levels of disease severity. It also provides new insights into the B.1.1.7 variant. According to the reproductive number (R 0), a person infected with SARS-CoV-2 will, on average, transmit their infection to three to five other people. While it is a useful metric in an epidemiological setting, ‘R 0’ does not lend itself to estimating the risk of transmission at the individual or group level. Once normal social and environmental factors are removed from the equation, individuals can differ markedly in terms of their infectiousness and the length of time during which they actively shed the virus. To better understand and estimate infectiousness in specific groups of individuals, a team led by Prof. Dr. Christian Drosten, Director of Charité’s Institute of Virology and a researcher at the German Center for Infection Research (DZIF), analyzed the PCR samples of more than 25,000 COVID-19 cases in order to determine their ‘viral loads’. A sample’s viral load – the total number of copies of the SARS-CoV-2 genome contained in the sample – provides a rough estimate of the quantity of virus present in a patient’s throat and, as such, is a useful metric for estimating an individual’s infectiousness. To further improve their estimates, the researchers also applied findings regarding the minimum viral load threshold typically required for the successful isolation of SARS-CoV-2 in cell culture (where isolation indicates the presence of infectious virus). Sequential samples were available for more than 4,300 of the cases studied. Using these to track throat viral load data over time, the researchers were able to model the typical development of viral loads over the course of the infection. The researchers then looked for significant differences in their data, specifically in relation to different age groups, disease severity and virus variants. No notable differences in viral load levels were recorded among SARS-CoV-2-positive individuals aged between 20 and 65 years, the average throat swab sample containing approximately 2.5 million copies of the SARS-CoV-2 genome. Viral loads were found to be lowest in very young children (0 to 5 years). Levels started at approximately 800,000 copies of the viral genome, increased with age, and approached adult levels in older children and adolescents. “While these numbers look very different at first glance, it is crucial to remember that viral load results are shown on a logarithmic scale,” says Prof. Drosten. “The differences in viral loads found in the youngest children are, in fact, barely below the threshold at which we would normally consider them clinically relevant. Crucially, one also has to understand how we arrive at these values and take this into account when interpreting them.” Highlighting the differences in the methodology of sample collection between children and adults, the virologist adds: “Children’s swabs are significantly smaller in size and collect less than half the sample quantity normally available for PCR testing. Moreover, the level of discomfort involved with the procedure means that deep nasopharyngeal swabs are often replaced with simple throat swabs. This of course further reduces the amount of viral material collected. For this reason, we fully expect that, in children, the same level of viral replication will produce lower viral load results during PCR testing.” When comparing peak viral loads in laboratory samples, the researchers estimated levels of infectivity in the youngest children (0 to 5 years) to be at approximately 80 percent of that found in adults. As previously, values for school-aged children and adolescents were found to be approaching adult values. “This shows that viral loads are not directly proportional to infectivity and cannot be converted directly,” explains Prof. Drosten. He adds: “Even these data-based estimates of infectivity have to be corrected upwards because of the different methods of sample collection used in children. All of this forms part of a clinical virologist’s overall assessment. My initial assumption, that all age groups have roughly the same level of infectivity, has been confirmed, both by this and by other studies.” A symptom-based comparison confirmed observations previously made in COVID-19 cases, namely that even asymptomatic individuals can have very high viral loads. Individuals who required hospitalization were found to have higher viral loads than others over the entire course of the disease. Based on their new models of viral load courses over time, the researchers estimate that individuals infected with SARS-CoV-2 reach peak viral load levels in their throats as early as 1 to 3 days before the onset of symptoms. Approximately 9 percent of the COVID-19 cases tested showed extremely high viral loads of one billion copies per sample or higher. More than a third of these potentially highly infectious individuals had either no symptoms or only mild symptoms. “These data provide a virological foundation for the notion that a minority of infected individuals cause the majority of all transmissions,” explains Prof. Drosten. He adds: “The fact that this includes so many people without any relevant symptoms underlines the importance of pandemic control measures such as social distancing and mandatory mask-wearing.” In samples collected from individuals infected with the B.1.1.7 (‘UK’ or ‘British’) variant, average viral loads were found to be increased by a factor of ten, while laboratory-based estimates of infectivity were increased by a factor of 2.6. To arrive at these data, the researchers took viral load data from approximately 1,500 cases infected with B.1.1.7 and compared them with data from approximately 1,000 people infected with other variants who had been tested at the same testing centers, outpatient departments and clinical wards around the same time. Prof. Drosten adds: “Laboratory studies may not as yet be in a position to provide a definitive explanation, but one thing is clear: B.1.1.7 is more infectious than other variants.” The researchers plan to continue their work on viral loads throughout the course of the pandemic. They hope to gain insights into the changes which occur as new variants arise as the virus adapts to increasing levels of population immunity.

A joint press release by Charité and the MDC Researchers from Charité – Universitätsmedizin Berlin and the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), together with scientists from the United States and Canada, have discovered a sugar molecule whose levels are reduced in the blood of patients with particularly severe multiple sclerosis. Their discovery could pave the way for a new therapeutic approach, the team reports in medical journal JAMA Neurology*. Multiple sclerosis, or MS for short, manifests itself slightly differently in each person – which is why some call it “the disease of a thousand faces.” Arguably the worst manifestation of MS is its chronic progressive form. Unlike the more common relapsing-remitting variant (RRMS), in which sufferers are often symptom-free for months or even years, patients with the primary progressive form of the disease (PPMS) see their condition steadily deteriorate with no remissions. Today’s therapeutic approaches are based on the assumption that the immune system is making a mistake and waging an inappropriate attack on the layer of myelin that surrounds and insulates the nerve cells’ long, cable-like branches called axons. “In progressive MS, neurodegenerative processes steadily multiply and cause more and more neurons in the brain and spinal cord to die,” explains Dr. Alexander Brandt, lead author of the study. “However, we still do not know what exactly causes this disease variant.” Together with Prof. Dr. Friedemann Paul from the Experimental and Clinical Research Center (ECRC), a joint institution of and the MDC, as well as eleven colleagues from Berlin, Irvine and Toronto, Dr. Brandt now hopes he has shed some more light on the subject. As the team reports in their study, it appears that the simple sugar N-acetylglucosamine, or GlcNAc for short, could play an important role in the development of progressive MS. Inside an organism, GlcNAc and other sugar molecules attach to proteins on the cell surface in the form of chains. This mechanism, which is known as glycosylation, controls various cell functions by forming branched structures from these sugar chains. “We studied 120 subjects from Irvine and were able to show that, in this particularly severe form of the disease, there are significantly lower concentrations of N-acetylglucosamine in the blood serum than there are in healthy people or patients with relapsing-remitting MS,” reports Dr. Brandt. At the time of this study, the physician was head of the Translational Neuroimaging laboratory in Prof. Paul’s Clinical Neuroimmunology group at Charité. Dr. Brandt has since moved to the School of Medicine at the University of California, Irvine (UCI) as an associate professor of neurology, but remains a guest researcher at Charité. “In another study of 180 patients from Berlin with relapsing-remitting or progressive MS, we also found that low serum levels of GlcNAc are associated with the development of the progressive form of the disease, clinical disability and neurodegeneration,” adds the study’s last author, Prof. Dr. Michael Demetriou of UC Irvine. “This opens up potential new avenues for identifying, at an early stage, which patients are at higher risk of progressive MS and adjusting their treatment accordingly.” The researchers hope that GlcNAc not only has potential as a suitable biomarker for progressive MS, but could also pave the way for new therapeutic strategies. “Our hope is that we can use GlcNAc and the associated glycosylation mechanism to promote myelin repair and thus reduce neurodegeneration,” summarizes Dr. Brandt. An initial, as-yet-unpublished phase I trial has just been completed with around 30 subjects, where the scientists investigated the safety of taking GlcNAc in certain doses. If it is shown to be safe, the scientists hope to be able to conduct further studies into this simple sugar’s possible efficacy as an MS therapy.

A joint press release by Charité and the PTB The brain processes information using both slow and fast currents. Until now, researchers had to use electrodes placed inside the brain in order to measure the latter. For the first time, researchers from Charité – Universitätsmedizin Berlin and the Physikalisch-Technische Bundesanstalt (PTB), Berlin Institute, successfully visualized these fast brain signals from the outside – and found a surprising degree of variability. According to their article in PNAS*, the researchers used a particularly sensitive magnetoencephalography device to accomplish this feat. The processing of information inside the brain is one of the body’s most complex processes. Disruption of this processing often leads to severe neurological disorders. The study of signal transmission inside the brain is therefore key to understanding a myriad of diseases. From a methodological point of view, however, it creates major challenges for researchers. The desire to observe the brain’s nerve cells operating ‘at the speed of thought’, but without the need to place electrodes inside the brain, has led to the emergence of two techniques featuring high temporal resolution: electroencephalography (EEG) and magnetoencephalography (MEG). Both methods enable the visualization of brain activity from outside the skull. However, while results for slow currents are reliable, those for fast currents are not. Slow currents – known as postsynaptic potentials – occur when signals created by one nerve cell are received by another. The subsequent firing of impulses (which transmit information to downstream neurons or muscles) produces fast currents which last for just a millisecond. These are known as action potentials. “Until now, we have only been able to observe nerve cells as they receive information, not as they transmit information in response to a single sensory stimulus,” explains Dr. Gunnar Waterstraat of Charité’s Department of Neurology with Experimental Neurology on Campus Benjamin Franklin. “One could say that we were effectively blind in one eye.” Working under the leadership of Dr. Waterstraat and Dr. Rainer Körber from the PTB, a team of researchers has now laid the foundations which are needed to change this. The interdisciplinary research group succeeded in rendering the MEG technology so sensitive as to enable it to detect even fast brain oscillations produced in response to a single sensory stimulus. They did this by significantly reducing the system noise produced by the MEG device itself. “The magnetic field sensors inside the MEG device are submerged in liquid helium, to cool them to -269°C (4.2 K),” explains Dr. Körber. He adds: “To do this, the cooling system requires complex thermal insulation. This superinsulation consists of aluminum-coated foils which produce magnetic noise and will therefore mask small magnetic fields such as those associated with nerve cells. We have now changed the design of the superinsulation in such a way as to ensure this noise is no longer measurable. By doing this, we managed to increase the MEG technology’s sensitivity by a factor of ten.” The researchers used the example of stimulating a nerve in the arm to demonstrate that the new device is indeed capable of recording fast brain waves. As part of their study on four healthy subjects, the researchers applied electrical stimulation to a specific nerve at the wrist whilst at the same time positioning the MEG sensor immediately above the area of the brain which is responsible for processing sensory stimuli applied to the hand. To eliminate outside sources of interference such as electric networks and electronic components, the measurements were conducted in one of the PTB’s shielded recording rooms. The researchers found that, by doing so, they were able to measure the action potentials produced by a small group of simultaneously activated neurons in the brain’s cortex in response to individual stimuli. “For the first time, a noninvasive approach enabled us to observe nerve cells in the brain sending information in response to a single sensory stimulus,” says Dr. Waterstraat. He continues: “One interesting observation was the fact that these fast brain oscillations are not uniform in nature but change with each stimulus. These changes also occurred independently of the slow brain signals. There is enormous variability in how the brain processes information about the touch of a hand, despite all of the stimuli applied being identical.” The fact that the researchers are now able to compare individual responses to stimuli opens the way for neurology researchers to investigate questions which previously remained unanswered: To what extent do factors such as alertness and tiredness influence the processing of information in the brain? What about additional stimuli which are received at the same time? The highly sensitive MEG system could also help scientists to develop a deeper understanding of, and better treatments for, neurological disorders. Epilepsy and Parkinson’s disease are examples of disorders which are linked to disruptions in fast brain signaling. “Thanks to this optimized MEG technology, our neuroscience toolbox has gained a crucial new tool which enables us to address all of these questions noninvasively,” says Dr. Waterstraat.

The progressive nature of chronic heart failure means that many patients will require long-term management. This can be achieved using a permanent circulatory support device such as a LVAD (left ventricular assist device). In 5GMedCamp project – led by Charité – Universitätsmedizin Berlin – researchers from Charité will work alongside with partners from the German Heart Center Berlin (DHZB), the Fraunhofer Heinrich Hertz Institute (HHI) and two technology companies. The aim is to improve the follow-up care of patients with implanted LVADs through the use of the latest telemedicine and 5G mobile network technology. This strategic stand-alone project is supported by the Federal Ministry of Economic Affairs and Energy (BMWi). It will receive approximately €2.1 million in funding over three years. Mechanical devices to support the heart were originally designed to provide temporary circulatory support in patients awaiting heart transplant surgery. Today, more than 1,000 patients a year receive such a device as a permanent treatment solution for chronic heart failure. The nature of the underlying heart disease, potential complications arising in relation to the implanted device and other comorbidities all present major challenges in the treatment of LVAD patients. Due to a lack of suitable technologies, telemedicine-based patient management options remain limited. “This is despite the fact that telemedicine offers enormous possibilities with regard to the early diagnosis and treatment of potential complications such as bleeding, infections and technical problems with the implanted device. Remote patient management, which is available 24/7, is therefore of enormous clinical importance for this patient group. It does, however, require the continuous transmission and monitoring of data,” explains Consortium Lead Prof. Dr. Friedrich Köhler, Head of Charité’s Center for Cardiovascular Telemedicine. Approximately one in six patients in Germany have their LVAD systems implanted at the DHZB. Nationwide, this consortium partner leads the field in terms of length and scope of experience in the management of this patient group. “While we must drive the development of new artificial heart pumps, we need also continue to improve the use of existing systems in a way that safeguards the interests of our patients. Telemedicine has enormous potential in this regard, but to enable its prompt and efficient realization we will need to work together,” says Prof. Dr. Volkmar Falk, Medical Director of the DHZB. In addition to their ability to receive vast amounts of data at speed, 5G-based artificial intelligence (AI) systems are capable of data transfer in real time. Until now, however, relevant models had been limited to a few individual parameters. The 5GMedCamp project sets out to test the integrated use of 5G campus networks, public cellular networks, and home networks to enable the continuous remote monitoring of vital data. The partners will also develop AI-based methods to analyze LVAD streaming data. The objective is to use these technological approaches to turn clinical multidimensional, high-frequency data into AI-based models. Once this step has been completed, the new systems will be tested in clinical practice. The partners also plan to develop 5G-compatible, non-invasive measuring devices to collect electrocardiogram (ECG) and ‘mean arterial blood pressure’ data. Prof. Dr. Slawomir Stanczak, Head of Wireless Communications and Networks at the Fraunhofer Institute for Telecommunication, Heinrich Hertz Institute (HHI), adds: “The continuous streaming of medical data in real time will require 5G-based transmission which meets the highest standards of information security, data protection and reliability. The real-time analysis of all collected data will require the use of AI-based methods which may result in the need for on-site pre-processing. In addition to these technological challenges, it will therefore be essential to make data protection and security mechanisms an integral part of data transmission.” Thanks to the new 5G wireless standard and campus networks, this first-ever, non-stop, real-time streaming of patient data will meet the high standards of security and data protection required within the medical field.

When the brain suffers injury or infection, glial cells surrounding the affected site act to preserve the brain’s sensitive nerve cells and prevent excessive damage. A team of researchers from Charité – Universitätsmedizin Berlin have been able to demonstrate the important role played by the reorganization of the structural and membrane elements of glial cells. The researchers’ findings, which have been published in Nature Communications*, shed light on a new neuroprotective mechanism which the brain could use to actively control damage following neurological injury or disease. The nervous system lacks the ability to regenerate nerve cells and is therefore particularly vulnerable to injury. Following brain injury or infection, various cells have to work together in a coordinated manner in order to limit damage and enable recovery. ‘Astrocytes’, the most common type of glial cell found in the central nervous system, play a key role in the protection of surrounding tissues. They form part of a defense mechanism known as ‘reactive astrogliosis’, which facilitates scar formation, thereby helping to contain inflammation and control tissue damage. Astrocytes can also ensure the survival of nerve cells located immediately adjacent to a site of tissue injury, thereby preserving the function of neuronal networks. The researchers were able to elucidate a new mechanism which explains what processes happen inside the astrocytes and how these are coordinated. “We were able to show for the first time that the protein ‘drebrin’ controls astrogliosis,” says study lead Prof. Dr. Britta Eickholt, Director of Charité’s Institute of Biochemistry and Molecular Biology. “Astrocytes need drebrin in order to form scars and protect the surrounding tissue.” By switching off the production of drebrin inside astrocytes, the researchers were able to study its role in brain injury in an animal model. They used electron microscopy and high-resolution light microscopy to investigate cellular changes in the brain, in addition to undertaking real-time investigations using isolated astrocytes in cell culture. “Loss of drebrin results in the suppression of normal astrocyte activation,” explains Prof. Eickholt. She adds: “Instead of engaging in defensive reactions, these astrocytes suffer complete loss of function and abandon their cellular identity.” Without protective scar formation, normally harmless injuries will spread, and more and more nerve cells will die. To enable scar formation, drebrin controls the reorganization of the actin cytoskeleton, an internal scaffold responsible for maintaining astrocyte mechanical stability. By doing so, drebrin also induces the formation of long cylindrical membrane structures known as tubular endosomes, which are used in the uptake, sorting and redistribution of surface receptors and are needed for the defensive measures of astrocytes. Summing up the researchers’ findings, Prof. Eickholt says: “Our findings also show how drebrin uses the dynamic and versatile cytoskeleton as well as membrane structures to control astrocyte functions which are fundamental to the defense mechanism against injury.” She continues: “In particular, the membrane tubules which are formed during this process have not previously been described in this manner, neither in cultured astrocytes nor in the brain.” “Drebrin’s role as a cytoskeletal regulator suggests that it may be a risk factor for severe outcomes in both neurological and other disorders, because loss of the protein can produce similar changes in astrocytes,” says Prof. Eickholt. She adds: “It is also possible that individuals with defects in the drebrin gene – comparable to those in the animal model – might remain without symptoms until triggers like cellular stresses, environmental toxins or diseases occur.” It is hoped that investigations involving patient samples will elucidate the extent to which drebrin also plays a role in degenerative brain disorders, such as Alzheimer's disease.

Researchers from Charité – Universitätsmedizin Berlin and the Francis Crick Institute have developed a mass spectrometry-based technique capable of measuring samples containing thousands of proteins within just a few minutes. It is faster and cheaper than a conventional blood count. To demonstrate the technique’s potential, the researchers used blood plasma collected from COVID-19 patients. Using the new technology, they identified eleven previously unknown proteins which are markers of disease severity. The work has been published in Nature Biotechnology*. Thousands of proteins are active inside the human body at any given time, providing its structure and enabling reactions which are essential to life. The body raises and lowers the activity levels of specific proteins as required, including when responding to external factors such as pathogens and drugs. The detailed patterns of the proteins found inside cells, tissues and blood samples can therefore help researchers to better understand diseases or make diagnoses and prognoses. In order to obtain this ‘protein fingerprint’, researchers use mass spectrometry, a technology known to be both time-consuming and cost-intensive. ‘Scanning SWATH’, a new mass-spectrometry-based technology, promises to change this. Developed under the leadership of Prof. Dr. Markus Ralser, Director of Charité’s Institute of Biochemistry, this technology, which is much faster and cost-effective than previous methods, enables researchers to measure several hundred samples per day. “In order to speed up this technology, we changed the mass spectrometer’s electric fields. The data produced are of such extreme complexity that humans can no longer analyze them,” explains Einstein Professor Prof. Ralser, who is also a Group Leader at the Francis Crick Institute in London. He adds: “We therefore developed computer algorithms that are based on neural networks and which use these data to extract the relevant biological information. This enables us to identify thousands of proteins in parallel and greatly reduces measuring timescales. Fortunately, this method is also more precise.” This high-throughput technology has a broad range of potential applications, ranging from basic research and large-scale drug development to the identification of biological markers (biomarkers), which can be used to estimate an individual patient’s risk. The technology’s suitability for the latter was demonstrated by the researchers’ study on COVID-19. As part of this research, the team analyzed blood plasma samples from 30 Charité inpatients with COVID-19 of varying degrees of disease severity, comparing the protein patterns obtained with those of 15 healthy individuals. The actual measurements conducted on individual samples only took a few minutes. The researchers were able to identify a total of 54 proteins whose serum levels varied according to the severity of COVID-19. While 43 of these proteins had already been linked to disease severity during earlier studies, no such relationship had been established for 11 of the proteins identified. Several of the previously unknown proteins associated with COVID-19 are involved in the body’s immune response to pathogens which increases clotting tendency. “In the shortest of timeframes, we discovered protein fingerprints in blood samples which we are now able to use to categorize COVID-19 patients according to severity of disease,” says one of the study’s lead authors, Dr. Christoph Messner, who is a researcher at Charité’s Institute of Biochemistry and the Francis Crick Institute. He continues: “This type of objective assessment can be extremely valuable, as patients will occasionally underestimate the severity of their disease. However, in order to be able to use mass spectrometry analysis for the routine categorization of COVID-19 patients, this technology will need to be refined further and turned into a diagnostic test. It may also become possible to use rapid protein pattern analysis to predict the likely course of a case of COVID-19. While the initial findings we have collected are promising, further studies will be needed before this can be used in routine practice.” Prof. Ralser is convinced that mass spectrometry-based investigations of the blood could one day complement conventional blood count profiles. “Proteome analysis is now cheaper than a complete blood count. By identifying many thousands of proteins at the same time, proteomic analysis also produces far more information. I therefore see enormous potential for widespread use, for instance in the early detection of diseases. We will therefore continue to use our studies to develop proteome technology for this type of application.”

Influenza vaccines need to be evaluated every year to ensure they remain effective against new influenza viruses. Will the same apply to COVID-19 vaccines? In order to gauge whether and to what extent this may be necessary, a team of researchers from Charité – Universitätsmedizin Berlin compared the evolution of endemic 'common cold' coronaviruses with that of influenza viruses. The researchers predict that, while the pandemic is ongoing, vaccines will need to undergo regular updates. A few years into the post-pandemic period, however, vaccines are likely to remain effective for longer. This study has been published in Virus Evolution*. Influenza viruses are masters at evading the human immune system. They undergo such rapid changes that antibodies produced by the immune system in response to a previous infection or vaccination become unable to neutralize them. This is why the complex task of evaluating and updating the seasonal influenza vaccine has to be repeated every year. Mutations within SARS-CoV-2 have already produced a number of variants, some of which (such as the South African variant) partially evade the body’s immune response. As a result, some vaccine manufacturers have already started to develop new versions of their vaccines. What does this mean for the future? Will COVID-19 vaccines mirror influenza vaccines in requiring regular updates? In order to gauge whether, over the long term, SARS-CoV-2 is likely to demonstrate an immune evasion capability on par with that of influenza viruses, Charité virologists have studied the genetic evolution of the four currently known ‘common cold’ coronaviruses. These relatively harmless coronaviruses are known to be responsible for approximately 10 percent of common colds in the world and have been in circulation in humans significantly longer than SARS-CoV-2. Just like SARS-CoV-2, they enter human cells using the ‘spike protein’, a surface protein which gives the virus its characteristic crown-like appearance (and name). The spike protein also forms the target of all current COVID-19 vaccines. For their study, the researchers focused on the two longest-known coronaviruses (termed 229E and OC43), tracing changes in the spike gene approximately 40 years into the past. The researchers started by comparing sequences from a range of old samples which had been deposited in a genetic sequence data bank. Based on the mutations which had emerged over time, they then produced phylogenetic trees for both coronaviruses. The researchers compared their findings with the phylogenetic tree of H3N2, an influenza subtype which is particularly effective at evading the human immune response. The researchers’ calculations revealed one feature which was common to the phylogenetic reconstructions of both the coronaviruses and the influenza virus: all three had a pronounced ladder-like shape. “An asymmetrical tree of this kind likely results from the repeated replacement of one circulating virus variant by another which carried a fitness advantage,” explains the study’s first author, Dr. Wendy K. Jó from Charité’s Institute of Virology. “This is evidence of ‘antigenic drift’, a continuous process involving changes to surface structures which enable viruses to evade the human immune response. It means that these endemic coronaviruses also evade the immune system, just like the influenza virus. However, one also has to look at the speed with which this evolutionary adaptation happens.” For this step, the researchers determined the three viruses’ evolutionary rates. While the influenza virus accumulated 25 mutations per 10,000 nucleotides (genetic building blocks) per year, the coronaviruses accumulated approximately 6 such mutations in the same timeframe. The rate of change of the endemic coronaviruses was therefore four times slower than that of the influenza virus. “As far as SARS-CoV-2 is concerned, this is good news,” summarizes Prof. Dr. Christian Drosten, Director of the Institute of Virology and a researcher at the German Center for Infection Research (DZIF). SARS-CoV-2 is currently estimated to change at a rate of approximately 10 mutations per 10,000 nucleotides per year, meaning the speed at which it evolves is substantially higher than that of the endemic coronaviruses. “This rapid genetic change in SARS-CoV-2 is reflected in the emergence of numerous virus variants across the globe,” explains study lead Prof. Dr. Jan Felix Drexler, a researcher at both the Institute of Virology and the DZIF. “This, however, is likely due to the high rates of infection seen during the pandemic. When infection numbers are so high, a virus is able to evolve more rapidly. Based on the rates of evolution seen in the endemic common cold coronaviruses, we expect that SARS-CoV-2 will start to change more slowly once infections start to die down – meaning once a large proportion of the global population has developed immunity either as a result of infection or through vaccination. We expect therefore that COVID-19 vaccines will need to be monitored regularly throughout the pandemic and updated where necessary. Once the situation has stabilized, vaccines are likely to remain effective for longer.”

Joint press release by Charité und the MDC Researchers from the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) and Charité – Universitätsmedizin Berlin have developed a new gene therapy based around a special T-cell receptor that helps the immune system effectively recognize and fight cancer cells. The safety of the novel therapy is now being tested on patients with bone marrow cancer in a phase I clinical trial. A new cancer-fighting gene therapy has been applied in the clinic for the first time after 20 years of preliminary research in the laboratories of MDC) and Charité. Other initiatives to have emerged from this work include biotech start-up T-knife. A few weeks ago, the first multiple myeloma patient received an infusion of her body’s own immune cells (the so-called T cells) that had been genetically modified to enable their receptors to recognize and fight the cancer. Multiple myeloma is one of the most common cancers affecting the bone and bone marrow. Twelve patients are to undergo this treatment over the course of the two-year phase I trial. “The primary concern right now is to make sure this new form of immunotherapy and gene therapy is safe for patients,” says Prof. Dr. Antonio Pezzutto, who is leading the study at the Department of Hematology, Oncology and Cancer Immunology on Charité’s Campus Benjamin Franklin. “We believe we will see indications that the principle behind the therapy is effective and hope that the patients will benefit,” adds Prof. Pezzutto, “but it is in the next clinical phase that the effectiveness of the therapy will be investigated in a large number of people.” The German Federal Ministry of Education and Research (BMBF) is funding the cooperative project with € 4 million. T cells monitor our body and protect it from diseases such as viral infections. Infected cells can be recognized by the viral antigens that appear as typical markers on their surface. If a T cell detects an antigen with the help of its receptor, it either destroys the affected cell or triggers a wider immune response. Cancer cells also have special antigens on their surface, but the problem is that the immune system often does not recognize them as malignant and therefore does not fight them. This could all be about to change with the new T-cell gene therapy, which was developed by a team led by Prof. Dr. Thomas Blankenstein, head of the Molecular Immunology and Gene Therapy Lab at the MDC and former director of Charité’s Institute of Medical Immunology. The researchers want to teach the study participants’ T cells to identify cancer cells as invaders. “Our preclinical experiments suggest that this should be possible without damaging any healthy tissue in the patients,” says Prof. Blankenstein. The research team started out focusing on the antigen MAGE-A1 as a potential candidate for treating multiple myeloma. This protein is a typical distinguishing feature that appears on the surface of cancer cells and is more common in multiple myeloma. The scientists were able to produce a specific T-cell receptor that recognizes this particular antigen, and thus the cell that carries it, as malignant and dangerous. This was possible thanks to a technology platform that Prof. Blankenstein’s team developed for the gene therapy – a transgenic mouse with an exclusively human T-cell repertoire – which is the only one of its kind. “If the transgenic mouse is immunized with a human antigen, it starts to produce only T cells with matching receptors, which can then be easily isolated,” explains Prof. Blankenstein. “This enables us to obtain the genetic blueprint of receptors of human origin, which cannot usually be obtained from humans. The T-cell receptors are then subjected to a series of safety and efficacy tests, which is very important to ensure the safety of this treatment for patients with bone marrow cancer.” The cell products for the entire study are being manufactured at the GMP Facility for Cellular Therapies at the Experimental and Clinical Research Center (ECRC), a joint institution of Charité and the MDC that specializes in the production of cell and gene therapies in clean rooms. First, doctors took T cells from the initial patient and handed them over to specialists at the ECRC. Here, the genetic information of the specific receptor was inserted into the patient’s own T cells, which were then activated and multiplied. A few days before the treatment, the patient received chemotherapy to eliminate other immune cells in the body. This makes the attack on the cancer cells particularly effective. After being treated with her own genetically modified T cells, the patient was monitored for a fortnight as an inpatient at Charité. She has undergone regular examinations since then, and these will continue into the future. The treating physicians include Matthias Obenaus, who isolated and characterized this T-cell receptor. In addition to MAGE-A1, the team has discovered other promising antigens that occur in other cancers. T-knife is currently in the process of manufacturing and testing suitable receptors. If successful, this should enable more and more patients to benefit from the MDC and Charité’s new gene therapy in the future. “We are excited to learn the results of the study and hope that this gene therapy will provide us with a new and promising way to better fight cancer in the future,” says Prof. Blankenstein.

Drugs such as beta-adrenergic antagonists (beta blockers) have been linked to a range of adverse effects, including depression. But how reliable are these data, and which psychiatric side effects might indeed be caused by these drugs? These questions have been addressed by a team of researchers from Charité – Universitätsmedizin Berlin, whose comprehensive meta-analysis has been published in Hypertension*. While treatment with beta blockers was not found to be associated with an increased incidence of depression, some studies recorded higher levels of sleep disturbance. Beta-adrenergic antagonists such as metoprolol or propranolol are among the drugs most commonly prescribed for the treatment of cardiovascular disease. Their effect is to slow the heart rate and reduce blood pressure, which is why they are used in patients with heart failure, arrhythmias, and high blood pressure. Beta blockers have repeatedly been linked to an increased risk of depression, but also other side effects such as anxiety, sleep disturbance and hallucinations; these links had not previously been explored in a systematic manner. “We found no evidence to suggest a link between the use of beta blockers and depression,” says Prof. Dr. Reinhold Kreutz, Director of Charité’s Institute of Clinical Pharmacology and Toxicology. “The same also goes for most of the other psychiatric symptoms described in the studies included in our analysis.” Continuing his description of the meta-analysis conducted by his team – the first to study the full range of psychiatric side effects – he adds: “However, some patients developed sleep-related symptoms during treatment with beta blockers.” The researchers analyzed data from more than 53,000 persons. These were taken from 285 individual studies and involved 24 different beta blockers. Only data from double-blind, randomized, controlled trials were included in the analysis. The majority of these related to high blood pressure and had been conducted more than 20 years ago. Despite being the most commonly reported psychiatric side effect, depression did not occur more frequently during treatment with beta blockers than during treatment with a placebo. Prof. Kreutz, currently President of the European Society of Hypertension, explains: “Patients with a history of cardiovascular problems such as heart attack or stroke are per se prone to develop mental health complications. This means that, while we found no causal link for this problem with beta blockers, these patients should be anyway monitored in this regard in clinical practice.” Patients treated with beta blockers were no more likely to discontinue their medications due to depression than patients undergoing different treatments. However, drowsiness and fatigue were the most commonly reported reasons for discontinuing treatment. Among the other side effects studied – such as anxiety and loss of appetite, memory, or libido – only sleep disturbance and abnormal dreams were found to be linked with beta blockers. Summing up the results of the research, Prof. Kreutz says: “Our results show that concerns regarding undesirable psychiatric effects, in particular depression, should not influence the decision-making process regarding the use of beta blockers. For the most part, beta blockers have a good psychiatric safety profile.” Therefore, concerns about psychological health should not affect the clinical use of beta-blockers.

Joint press release by Charité and TU Berlin Researchers at Charité – Universitätsmedizin Berlin and TU Berlin as well as the University of Oslo have developed a new tissue-section analysis system for diagnosing breast cancer based on artificial intelligence (AI). Two further developments make this system unique: For the first time, morphological, molecular and histological data are integrated in a single analysis. Secondly, the system provides a clarification of the AI decision process in the form of heatmaps. Pixel by pixel, these heatmaps show which visual information influenced the AI decision process and to what extent, thus enabling doctors to understand and assess the plausibility of the results of the AI analysis. This represents a decisive and essential step forward for the future regular use of AI systems in hospitals. The results of this research have now been published in Nature Machine Intelligence*. Cancer treatment is increasingly concerned with the molecular characterization of tumor tissue samples. Studies are conducted to determine whether and/or how the DNA has changed in the tumor tissue as well as the gene and protein expression in the tissue sample. At the same time, researchers are becoming increasingly aware that cancer progression is closely related to intercellular cross-talk and the interaction of neoplastic cells with the surrounding tissue - including the immune system. Although microscopic techniques enable biological processes to be studied with high spatial detail, they only permit a limited measurement of molecular markers. These are rather determined using proteins or DNA taken from tissue. As a result, spatial detail is not possible and the relationship between these markers and the microscopic structures is typically unclear. “We know that in the case of breast cancer, the number of immigrated immune cells, known as lymphocytes, in tumor tissue has an influence on the patient’s prognosis. There are also discussions as to whether this number has a predictive value - in other words if it enables us to say how effective a particular therapy is,” says Prof. Dr. Frederick Klauschen of Charité’s Institute of Pathology. “The problem we have is the following: We have good and reliable molecular data and we have good histological data with high spatial detail. What we don’t have as yet is the decisive link between imaging data and high-dimensional molecular data,” adds Prof. Dr. Klaus-Robert Müller, professor of machine learning at TU Berlin. Both researchers have been working together for a number of years now at the national AI center of excellence the Berlin Institute for the Foundations of Learning and Data (BIFOLD) located at TU Berlin. It is precisely this symbiosis which the newly published approach makes possible. “Our system facilitates the detection of pathological alterations in microscopic images. Parallel to this, we are able to provide precise heatmap visualizations showing which pixel in the microscopic image contributed to the diagnostic algorithm and to what extent,” explains Prof. Müller. The research team has also succeeded in significantly further developing this process: “Our analysis system has been trained using machine learning processes so that it can also predict various molecular characteristics, including the condition of the DNA, the gene expression as well as the protein expression in specific areas of the tissue, on the basis of the histological images. Next on the agenda are certification and further clinical validations - including tests in tumor routine diagnostics. However, Prof. Klauschen is already convinced of the value of the research: “The methods we have developed will make it possible in the future to make histopathological tumor diagnostics more precise, more standardized and qualitatively better.”

Ribosome formation is viewed as a promising potential target for new antibacterial agents. Researchers from Charité – Universitätsmedizin Berlin have gained new insights into this multifaceted process. The formation of ribosomal components involves multiple helper proteins which, much like instruments in an orchestra, interact in a coordinated way. One of these helper proteins – protein ObgE – acts as the conductor, guiding the entire process. The research, which produced the first-ever image-based reconstruction of this process, has been published in Molecular Cell*. Ribosomes are an essential component of all living cells. Frequently referred to as ‘molecular protein factories’, they translate genetic information into chains of linked-up amino acids which are otherwise known as proteins. The process of protein biosynthesis is the same in all cells, even in bacteria (including the widely known intestinal bacterium Escherichia coli). If this process cannot take place, the cell dies; single-celled organism (such as E. coli and other bacteria) cannot survive. Researchers are hoping to exploit this circumstance for the development of novel antibiotic agents. The need for these new drugs is not only the result of an increase in antibiotic resistance and the emergence and spread of new multidrug-resistant pathogens, but also because it has been a long time since a new class of antibiotic substances emerged. A new type of antibiotic might be designed to interfere with ribosome formation in a way that inhibits their assembly. “It is a coincidence that we are currently in the middle of a viral pandemic. The next pandemic could easily be of bacterial origin because both bacterial antibiotic resistance and multidrug resistance are spreading rapidly, across species barriers”, explains the study’s last author, Prof. Dr. Christian Spahn, Director of Charité’s Institute of Medical Physics and Biophysics. He adds: “The long-term aim of our basic research is therefore to contribute to the development of new antibiotics.” Working with colleagues from the Max Delbrück Center for Molecular Medicine MDC) in Berlin and the University of Konstanz, the Charité researchers explored the early stages of ribosome formation to identify points in the process which might serve as targets for new antibacterial and antimicrobial drugs. Ribosomes consist of two subunits: one larger subunit and one smaller one. As part of their latest endeavors, the team, led by Dr. Rainer Nikolay of Charité’s Institute for Medical Physics and Biophysics, focused on studying the nature and development of the larger ribosomal subunit in the bacterium E.coli. Hoping to identify a potential target for new antibiotics, the researchers wanted to isolate and visualize the precursor stages of this larger subunit. To do so, they wanted to use the subunit in its unadulterated form, i.e. as close to its natural condition as possible. For the first time, the researchers succeeded in not only isolating one such precursor from bacterial cells (in this case, E. coli), but also visualizing it using cryo-electron microscopy imaging at near-atomic resolution. “We now have a better understanding of the way in which the larger bacterial ribosomal subunit develops at the molecular level, although our understanding remains far from complete,” says first author Dr. Nikolay. The research team chose a minimally invasive protocol in order to minimize the degree to which the bacterial cell would need to be manipulated. One of the key agents in the process of ribosome formation, the protein ObgE, was marked using what is known as a ‘Strep tag’. This step involves a ‘gene knock-in’ procedure – the insertion of genetic information into the bacterial genome. A bacterium thus treated will produce only marked ObgE. After minor processing of the cell, this ObgE can then be visualized using an electron microscope. Strep tagging enabled the researchers to study the entire complex for the first time. This is because the helper protein ObgE effectively carries the precursor of the larger ribosomal subunit on its back. The results came as a surprise, as Dr Nikolay explains: “We found that this precursor is covered in multiple helper proteins, which either interact or directly communicate with one another. The ObgE protein takes on a key role in this process, effectively directing and coordinating it.” This could constitute a target for new drugs, which might stop bacterial growth by inhibiting the assembly of functional ribosomes. The team want to use similar strategies to gain further insights into the development of bacterial ribosomal subunits and enhance their understanding of the relevant biological processes at the molecular level. Previous research, conducted at Charité and the Max Planck Institute for Molecular Genetics, had produced valuable information on the fundamental structure of ribosomes and the various steps of the maturation process which these cellular protein factories must undergo. While all of these earlier insights were based on in vitro studies, the researchers knew that the formation of the large chromosomal subunit could only be observed in a living cell. The latest step in their endeavors has therefore been a crucial one: in order to identify new cellular drug targets, it is necessary to understand how the process of ribosome formation seen in bacteria differs from that in human cells. “We have managed to make some headway in that respect,” says Dr. Nikolay. “We were able to reveal the existence of both conserved and divergent evolutionary features between prokaryotes – such as bacteria – and eukaryotes – organisms whose genetic information is contained inside a cell nucleus.” These findings are important if we are to target features specific to bacteria while also protecting human cells against unwanted side effects.

Joint press release by Charité and TU Berlin How can dental restorations – such as fillings and crowns – be made to last longer? A new research group centered at Charité – Universitätsmedizin Berlin and Technische Universität (TU) Berlin plans to address this topic by utilizing approaches from both materials science and dentistry. The aim is to gain a better understanding of the composition and structure of the material-tissue interfaces and the stresses exerted on them. The interdisciplinary ‘InterDent’ research group is funded by the German Research Foundation (DFG). It will receive an initial funding of €2.1 million Euro over three years. Restorative dentistry uses synthetic biomaterials such as ceramics, alloys and composites to restore damaged teeth. These materials must withstand heavy and repeated stresses in order to retain their ability to function for many years. Secure adhesion to the remaining healthy tooth tissue depends on the creation of ‘interface zones’, three-dimensional structures which consist of different connecting layers of varying composition, microstructure and properties. Interzones are never as resilient as their natural counterparts. This is one of the reasons why dental restorations often fail early and become detached. The new DFG research group – known as FOR2804 ‘InterDent’ – is a collaborative effort involving medical experts and materials scientists. Partners also include the Helmholtz-Zentrum Berlin (HZB), a research center for energy materials research, and the Max Planck Institute of Colloids and Interfaces (MPI-KG), which is located in Potsdam. The researchers hope that a better understanding of what causes tooth-related structural weaknesses will pave the way toward more resilient interzones. “The research group is organized into four sub-projects and one overarching, coordinating project, which serves as the basis for close interaction between experts from materials science and dentistry in different institutes. The purpose of this interdisciplinary collaboration is to identify key parameters which can be used to predict the risk of degradation and which are capable of implementation into clinical practice,” explains the research group’s spokesperson, Dr. Paul Zaslansky, who is project leader at Charité’s Institute of Dental, Oral and Maxillary Medicine. He adds: “Thanks to the close proximity of ultra-modern materials laboratories and outstanding dental expertise, the Berlin-Brandenburg area offers an ideal growth environment for inspiring collaborations and innovative findings.” The goal of the team is to create better dental materials by shedding light on the ways in which different materials interact with the surrounding tissues. One of the sub-projects aims at predicting the way in which dentine (the hard bony tissue that makes up the tooth´s core) changes over time, depending on the material used for the filling to which it is attached. Employing non-destructive, highly sensitive, high-resolution technology, the researchers will study the microstructure and chemical characteristics of dentine, tracking progressive changes over time as part of an aging process known as ‘sclerosis’. “We want to use this approach in order to develop a model of sclerotic dentine which will enable us to gain a better understanding of changes in its structure and composition,” says Dr. Ioanna Mantouvalou of the HZB, who leads the sub-project together with Dr. Zaslansky. Another sub-project will focus on the structure and mechanical properties of a natural tooth interzone which is exposed to particularly severe stress: the junction between dentine and cementum surrounding it. While this structure is remarkably robust and resilient to cyclic loading, surprisingly little is known about its microstructure and mechanical properties. “We want to gain a better understanding of the structure and function of junction zones in farm mammals and human teeth, comparing younger and older teeth and teeth which have been subject to altered mechanical stresses. This will enable us to deduce general underlying principles which contribute to the long-term fatigue resistance of the dentino-cemental junction and which we will explore for bioinspired structures,” says Prof. Dr. Claudia Fleck, Head of Materials Engineering at TU Berlin and Deputy Spokesperson for the research group. When oral bacteria colonize the surfaces of teeth and of the biomaterials used in restorative dentistry, they produce ‘biofilm’: a cohesive community of microorganisms which forms a slime layer. “We will explore and understand the formation and growth of biofilms by focusing on both composition and microstructure as well as the interzone areas where they interface with dental materials,” says Dr. Cécile Bidan, a group leader of the MPI-KG Biomaterials department and the third sub-project’s co-lead alongside Prof. Dr. Sebastian Paris, Director of Research at Charité’s Institute of Dental, Oral and Maxillary Medicine. “To do this, we will conduct quantitative and systematic analyses to determine the spatial and temporal development of specific bacteria in biofilms grown on different surfaces and in contact with dental restoratives.” How the teeth may be better sealed against bacteria following root canal treatments forms the focus of the fourth InterDent sub-project. “By combining high-resolution imaging, digital image analysis and mechanical testing methods, we want to determine parameters which are critical to establishing a sealed interzone between biomaterials and the root. We have several new ideas how to lay the foundations for more durable root canal restorations,” explains PD Dr. Kerstin Bitter of the Department of Restorative and Preventive Dentistry, who shares the co-project lead role on this project with Prof. Fleck. To overcome the existing deficiencies and limitations of dental biomaterials, it will be necessary to use available resources and samples in a coordinated manner, and raise a new generation of doctoral researchers integrating findings across all sub-projects. A key objective of the coordinating project is to create a culture of interdisciplinary collaboration – leading to a better understanding of dental interzones with the ultimate goal of improving dental treatment.

Variants such as B.1.1.7 and B.1.351 are currently attracting attention, as they could have an impact on infection rates. Charité – Universitätsmedizin Berlin and Vivantes – Netzwerk für Gesundheit GmbH responded to this development at an early stage, subjecting all samples returning positive SARS-CoV-2 PCR test results to specific genotyping assays which test for the presence of these mutations. Genotyping was conducted at Labor Berlin – Charité Vivantes GmbH, a joint subsidiary of the two organizations. The Labor Berlin website now publishes the numbers of infections identified in samples from Vivantes, Charité and external contributors. The aim is to gain a better overview of coronavirus infections in Berlin. Together, Charité and Vivantes cover approximately 40 percent of all hospitalized patients in Berlin. The data collated by their joint subsidiary, Labor Berlin, therefore serve as an important indicator for the spread of coronavirus variants of concern (VOCs). Dr. Johannes Danckert, Executive Director of Hospital Management, Vivantes: “A clear overview of infections and developments provides the best possible position from which to control the spread of these new variants. We want to create more transparency in this area and will therefore be publishing our infection statistics for the new variants on the Labor Berlin website. To optimize our ability to track the rapidly evolving situation of new variants within the region, it would be helpful if other hospital operators and laboratories were to follow this example.” Prof. Dr. Heyo K. Kroemer, Charité’s Chief Executive Officer: “Labor Berlin initiated routine testing for variants early on in the pandemic. Large numbers of SARS-CoV-2 samples from both hospital providers and other institutions have been undergoing additional testing to identify mutations. This program was initially developed at Charité’s Institute of Virology, under the leadership of Prof. Dr. Christian Drosten. All routine coronavirus testing has since moved to Labor Berlin. All samples which test positive for SARS-CoV-2 undergo additional, mutation-specific PCR testing to confirm the presence or absence of the variants currently of particular concern. This is enormously helpful in keeping track of the pandemic situation in Berlin.” Infection statistics for all identified variants will be updated on a weekly basis at: https://www.laborberlin.com Labor Berlin has more than 600 members of staff working across 13 sites. Labor Berlin processes more than 65 million laboratory tests every year, serving more than 23,000 hospital beds. Founded in 2011 as the first joint subsidiary of Charité – Universitätsmedizin Berlin and Vivantes – Netzwerk für Gesundheit, Labor Berlin is the largest hospital laboratory in Europe.

Joint press release by Charité und the MDC The immune system actually wants to fight SARS-CoV-2 with antiviral signaling molecules. But a research team from Charité – Universitätsmedizin Berlin and the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) has now shown how such a signaling molecule can promote the replication of the virus. The results have been published in the journal EMBO Molecular Medicine*. Most people infected with SARS-CoV-2 are able to recover from the disease at home – even if they might experience very stressful disease progressions. Some have no symptoms at all. But about ten percent of those affected become so severely ill that they have to be treated in a hospital. The assumption that a weak immune system is behind a severe progression is short-sighted. Especially with critical progressions, the immune system works under intense pressure, but does not manage to control the virus. A Berlin research group has now observed how SARS-CoV-2 uses an immune system defense mechanism to increasingly hijack the body’s mucous membrane cells and multiply there. “This may give us part of the explanation as to why the immune system has difficulty regulating or even defeating the infection in some people,” says Dr. Julian Heuberger, scientist at Charité’s Medical Department, Division of Hepatology and Gastroenterology. He is the first author of the study and a member of an Emmy Noether Research Group led by PD Dr. Michael Sigal at Charité and the Berlin Institute for Medical Systems Biology (BIMSB), part of the MDC. For the study, the research group cooperated with researchers from the Max Planck Institute for Infection Biology (MPIIB), Freie Universität Berlin and Hong Kong University. Actually, the human body has a very effective defense mechanism against invaders, based on the interaction of various immune cells. T cells play an important role in this: When they encounter viruses in the organism, they destroy the affected cells. They also secrete the signaling molecule interferon-gamma (IFN-γ). On the one hand, IFN-γ fights infectious agents. On the other hand, it calls other immune cells to the scene. Dr. Heuberger and his colleagues have now shown how SARS-CoV-2 can turn this protective mechanism mediated by IFN-γ into its opposite. For in addition to immune cells, the body’s mucous membrane cells (epithelial cells) also respond to IFN-γ by forming more ACE2 receptors. SARS-CoV-2 needs these ACE2 receptors as a port of entry into the cells. Infected cells, in turn, make more ACE2. In this way, both the IFN-γ response of epithelial cells and the virus itself intensify the SARS-CoV-2 infection. Patients infected with SARS-CoV-2 sometimes show gastrointestinal symptoms. In order to observe the immune cascade in the intestinal cells, Dr. Heuberger cultivated organoids of the human colon. An organoid is a kind of mini-organ in a petri dish, barely the size of a pinhead. The colon organoids are based on cells that come from intestinal biopsies. They grow in three-dimensionally arranged units and replicate the physiology of mucous membrane cells in the human intestinal tract. “These colon organoids are a very helpful tool,” Dr. Heuberger emphasizes. “We can use them to explore the complex interplay of different signaling pathways that control cell differentiation from stem cells to specialized epithelial cells.” The scientists first treated the cultured intestinal cells with IFN-γ to simulate the body’s immune response. Then they infected the organoids with SARS-CoV-2. Using gene expression analysis and a laser scanning microscope – a special optical microscope that scans a sample point by point – they were able to measure increased ACE2 expression in the organoids. In addition, quantitative polymerase chain reaction (PCR) detected increased virus production. In other words, more IFN-γ means more ACE2. More ACE2 means more viruses can enter the cells. The more viruses that enter the cells, the more viruses produced. Thus, the immune response and the surface cell response to infection pave the way for SARS-CoV-2. “We hypothesize that a strong immune response may increase the susceptibility of mucous membrane cells to SARS-CoV-2,” says the head of the study, PD Dr. Sigal. He directs a lab at Charité and the MDC and is a gastroenterologist at Charité. “If the IFN-γ concentration is higher from the outset or the infection triggers a very excessive production of IFN-γ, the viruses probably have an easier time entering the cells.” However, the conditions under which this actually happens must still be investigated in clinical trials. The results of the study carry the idea of a treatment approach for severe COVID-19 courses, Dr. Heuberger feels: “One possible strategy could be to balance the IFN-γ response with drugs.” However, this would first require a very detailed analysis of the mechanisms underlying the IFN-γ response.

Joint press release by Charité – Universitätsmedizin Berlin and the Max Planck Institute for Molecular Genetics An international team of researchers discovered a rare genetic disease characterized by severe malformations of the limbs. As scientists from Charité – Universitätsmedizin Berlin and the Max Planck Institute for Molecular Genetics describe in Nature*, the condition is caused by a newly identified epigenetic mechanism involving sequences of the genome with previously unknown function. This process could also explain the cause of other congenital diseases. When the human genome was sequenced 20 years ago, it was almost disappointing to realize that only 20,000 protein-coding genes could be identified. Furthermore, these genes occupy less than two percent of the entire genome raising the question about the function of the other, non-coding part. In fact, scientists once thought the non-coding DNA between genes was “junk”, with no known purpose. However, as has been discovered in the meantime, cells use the information “between the lines of the genome” to control which genes become active at what time and at which place. An international team of researchers in Berlin, Germany in collaboration with human geneticists from Lausanne, Switzerland discovered a new mechanism causing a rare genetic disease that involves such non-coding DNA sequences. As the scientists report, the transcription of a non-coding DNA segment that is located in the vicinity of the developmental gene “engrailed-1” (En1) is an essential factor for the activation of the gene. The En1 gene is known for its major control functions, being responsible for the development of the limbs, the brain, the sternum, and ribs. In their study, the scientists show how the process of En1 activation is controlled specifically in the limbs and how its disruption causes so far undescribed severe congenital limb malformations. “I expect that there are more congenital diseases with a similar cause that just evaded our attention,” says Prof. Dr. Stefan Mundlos, Director of Charité’s Institute for Medical Genetics and Human Genetics and head of a research group at the Max Planck Institute for Molecular Genetics in Berlin. “More than half of genetic diseases still remain unexplained, so there is great potential in exploring this further.” The three patients included in this study show a striking type of malformation. Their knees are not oriented to the front, some fingers are fused together, and nails grow from the other side of the digits, for example. “It appears that during the development of the limbs, the distinction between the ventral and dorsal – i.e. the palm and back side – of the extremities has been lost,” says Prof. Mundlos. Clinical researchers from Brazil and India first identified the patients and sent their DNA samples to the team of Prof. Dr. Andrea Superti-Furga at the University of Lausanne for genetic testing. There, the team of human geneticists discovered that a similar piece of non-coding DNA was missing in all three patients. To explore this further, they teamed up with Prof. Mundlos’ lab in Berlin. At the Max Planck Institute for Molecular Genetics, scientist Dr. Lila Allou took on the search for the molecular cause of the disease. “When we started, we just knew that the three patients had a similar small piece of DNA missing,” she says. “But this sequence was in a large gene desert, a region between two genes that we did not know anything about.” Nevertheless, this small missing piece was the underlying cause for the disorder, as Dr. Allou found out with the help of a mouse model. Using CRISPR-Cas technology, the researcher removed the corresponding DNA sequence in the genome. “Mice with this deletion recapitulated the appearance of the disease to a large extent,” says Dr. Allou. “The results confirmed that we found the root of the problem.” Further studies showed that the genetically modified animals had lost the activity of the nearby gene En1 specifically in the limbs. The En1 gene has been known for its developmental importance for decades and its dysregulation was apparently causing the disease. But the mechanism – how exactly the deletion of the DNA segment resulted in the loss of En1 expression – was still in the dark. The scientists discovered that an RNA molecule, which they named “Maenli” (for Master Activator of Engrailed-1 in the Limb), was transcribed from the region that was missing in the patients. This non-coding RNA site turned out to be the key to the puzzle. RNA molecules in most cases serve as messengers for information. They can contain the blueprints for proteins, but in this case, the information was not translated. “These kinds of transcribed snippets arise all over the genome. It is hard to know which ones are important and which ones are not,” says Dr. Allou. “Many scientists still regard them as coincidental molecules, but in this case, it was what captured our attention.” The scientist investigated the function of the non-coding RNA by inactivating its transcription. Animals with an inactivated Maenli site showed the same malformations as those with the deletion, indicating that indeed the missing non-coding transcription was the cause of the disease. Furthermore, it seemed like having an entire correct RNA molecule was not that important for the activation of the developmental gene En1, but rather its transcriptional activity. After Dr. Allou replaced the transcribed snippet with a completely different sequence, the animals were still affected, but to a lesser degree than due to a complete inactivation of Maenli. Thus, a different genetic expression at the site was sufficient to activate the En1 gene – although to a lesser extent than the original sequence. How the transcribed snippet activates the En1 gene in detail is subject of ongoing research at Prof. Mundlos’ lab. Nevertheless, the implications of the new findings are extensive already: “Our results impact the scientific fields of human genetics, RNA research, development and gene regulation,” says the researcher. “From a developmental point of view, we identified a new key epigenetic mechanism that decides which cells will give rise to the ventral or palm side of the limbs during development,” Dr. Allou adds. “But I believe that this work has a wider impact on patient diagnostics with the potential of solving other puzzles of rare genetic diseases.“ “More than 90 percent of the genetic variants are found in the non-coding part of the genome but it is very difficult to interpret them for diagnostic purposes,” she says. “Our work clearly shows that information that has so far been ignored for the interpretation of genetic variants can be crucial for understanding the molecular cause of diseases.” To help unravel other unsolved cases, it will be then critical to take into account all the available genetic and epigenetic data, including data previously regarded as not that important, says the researcher. “What we assume is not worth looking at may in fact hold the answer to major findings.”

STEMOs (Stroke-Einsatz-Mobile) have been serving Berlin for ten years. The specialized stroke emergency response vehicles allow physicians to start treating stroke patients before they reach hospital. For the first time, a team of researchers from Charité – Universitätsmedizin Berlin has been able to show that the dispatch of mobile stroke units is linked to improved clinical outcomes. The researchers’ findings, which show that patients for whom STEMOs were dispatched were more likely to survive without long-term disability, have been published in JAMA*. The phrase ‘time is brain’ emphasizes a fundamental principle from emergency medicine, namely that after stroke, every minute counts. Without treatment, the brain will lose two million brain cells every minute. When dealing with stroke caused by an arterial blockage in the brain, prompt dissolution of the blood clot – known as thrombolysis – is essential. Ten years ago, a team led by Prof. Dr. Heinrich Audebert (Center for Stroke Research Berlin (CSB) and Charité’s Department of Neurology and Experimental Neurology) set itself the aim of further reducing time to treatment by bringing the necessary diagnostic and treatment procedures to the patient rather than the other way around. They did so with great success: Berlin’s first purpose-built mobile stroke unit, developed in conjunction with the Berlin Fire Department and MEYTEC GmbH, was launched in February 2011. Following years of research, the team was able to confirm that STEMO-based stroke treatment is safe and, more importantly, reduces time to treatment. Today, the Berlin Fire Department operates three STEMO vehicles. As part of a collaboration between Charité, Vivantes - Netzwerk für Gesundheit GmbH and Unfallkrankenhaus Berlin, these vehicles cover most of the Berlin area. Data from the now-published B_PROUD study show that dispatch of STEMO mobile stroke units is associated with improved outcomes in patients with stroke. “In our study, dispatch of a mobile stroke unit was linked to increased survival and reduced risk of disability,” says Prof. Audebert. He adds: “The relative odds of these patients having significant disabilities three months after stroke was 29 percent lower than in patients cared for by the conventional emergency medical services. STEMO dispatch therefore results in significantly more stroke patients returning to an independent life after stroke.” A selection of voices and opinions on the STEMO initiative – from Michael Müller (Governing Mayor of Berlin and Senator for Higher Education and Research), Prof. Dr. Heyo K. Kroemer (Chief Executive Officer of Charité), as well as the initiative’s partners and other supporters – can be found here. Under the leadership of Prof. Audebert and the study’s first author, Prof. Dr. Dr. Martin Ebinger (Medical Director of the Medical Park Humboldtmühle Rehabilitation Hospital), the team studied cases of stroke emergencies which occurred in Berlin between February 2017 and May 2019. Whether a STEMO mobile stroke unit was dispatched was effectively decided by chance: if one was available within the relevant area, it was dispatched at the same time as the conventional ambulance, enabling the patient to receive treatment before their arrival in hospital. A STEMO mobile stroke unit was dispatched in 749 of a total of 1,543 cases analyzed as part of the study (49 percent). If no STEMO was available at the time of the emergency call, only a conventional ambulance was dispatched to ensure transport to a specialist hospital. In 794 cases (51 percent), patients were cared for within the conventional emergency medical system. Using a standardized protocol, the researchers then determined survival at three months post-stroke and the extent of any neurological impairment affecting the patients. Results from their comparison of the STEMO and control groups were unequivocal. Not only did a greater number of STEMO patients receive thrombolysis (60 percent vs 48 percent in the control group), they received this treatment on average 20 minutes earlier than controls. After three months, approximately 7 percent of patients in the STEMO dispatch group had died. This figure compared with 9 percent in the conventional ambulance group. Similarly, while approximately 51 percent of patients in the STEMO group reported no stroke-related impairments in day-to-day functioning, the corresponding figure in the control group was only 42 percent. Patients in the STEMO group also scored significantly better on quality-of-life measures.

Press release by Charité and the Berlin Institute of Health In patients with bladder cancer, chemotherapy effectiveness is partially determined by the body’s immune system response to the malignancy. This is the conclusion of research conducted by a team of scientists from Charité – Universitätsmedizin Berlin and the Berlin Institute of Health. The findings, which have been published in Science Translational Medicine*, can be used to predict treatment success and may increase survival in patients with bladder cancer. Bladder cancer is one of the ten most common types of cancer in Germany, and one of the five most common cancers in men. Nationwide, the disease affects approximately 30,000 people a year. The risk of the cancer spreading (metastasizing) is particularly high once it invades the muscle layer inside the bladder wall. In patients with non-metastatic muscle-invasive bladder cancer, treatment usually consists of the surgical removal of the bladder. According to current professional guidelines, patients must undergo chemotherapy prior to surgery; they receive drugs which will target the cancer’s fast-growing cells. The aim of this ‘neoadjuvant’ chemotherapy is to shrink the tumor prior to surgery in order to reduce the risk of recurrence and/or metastases. However, in more than fifty percent of patients, chemotherapy will not shrink the tumor. Not only do these people not benefit from neoadjuvant chemotherapy, they are losing valuable time – time during which the cancer can continue to grow and metastasize. An international team of researchers led by Dr. Michael Schmück-Henneresse, a scientist at the Berlin Institute of Health Center for Regenerative Therapies (BCRT) as well as Charité’s Institute of Medical Immunology and the Berlin Center for Advanced Therapies (BeCAT), has discovered a way to differentiate between patients who will benefit from chemotherapy and those who will not. The status of the patients’ immune systems before the start of treatment was found to hold the key. Subsequent chemotherapy only proved effective if the cancerous tissue contained large quantities of two specific immune system components known as CXCL11 and CXCR3alt. “The process of measuring these two components in the laboratory is relatively straightforward and only requires the biopsy sample which is collected in order to diagnose the cancer,” says Dr. Schmück-Henneresse. “This technologically simple method will make it possible to predict the likelihood of chemotherapy success in a specific patient at the point of diagnosis. If neoadjuvant chemotherapy is unlikely to be successful, one could dispense with this therapy altogether and directly move to the bladder cancer’s surgical removal. This type of personalized approach would not only spare patients the side effects of an ineffective treatment, it would probably increase their chances of survival. However, our results will need to be confirmed by further, independent studies before we can get to a stage where CXCL11 and CXCR3alt measurements become standard in patients with bladder cancer.” As part of this research, the team studied tumor samples from 20 patients with muscle-invasive bladder cancer who had completed their chemotherapy treatment at Umeå University in Sweden. Dating back to before the start of treatment, the samples had been collected by Dr. Amir Sherif and his team during diagnostic cytoscopy procedures. The research group identified which immunological messengers were present in the biopsy tissue and which receptors (effectively the ‘recipients’ of these messengers) the immune cells inside the tumors were producing. For each of the components identified, they then tested whether there was a link between the quantities at which these were present and treatment success. Results confirmed this was the case for both the messenger substance CXCL11 and the receptor CXCR3alt. Chemotherapy only had an effect if the immune cell attractant CXCL11 was present at particularly high levels inside the tumor tissue and if specific immune system cells known as T cells produced the corresponding CXCR3alt receptor. The team subsequently examined their observations using existing data from ‘The Cancer Genome Atlas’. Their comparison confirmed that, out of a total of 68 patients with bladder cancer who had received chemotherapy, patients whose tumor tissue contained large quantities of CXCL11 were more likely to survive. “The signaling molecule CXCL11 attracts specific T cells into the tumor tissue, where it prompts them to proliferate and fight the cancer,” explains the study’s first author, Tino Vollmer, a doctoral student at Charité’s Institute of Medical Immunology and scientist at the BCRT and BeCAT. “Chemotherapy appears to support the body’s own fight against the tumor, possibly because the resulting degradation of cancerous tissue makes it easier for T cells to invade it.” The immune system’s effect on treatment outcome directly contradicts established scientific consensus, which posits that the effect of chemotherapy drugs is solely due to the ability of cancer cells to divide and replicate. “Along with other studies, our research demonstrates the importance of the immune system’s active involvement in fighting the tumor,” says Vollmer. As a next step, the researchers plan to study whether cell therapy could be used to activate the T cells of patients whose immune systems show a weak response to their bladder cancer. To do this, the team wants to harvest T cells from affected patients, fit them with synthetic CXCR3alt receptors in the laboratory, and then reintroduce them into these patients. The researchers will also study the same approach in relation to the treatment of other cancers. Furthermore, they plan to advance the use of personalized chemotherapy in patients with bladder cancer. To achieve this, the researchers intend to test the predictive power of both immune system components (CXCL11 and CXCR3alt) using a process known as ‘predictive validation’, which will involve the study of independent groups of patients with muscle-invasive bladder cancer at various European hospitals. “Should the method’s predictive reliability be confirmed, the analysis of a patient’s immune status could become a routine tool to support decision-making in the treatment of bladder cancer,” says Dr. Schmück-Henneresse.

A digital kickoff event on January 14 and 15 marks the launch of ‘SIMCor’ (In silico testing and validation of cardiovascular implantable devices), a Horizon 2020 project coordinated by Charité – Universitätsmedizin Berlin. The aim of the project is to create a platform for the testing, development, and regulatory approval of cardiovascular implants. New methods such as computer simulations and virtual animal models are used, which contribute to an even better quality and safety of such implants. The collaborative project, which is funded by the European Union, will receive a total of € 7.2 million over three years. Nearly € 1 million of this funding will go to Charité. Cardiovascular implantable medical devices are some of the most advanced, commonly used and life-sustaining implants. Their development, however, remains a major challenge. Computer-based (in silico) methods for the testing and validation of these devices – such as virtual animal models and computer modeling – can help to improve their quality, efficacy and safety while also reducing cost and time-to-market. Their use could improve access to treatment and minimize the need for in vivo studies (which involve the whole, living organism). Funded as part of the Horizon 2020 program from January 2021, this collaboration involves 12 partners from eight countries and includes stakeholders from clinical practice, research, and industry. “We are firmly convinced that, through the use of computer simulation and virtual studies, SIMCor will speed up the development, validation and regulatory approval of cardiovascular medical devices,” says project coordinator Prof. Dr. Titus Kühne, Director of Charité’s Institute of Cardiovascular Modeling and Image-Guided Cardiovascular Interventions (ICM) and Research Group Lead at the German Heart Center Berlin (DHZB). He adds: “Our Institute is one of the drivers of innovation in the field of digital transformation.” Using an interdisciplinary approach and maintaining close links with clinical practice, the institute combines state-of-the-art imaging, data science and data modeling methods to lay the foundations for improvements in diagnostics, treatment planning and the clinical decision-making process. The newly funded SIMCor project aims to establish a computer platform which will serve as a joint, open research and development resource for device manufacturers, medical institutes, and regulatory authorities. The idea is to support device validation along the entire research and development pathway – from in silico modeling to virtual animal and clinical studies. The processes involved will be used on device implants from two representative areas: transcatheter aortic valve implantation (TAVI) and pulmonary artery pressure sensors (PAPS). Results will be used to develop a best practice framework and standard operational procedures (SOPs). The project will also develop a method for creating virtual patient groups known as cohorts. These will enable new implant devices to be tested using a range of geometries, pathological changes and clinical features which are relevant to both adult and pediatric patients. The aim is to make medical implants suitable for use in younger patients. SIMCor will also deliver device-specific models which are capable of predicting the safety, efficacy, and user-friendliness of medical devices.

A new testing strategy introduced by Charité – Universitätsmedizin Berlin and Vivantes – Netzwerk für Gesundheit GmbH will see all positive SARS-CoV-2 samples undergo testing for the UK and South African variants. Testing currently takes place at Charité’s Institute of Virology but will shortly move to Labor Berlin, the joint subsidiary of Charité and Vivantes. The aim of the new, supplementary checks is to continually monitor the incidence of SARS-CoV-2 mutations in samples processed by Labor Berlin. Currently, the focus of testing is on the B.1.1.7 variant, which is dominant in England, and the B.1.351 variant, which was first detected in South Africa. The mutations common to both of these variants include changes in the main surface protein which the virus uses to bind to the human target receptor. This could make it easier for the virus to enter host cells, which in turn could render it more infectious. The additional testing Labor Berlin and Charité have put in place for all positive samples will be launched later this week. The aim is to establish the proportion of samples with known mutations within a specific test cohort. This information can be used to establish whether certain variants spread more effectively than others. The additional testing steps are performed for monitoring purposes and only take place once the original PCR test results have been obtained and reported. Labor Berlin is also preparing to carry out genome sequencing on positive samples in order to confirm the presence of other mutations. This type of testing, which currently takes place at Charité’s Institute of Virology, will ensure that any other relevant changes affecting the coronavirus are detected early.

On 1 January 2021, Prof. Dr. Falk Schwendicke took up his new position as W3-Professor for Oral Diagnostics, Digital Health and Health Services Research at Charité – Universitätsmedizin Berlin. As part of his new role, he will head a newly created department within the CharitéCenter for Dental, Oral and Maxillary Medicine (CC3). The department’s aim is to make artificial intelligence (AI) tools such as machine vision available for use in dentistry, with the objective of further enhancing treatment. An expert in the use of artificial intelligence in dentistry and integrative health services research, Prof. Schwendicke joined Charité as a Senior Physician in 2013. He was appointed Deputy Head of the CC3’s Department of Operative and Preventive Dentistry in 2015, a role which enabled him to establish digital dentistry as a new form of data-led and evidence-based dentistry at Charité. His newly created professorship and appointment as Head of the Department of Oral Diagnostics, Digital Health and Health Service Research will enable the 38-year-old to shape the new department’s research and teaching. In addition to the department’s key specialisms, it is responsible for teaching dental students regarding treatment planning, the management of pain and acute dental problems, dental radiography, epidemiology, evidence-based medicine, and health economics. A single department comprising this range of subject areas is unique in Germany. Similarly unique is the department’s research focus in the areas of artificial intelligence in dentistry, data-driven precision dental medicine and integrative health services research. Machine vision in particular has the potential to revolutionize medical imaging and benefit patients by enabling us to better understand and analyze dentistry data for use in predictive modeling. Through his involvement in international research (including his collaboration with the World Health Organization (WHO)), Prof. Schwendicke aims to establish AI-based applications as an integral part of diagnostics and treatment. Thanks to his strong publication record, he has also established himself as an influential figure within the professional community. According to Stanford University’s current citation index rankings for last year, Prof. Schwendicke was one of the most-cited dental experts globally and the most-cited dental expert from Germany. “I look forward to the challenge of exploring new horizons within the field of dentistry here at Charité. In my view, the department’s new organizational structure and research interests represent a real opportunity for us to create new impetus within the areas of teaching and patient care,” says Prof. Schwendicke. He adds: “Our research is already on a fantastic trajectory. In addition to our international collaborations, the use of AI and Big Data within the fields of diagnostics and health services research gives me great cause for optimism. We are working to create the future of dentistry!”

Joint press release by the German Biobank Node (GBN), Charité – Universitätsmedizin Berlin and the Berlin Institute of Health (BIH) Biobanks play an important role in biomedical research. They ensure that human biospecimens meet uniform standards of quality and that both the samples and their associated data are easily accessible. Charité – Universitätsmedizin Berlin is home to the German Biobank Node (GBN), the umbrella organization for German biobanks, which was founded in 2017. Since its foundation, GBN has provided the auspices for the development of a powerful partnership comprising a total of 20 university biobanks: the German Biobank Alliance (GBA). Coordinated by GBN, the partners are harmonizing their quality management processes and developing a linked-up IT infrastructure. The Federal Ministry of Education and Research (BMBF) will continue to support GBN’s work for a further three years, providing approximately € 3.5 million in funding. Approximately € 2.4 million of this money has been allocated to Charité, another € 1.1 million to the partner sites in Heidelberg and Jena. From 2024, the German Biobank Node will become a permanent structure within the Berlin Institute of Health (BIH). Blood, tissue samples, isolated cells or extracted DNA. The biobanks of the German Biobank Alliance (GBA) currently hold approximately 22 million human biosamples, with more being added all the time. The samples have to be processed before being banked and later released for use in preclinical research, the testing of new drugs and treatments at all stages of the clinical trials process and the development and testing of new diagnostic methods. The collections are an essential resource for many research disciplines, including in COVID-19 research, where biobanks and their services play a key role. When it comes to producing robust research data, the quality of biosamples and their associated data is of paramount importance. Operating on behalf of the alliance partners, GBN has therefore introduced harmonized quality standards, and provides training for members of staff of the partner biobanks. Furthermore, GBN’s online ‘Sample Locator’ tool (samplelocator.bbmri.de) enables researchers to search information from multiple biobanks to locate specific samples and data. “The new funding phase will see us continue in our efforts to drive our quality agenda and develop and improve the IT infrastructure linking the various biobanks,” says Prof. Dr. Michael Hummel, Head of GBN and Central Biobank Charité/BIH (ZeBanC). “We will also expand the membership of GBA in order to widen our pool of high-quality samples and data and make it more accessible to researchers. In the medium term, our aim is to expand our alliance to include all academic biobanks.” GBN and the Medical Informatics Initiative (which is also funded by the BMBF) plan to work closely together over the coming years. A joint project will see the partners create closer links between their respective IT infrastructures and develop a standardized and fully data protection-compliant nationwide platform to store research data sets and make them available to users. Comprising clinical, imaging, and biosample-related data on individual patients, these data sets combine data from multiple centers and store them in pseudonymized form. “Our work also extends to the European level, where we are working with the European biobanking organization, the BBMRI-ERIC. GBN has been one of the organization’s National Nodes since 2013. Within the organization, our role is to represent the interests of German biobanks and promote European research collaborations,” says Dr. Cornelia Specht, Managing Director of GBN. In order to further strengthen GBN’s position within the research environment and create a sustainable infrastructure, 2024 will see the umbrella organization for German academic biobanks become a permanent entity within the Berlin Institute of Health (BIH). “The BIH gains a strong partner in the German Biobank Node, one which will enable it to tackle important national and international challenges. Its vision aligns wonderfully well with the BIH’s strategic concept, meaning that we will be able to join forces in our fight to improve research quality,” says BIH Chief Executive Officer Prof. Dr. Christopher Baum, who has been a member of GBN’s Scientific Advisory Board since the start of 2021.

Joint press release of Charité and the Berlin Institute of Health On January 1, 2021, the Berlin Institute of Health (BIH) will become the translational research unit of Charité – Universitätsmedizin Berlin and will then form – alongside the hospital and the medical faculty – Charité’s third pillar. The Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) will become the Privileged Partner of the BIH. The three institutions are completing the final stage of implementing the administrative agreement between the federal government and the State of Berlin that was signed by German Research Minister Anja Karliczek and Governing Mayor of Berlin and Senator for Science and Research Michael Müller in July 2019. Through this novel science policy initiative, the federal government will be structurally involved for the first time in an institution of a university medical center and will have a seat on Charité’s Supervisory Board. German Research Minister Anja Karliczek explains: “The integration of the BIH into Charité will finally become reality at the turn of the year. We are placing great hope in this new structure, which closely links together medical research and clinical practice. I would like to thank all those involved for their commitment and dedication to implementing the integration over the past months. We are all very excited about the research activities. I wish the BIH, Charité and the Max Delbrück Center much success with their joint cooperation. I am convinced that this alliance will become a national and international beacon for translational biomedical research.” Governing Mayor of Berlin and Senator for Science and Research Michael Müller says: “The integration of the BIH into Charité will greatly benefit medical research and the healthcare hub of Berlin, but above all patients all across Germany. The path was not always easy, but it was always right to pursue this goal. I would therefore like to warmly thank everyone who in the past months has helped bring this process to a successful conclusion. The fact that the federal government is so strongly committed to a state institution on a permanent basis and that we are all working in unison is not something that can be taken for granted and is a sign of confidence in the outstanding work that is being done at Charité, the BIH and the MDC.” Prof. Dr. Christopher Baum will in the future represent the BIH in Charité’s Board of Directors as Board Member responsible for the translational research unit. He welcomes the integration for he is convinced that translational medicine depends on close interaction between research and clinical care. “We belong together, but at the same time we will maintain our special identity and purpose. We are working together for the benefit of patients who urgently need new medical approaches. Both perspectives – that of today’s clinical care practices and that of tomorrow’s medicines – stimulate our scientific work.” Prof. Dr. Heyo K. Kroemer, Chief Executive Officer of Charité, welcomes the BIH as the third pillar for translational research within Charité: “I look forward to working with the BIH to further advance the translation of research findings into clinical care for our patients and to fruitfully use the synergies between Charité and the BIH. Yet the integration is not only important for us, but has the potential to serve as a blueprint for future federal-state cooperation in supporting research. Special thanks are especially due to Axel Pries, who over the past years has not only been deeply committed to this project, but has also played a key role in driving it forward.” Prof. Dr. Axel Radlach Pries, Dean of Charité, served for two years, until early October 2020, as interim Chief Executive Officer of the BIH. He looks with satisfaction on what has been achieved and with much anticipation to the next phase: “Integrating the BIH into Charité and establishing the Privileged Partnership with the MDC has required very extensive coordination between our three institutions. The implementation of the administrative agreement can now be concluded as planned. Parallel to this process, the BIH has established new structures, made dynamic scientific progress and attracted outstanding researchers to Berlin. I therefore have no doubt that going forward the BIH will be successful as the Charité’s third pillar.” Prof. Dr. Thomas Sommer, interim Scientific Director of the MDC, says: “I very much look forward to the close collaboration. As a bridge between basic research and clinical practice, the BIH is the ideal partner for us in Berlin. Our scientists provide innovative capabilities in vascular biomedicine and single cell analysis and help advance technology facilities. The MDC, the BIH and Charité want to further develop the idea of a translational research commons focused on improving the well-being of patients. Our close links will give the healthcare hub of Berlin a boost.” The mission of the BIH, which was founded in 2013, is to transfer basic research findings to the patient’s bedside and, vice versa, to use clinical observations to develop new research ideas. In the past this has already required close collaboration between the BIH, Charité and the MDC. For example, Charité and the BIH jointly run the Clinical Study Center (CSC) in order to significantly improve the quality of all clinical studies and together with other partners have launched the BIH Charité Clinician Scientist Program to provide a new generation of scientists with translational training. The technology transfer unit BIH Innovations is also a joint undertaking by the two institutions. During the coronavirus pandemic, BIH researchers have teamed up with Charité scientists and physicians to make valuable discoveries in the fight against the SARS-CoV-2 virus and the COVID-19 disease. Their findings have been published in leading scientific journals. “The trusting collaboration between Charité and the BIH, as well as the MDC, is not only tried and tested, but also works excellently,” says Prof. Kroemer. “The successful application of our three institutions to be a location of the National Center for Tumor Diseases in Berlin is an expression of this. Now it’s a matter of optimizing the framework conditions even further to create the best environment for translational research.” With its integration into Charité, the BIH has also received a mandate from the federal government to support promising translational projects throughout Germany. “We are delighted to take on this mandate,” says Prof. Baum. “And here, in particular, I see us playing a role in rare and complex diseases, for which we want to specifically expand the possibilities of university medicine.” Baum also wants to further develop translation into an exact science whose results can not only be measured quantitatively and objectively but also reproduced. “That will be necessary in order to identify those projects that are most promising and take the best possible next steps in each case,” he explains. Here the BIH Quest Center has already done crucial groundwork to raise the quality of biomedical research. The BIH has established three focus areas in collaboration with Charité and the MDC, selecting areas that link up excellent research approaches with clinical expertise. The focus area “Single Cell Technologies for Personalized Medicine” aims to use innovative single cell technologies to answer clinical research questions, while the focus area “Translational Vascular Biomedicine” seeks to gain a better understanding of how malfunctions in the smallest of blood vessels are responsible for many common diseases. Through the full takeover of the BCRT, the BIH Center for Regenerative Therapies, from 2021 and the cooperation with the German Stem Cell Network (GSCN), the BIH will conduct research in particular in the field of stem cell research and advanced therapy medicinal products (ATMPs) and translate its findings into practice. The integration of the BIH into Charité will increase the number of scientific teams belonging to the BIH from 43 at present to 58; by the end of 2021 this number will be 71. The BIH will then have around 400 employees, who will be spread across multiple locations: Starting in March, the scientific teams working on vascular biomedicine will move into the Käthe Beutler Building in Berlin-Buch, in the immediate vicinity of the Privileged Partner, the MDC. In this building, named after a Jewish pediatrician and researcher, BIH and MDC teams will work together under one roof. In the Outpatient, Translation and Innovation Center (Ambulanz-, Translations- und Innovationszentrum – ATIZ) in Berlin-Mitte, which celebrated its topping-out ceremony in July 2020 and is scheduled for completion in early 2022, teams involved in digital medicine, such as the BIH Digital Health Center, and other research groups will work together with experts from Charité. ATIZ will also house the joint Clinical Study Center. The single cells focus area will be based at the MDC’s Berlin Institute for Medical Systems Biology (BIMSB), which is also located in Berlin-Mitte. The scientific teams working in the field of regenerative medicine will primarily carry out research at the Charité Campus Virchow Clinic in Berlin-Wedding, on the premises of the BCRT. The BIH Digital Health Accelerator will move into new offices at Zirkus in Berlin-Mitte at the beginning of 2021.

Alexei Navalny received treatment at Charité – Universitätsmedizin Berlin. A case report on the patient’s clinical course has now been published in response to a request from The Lancet*. Alexei Navalny was flown to Berlin for medical treatment on 22 August 2020. Two days earlier, he had been taken seriously ill while on a domestic Russian flight. At Charité, physicians diagnosed Mr. Navalny with severe poisoning caused by a cholinesterase inhibitor. On 2 September 2020, the German government announced that testing requested by Charité and carried out at a German Federal Armed Forces laboratory had delivered proof of the chemical nerve agent Novichok. This finding was confirmed by the Organization for the Prohibition of Chemical Weapons (OPCW). With the consent of Mr. Navalny, the team of physicians have now responded to a request by The Lancet to publish a case report.

Protein synthesis is a finely tuned process in the cell by macromolecules known as ribosomes. Which regulators are responsible for controlling protein synthesis in the brain, and how do they exert their control on the ribosome? To address this question, a team of researchers from Charité – Universitätsmedizin Berlin studied the structure of the brain’s ribosomal complexes in great detail. The team was able to identify a new factor which is also involved in controlling brain development. Details of this research have been published in Molecular Cell*. Proteostasis refers to maintaining a delicate balance of protein levels in the cell, which is of particularly crucial importance to neurons. Abnormal protein production is a characteristic feature of many brain disorders. High precision protein production is of immense importance during the early development of a complex part of the cerebral cortex known as the neocortex. It is particularly important in the production of membrane proteins, which play an important role in cell-to-cell sites of synaptic contact between nerve cells. As the cell’s ‘molecular protein factories’, ribosomes are at the heart of the regulatory processes involved in proteostasis. A range of molecules can influence ribosome function, and are responsible for controlling the production of specific proteins in different tissues and at different developmental stages. The way in which these various factors interact with the ribosome during development remains widely unknown. However, a group of Charité researchers has successfully observed protein production by ribosomes in the developing brain. “It is the first time the ribosomal complex has been visualized in action inside the brain at near atomic-level resolution,” says Prof. Dr. Christian Spahn, Director of Charité’s Institute of Medical Physics and Biophysics. “While the structure of the ribosomal complex has been mapped in other tissues and organisms, our approach enabled us to identify Ebp1 as the new key factor responsible for controlling both ribosome function and the synthesis of specific proteins during brain development.” The interaction between the regulatory protein Ebp1 (short for ErbB3 binding protein 1) and the ribosome takes place at the ribosome’s exit tunnel, through which the newly formed protein chain emerges from the ribosome. Through this interaction, Ebp1 influences the production of membrane proteins that play an important role in neuronal interactions, thus maintaining neuronal proteostasis. As part of a multidisciplinary project linking aspects of structural biology and neuroscience, the researchers used cryo-electron microscopy (cryo-EM) as their main investigative tool, combining it with mass spectrometry, RNA sequencing and genetic techniques. The cryo-EM imaging technique enables scientists to determine protein structures – particularly larger complexes comprising multiple molecules – at extremely low temperatures and near-physiological conditions. The study’s first author, Dr. Dr. Matthew L. Kraushar (a neuroscientist at the Max Planck Institute for Molecular Genetics (MPIMG) in Berlin and previously a member of Prof. Spahn’s laboratory), explains: “We could therefore visualize the molecular architecture of the ribosome at high resolution, as it would be found inside brain cells. We were able to capture snapshots of the ribosome in action.” “Protein production in various types of brain cells is subject to finely tuned control mechanisms. Small changes can lead to big consequences, such as neurodegenerative diseases or disrupted development. Our findings on the role of ribosomes during normal brain development will help us to better understand pathological changes affecting the brain,” says Prof. Spahn. As a next step, the researchers are conducting a large-scale study to understand the way ribosomes translate messages from the genetic code (mRNA) into numerous essential proteins throughout brain development.

Joint press release by Charité – Universitätsmedizin Berlin and Berlin Institute of Health (BIH) Like all viruses, the novel coronavirus is dependent on help from the human host cell. Proteins are the functional units of the cell and enable the virus to enter the host cell or help the virus to replicate. Scientists from Charité – Universitätsmedizin Berlin and from the Berlin Institute of Health (BIH), along with colleagues from the United Kingdom, Germany and the United States, have examined the corresponding genes of the helper proteins in a large study. They discovered numerous variants that influence the amount or function of the proteins as well as their ability to support the virus. The gene variants reveal potential target structures for new drugs. The researchers have now published their results in the journal Nature Communications*. An infection of the novel coronavirus SARS-CoV-2, just like any other viral infection, follows a specific pattern: The viruses first bind to receptor proteins on the surface of the human host cells in the throat, nose or lungs before entering the cell, where they replicate with the help of the host cell machinery. The newly formed virus particles cause the infected cell to burst and infect other cells. As soon as the immune system notices what is happening, a defense mechanism is activated with the goal of destroying and removing both the viruses and virus-infected cells. Under normal circumstances, the infection is over within two weeks at the most. For all these processes, however, the virus is dependent on human or host proteins. “In severe courses of COVID-19, this regulated process gets out of control and the immune system causes an excessive inflammatory response that attacks not only virus-infected cells but also healthy tissue,” says Prof. Dr. Claudia Langenberg, BIH Professor of Computational Medicine and head of the study now being published. “Naturally occurring variations in the genes that make up the blueprint for these human proteins can alter their concentration or function and may thus be responsible for the different course of the disease.” The team is well versed in the discovery of genetic variants that not only affect specific proteins but also common complex diseases. “As molecular epidemiologists, we study the diversity of genes – that is, the building instructions for proteins – of entire population groups in order to uncover susceptibilities to diseases whose cause lies in the interaction of many small deviations,” explains the epidemiologist, who joined the Berlin Institute of Health from the Medical Research Council Epidemiology Unit at the University of Cambridge in September. “We wanted to use these experiences and data sets for the COVID-19 epidemic and make them available to the scientific community.” “We examined 179 proteins known to be involved in SARS-CoV-2 infection for their naturally occurring variants,” reports Dr. Maik Pietzner, the study’s lead author and a scientist in Prof. Langenberg’s lab. “We were able to draw on findings which were based on samples of the first COVID-19 patients at Charité. ” This was possible due to close collaboration with the research group led by Professor Dr. Markus Ralser, Director of the Institute of Biochemistry at Charité, which had previously reported these findings. The team of Prof. Langenberg was able to use data from the MRC Fenland Cohort, a large population study that contains information from more than 10,000 individuals. They discovered 38 targets for existing drugs as well as evidence that certain proteins that interact with the virus influence the immune system. “Our findings also help to better understand risk factors for severe courses of COVID-19. We were able to show that blood coagulation proteins are influenced by the same genetic variant that increases the risk of contracting COVID-19 and that determines blood group 0,” reports Dr. Pietzner. The team immediately made the results publicly available via an interactive webserver, which was developed with colleagues from Helmholtz Zentrum München (https://omicscience.org/apps/covidpgwas/). Scientists from around the world have since been using the data to identify new drug targets or to better understand the course of COVID-19. “Journal articles that used our findings appeared even before our work was officially published,” says a delighted Prof. Langenberg. “This is exactly what we had hoped for.”

Under certain conditions, antigen testing using self-collected swabs from the anterior nose may constitute a reliable alternative to antigen testing using nasopharyngeal swabs collected by health professionals. This is the conclusion drawn by a team of researchers from Charité – Universitätsmedizin Berlin and Heidelberg University Hospital. Results from their study have been published in the European Respiratory Journal*. Rapid antigen tests may be less reliable than PCR tests, but their speed and simplicity make them an important complementary tool which can assist efforts to curb the current pandemic and reduce risks in certain day-to-day situations. Rapid antigen tests are intended for use at the point of care. Confirming whether or not a person is infected and contagious at the time of testing, they can provide results in less than 30 minutes. This type of test could therefore be used to make it safer for people to visit a loved one in a care home or hospital. Despite this potential, they are not yet widely used. One of the reasons for this is that, until now, most antigen testing systems used nasopharyngeal swabs which required collection by trained medical staff. “There are two reasons why professional-collected nasopharyngeal swabs represent a barrier to the widespread use of rapid antigen testing,” says Prof. Dr. Frank Mockenhaupt, Acting Director of Charité’s Institute of Tropical Medicine and International Health. “Firstly, most people find a nasopharyngeal swab uncomfortable and, for this reason, are likely to avoid regular testing. Secondly, swabbing ties up staff resources, is complex and time-consuming, and necessitates the use of personal protective equipment.” Working with PD Dr. Claudia Denkinger, Head of Heidelberg University Hospital’s Clinical Tropical Medicine Section, Prof. Mockenhaupt therefore designed a study to test whether self-collected anterior nasal swabs administered under medical guidance could provide an alternative to a professional-collected nasopharyngeal swab. The study, which was conducted at Charité’s Ambulatory Coronavirus Testing Facility, took place between late September and mid-October. Individuals with characteristic SARS-CoV-2 symptoms wishing to take part in the study were instructed by medical staff as to the procedure for self-collected nasal swabs. Participants were instructed to insert a swab into both of their nostrils to a depth of 2 to 3 cm, rotating it against the nasal wall for a duration of 15 seconds. This was followed by a professional-collected nasopharyngeal swab. Both swab samples were analyzed on site using a commercially available rapid antigen test approved for use in Germany. Test results were then compared. Staff also collected a naso-oropharyngeal (combined nose and throat) swab which was analyzed using PCR testing. This served as a diagnostic reference standard. 39 out of a total of 289 participants (13.5 percent) were diagnosed with SARS-CoV-2, based on PCR results. In 31 of these infected individuals (nearly 80%), the professional-collected nasopharyngeal swabs also produced a positive result with the rapid antigen test. For self-collected swabs collected from the anterior nose, correct results were obtained in 29 (approximately 74 percent) of the infected individuals. “We had of course expected rapid antigen tests to be less sensitive than PCR,” says PD Dr. Denkinger. “Upon closer inspection, however, cases of antigen tests missing infections were primarily associated with patients who had low viral loads.” When looking exclusively at patients with high viral loads, the researchers found that the antigen tests correctly identified every single positive sample obtained via nasopharyngeal swab, and nearly 96 percent of self-collected swabs. “This study shows that supervised, self-administered swabs are no less effective than professional-collected nasopharyngeal swabs when used with the antigen test selected for this research,” explains PD Dr. Denkinger. She adds: “Firmer swabs, which are more suited for use in the anterior part of the nose, may improve the test’s accuracy further.” In November, the Federal Government introduced legal provisions which pave the way towards a more widespread use of rapid antigen testing, including by trained staff in childcare centers and schools**. “The new legal provisions eliminate our dependence on medical staff,” says PD Dr. Denkinger. “This makes rapid antigen testing more suited to large-scale roll-out. Research data on self-collected swabs, such as the findings obtained in this study, will be useful to those in charge of finding and implementing new concepts.” Prof. Mockenhaupt adds: “Rapid antigen tests are a significant additional resource to supplement our strained PCR-based testing capacity. Naturally, self-collected swabs and self-administered tests are not without their problems. A test that is administered or interpreted incorrectly, for instance, could result in a false sense of security. On the other hand, a positive rapid antigen test result should always be confirmed by PCR.” As a next step, the research team therefore want to study whether rapid antigen tests provide reliable results even when used by lay persons in the absence of professional guidance or supervision.

The Einstein Foundation Berlin has launched its new ‘Award for Promoting Quality in Research’. This international, first-of-its-kind award aims to recognize researchers and institutions that have made major contributions to improving the quality of research and the robustness of research results. The Awards Office will be headed by Prof. Dr. Ulrich Dirnagl, founder of the BIH QUEST Center and Head of the Department of Experimental Neurology at Charité – Universitätsmedizin Berlin. The award’s monetary prizes, which total € 500,000 a year, will be funded by the ‘Damp Stiftung’ foundation. The award receives endorsement from the Nature Research publishing group, which is assisting with its promotion and call for submissions. It will be awarded for the first time in November 2021 in Berlin. Evidence-based research, reliable standards of quality and unrestricted access to new research findings are more important to scientific practice than ever, a fact that has been thrown into particularly stark relief during the coronavirus pandemic. Which hypotheses, methods and data sets are selected, how these are used, and whether a particular study can be built on with further research – all of these issues must be verifiable and robust. There is also increasing public interest in and awareness of the issues surrounding research quality. Acknowledging this development, the Einstein Foundation Award for Promoting Quality in Research will reward measures and projects from any of the scientific disciplines which help to improve research standards. “The award seeks to raise awareness of the need to promote and maintain transparent research standards as a prerequisite to reinforcing public trust in science and research. This is particularly relevant in a knowledge society with an increasingly fast-paced research environment,” says Günter Stock, Chair of the Einstein Foundation’s Executive Board. The Award can be given in three categories: individual researchers, institutions, and early career researchers. The Award Office will be headed by neuroscientist Prof. Dr. Ulrich Dirnagl, who is the Founding Director of the QUEST Center for Transforming Biomedical Research at the Berlin Institute of Health (BIH). “This generous award is a wonderful opportunity to highlight the work of researchers, initiatives and institutions that help make research more trustworthy, useful and ethically sound. It is unique in the world and, hopefully, will inspire others to engage with measures which aim to promote quality in research,” says Prof. Dirnagl. The first award ceremony will be held in November 2021 in Berlin. Nominations and applications can be submitted via www.einsteinfoundation.de/award until 31 March 2021.

Is it possible to predict the course of a viral respiratory tract infection – for instance one caused by a coronavirus – based on individual patient characteristics? This question will be addressed by Dr. Victor Corman and his junior research group at Charité – Universitätsmedizin Berlin. Submitted for approval last year, this research endeavor has taken on a new level of significance within the context of the current pandemic. The project will be funded by the Federal Ministry of Education and Research (BMBF) and has been allocated close to €2 million over five years. Viral respiratory tract infections are the most common type of infection in humans. Adults are affected approximately three times a year, children about six times a year. Most infections are mild. In some cases, however, they can lead to severe pneumonia, which can be fatal. One question increasingly being asked since the start of the COVID-19 pandemic – and not just by experts – is: why is there such variability in disease severity, and are there individual patient characteristics that could be used to predict disease severity? It was back in 2019 that Dr. Victor Corman, a researcher and clinician from the Institute of Virology on Campus Charité Mitte, made the study of these issues his long-term research goal – and the extremely common coronaviruses and picornaviruses the targets of his work. He submitted his research proposal, entitled ‘VARIPath’, for funding under the BMBF’s ‘Junior Research Groups in Infection Research’ program, and he was successful. It has since become clear that Dr. Corman showed a remarkable degree of foresight in submitting his proposal, and that the ability to predict disease severity in respiratory tract infections represents a true clinical need. In his pursuit of the ability to predict disease progression, the German Center for Infection Research (DZIF) researcher and Deputy Director of the National Consultation Laboratory for Coronaviruses at Charité will take a two-pronged approach. His research group will study characteristics of both viral pathogens and the immune systems of those infected. “Whenever a respiratory virus replicates inside its human host, this will produce changes in the virus population,” explains Dr. Corman. He adds: “We want to find out whether characteristics of the virus populations can be used to predict disease progression in those who have been infected.” The physician will use state-of-the-art high-throughput sequencing techniques to analyze in detail how viruses evolve inside their host patients. His research will focus on picornaviruses and coronaviruses, both of which store their genetic information in the form of RNA but show very different rates of mutational change. While coronaviruses mutate very slowly, picornaviruses show a substantially faster rate of genetic change. Dr. Corman’s original plans were limited to the study of well-known and widely spread coronaviruses such as HCoV-NL63 or HCoV-OC43. These have now been expanded to include the novel coronavirus, SARS-CoV-2. In a parallel series of experiments, the researcher will study how host immune response characteristics differ in individual patients. Dr. Corman will use genetic analysis to map out which viral surface structures are targeted by specific immune cells known as B-cells and T-cells. Further plans include the study of the body’s antibody response and the release of a group of immune mediators known as cytokines. “For all of these parameters, we will then check whether they enable us to predict, for instance, incapacity to work, secondary bacterial infections or ICU admissions,” explains Dr. Corman. He adds: “Predictive parameters such as these could help us to adapt treatment strategies early on and have a positive impact on prognosis.”

With its ‘Strategy 2030 – Rethinking Health’, Charité has set itself an ambitious agenda for the coming years. Its bold and innovative vision for pioneering developments within research, teaching and health care was presented today. The aim of this strategy is to position Charité as the leading academic institution in the core areas of training, research, translation, and medical care. Charité wants to continue to take an active role in shaping developments within the field of biomedicine and the health care system, ensuring these are in the interest of the people of Berlin and the rest of Germany. Michael Müller, Governing Mayor of Berlin, Senator for Higher Education and Research and Chair of Charité’s Supervisory Board, emphasized: “Charité is a pivotal partner in our plan to develop Berlin into a leading health metropolis, one which will stand for medical progress, outstanding expertise and health care which is focused on meeting future needs. We have achieved a great deal together over the past few years and we are determined to continue down this path. Charité’s 2030 strategy acts as a compass and guide in this endeavor, and I am grateful to all those whose work – both now and in the future – will ensure that each step of this vision is implemented.” Launched by Prof. Dr. Heyo K. Kroemer and the other members of the Executive Board, the strategic planning process for the next ten years began last fall. A thorough analysis of the current situation, trends within the health care sector and data from internal interviews and surveys was used to identify and prioritize areas of particular interest. Their selection was guided by an emphasis on a value-based approach to health care development, the development of precision treatment and prevention solutions, and a focus on robust and relevant research results. The creation of a digitalization strategy also forms an integral part of this process. Stressing that the need to focus on likely future developments is particularly stark during the current pandemic, Prof. Dr. Heyo K. Kroemer, Charité’s Chief Executive Officer, said: “The coming months, too, will be marked by the challenges of the COVID-19 pandemic, and Charité will be extremely busy – in medical care and in research. However, a challenging pandemic will throw into particularly sharp relief the critical importance of a sustainable strategy. The pandemic has also shown that an organization must be agile enough to quickly respond to wholly unexpected challenges without ever losing sight of what lies ahead.” The result of this process has been a new goal and vision for Charité. The concept of ‘Rethinking Health’ sits at the heart of the organization’s 2030 strategy. The following six priority areas form the focus of this vision’s strategic direction and implementation over the next few years: • ‘The Future of Medicine’ forms the core of Charité’s strategic plan. It focuses on the translation of research findings into clinical practice and the transfer of relevant knowledge to society as a whole. • ‘Health Care’ encompasses a person-focused and evidence-based approach to maintaining and restoring health. Charité will pursue a complementary approach which combines the highest standards of academic medicine with community-based tertiary care. • ‘Innovation and Research’ stands for translation as the key feature of Charité and the use of strategic fields of research to define and enhance its research profile. • ‘People and Education’ stands for diversity, equal opportunities, and professional development opportunities at Charité. • ‘Campuses, Infrastructure and Economic Viability’ stands for distinct, campus-specific profiles for each of Charité’s clinical sites and the targeted structural development of each campus. • ‘Internal Transformation’ stands for the reconfiguration of Charité’s organizational and management processes and the development and strengthening of its role as partner and expert. The decision to reshape Charité’s strategic direction was prompted by a specific development, namely a growing need for change within the health care system as a consequence of demographic change, our approach to biomedical innovation and the need to address digitalization as this decade’s key challenge. The expectation is furthermore that both increasing global mobility and climate change will result in further consequences to human health, creating a fundamentally new set of challenges. Explaining his vision for Charité – Universitätsmedizin Berlin, Prof. Kroemer added: “Charité will be a leader in the core areas of training, research, translation and medical care. Working alongside its partner institutions, Charité will drive developments within the regional and national health care systems. At the same time, it will be an innovative and economically viable organization.” Outlining the first and most important step in this development, Prof. Kroemer said: “We must work together to rethink health. Only together with our members of staff will we be able to move forward and achieve tangible long-term impact. This is why, over the next few weeks and months, our greatest emphasis will be on internal communication.”

Using post-mortem tissue samples, a team of researchers from Charité – Universitätsmedizin Berlin have studied the mechanisms by which the novel coronavirus can reach the brains of patients with COVID-19, and how the immune system responds to the virus once it does. The results, which show that SARS-CoV-2 enters the brain via nerve cells in the olfactory mucosa, have been published in Nature Neuroscience*. For the first time, researchers have been able to produce electron microscope images of intact coronavirus particles inside the olfactory mucosa. It is now recognized that COVID-19 is not a purely respiratory disease. In addition to affecting the lungs, SARS-CoV-2 can impact the cardiovascular system, the gastrointestinal tract and the central nervous system. More than one in three people with COVID-19 report neurological symptoms such as loss of, or change in, their sense of smell or taste, headaches, fatigue, dizziness, and nausea. In some patients, the disease can even result in stroke or other serious conditions. Until now, researchers had suspected that these manifestations must be caused by the virus entering and infecting specific cells in the brain. But how does SARS-CoV-2 get there? Under the joint leadership of Dr. Helena Radbruch of Charité’s Department of Neuropathology and the Department’s Director, Prof. Dr. Frank Heppner, a multidisciplinary team of researchers has now traced how the virus enters the central nervous system and subsequently invades the brain. As part of this research, experts from the fields of neuropathology, pathology, forensic medicine, virology and clinical care studied tissue samples from 33 patients (average age 72) who had died at either Charité or the University Medical Center Göttingen after contracting COVID-19. Using the latest technology, the researchers analyzed samples taken from the deceased patients’ olfactory mucosa and from four different brain regions. Both the tissue samples and distinct cells were tested for SARS-CoV-2 genetic material and a ‘spike protein’ which is found on the surface of the virus. The team provided evidence of the virus in different neuroanatomical structures which connect the eyes, mouth and nose with the brain stem. The olfactory mucosa revealed the highest viral load. Using special tissue stains, the researchers were able to produce the first-ever electron microscopy images of intact coronavirus particles within the olfactory mucosa. These were found both inside nerve cells and in the processes extending from nearby supporting (epithelial) cells. All samples used in this type of image-based analysis must be of the highest possible quality. To guarantee this was the case, the researchers ensured that all clinical and pathological processes were closely aligned and supported by a sophisticated infrastructure. “These data support the notion that SARS-CoV-2 is able to use the olfactory mucosa as a port of entry into the brain,” says Prof. Heppner. This is also supported by the close anatomical proximity of mucosal cells, blood vessels and nerve cells in the area. “Once inside the olfactory mucosa, the virus appears to use neuroanatomical connections, such as the olfactory nerve, in order to reach the brain,” adds the neuropathologist. “It is important to emphasize, however, that the COVID-19 patients involved in this study had what would be defined as severe disease, belonging to that small group of patients in whom the disease proves fatal. It is not necessarily possible, therefore, to transfer the results of our study to cases with mild or moderate disease.” The manner in which the virus moves on from the nerve cells remains to be fully elucidated. “Our data suggest that the virus moves from nerve cell to nerve cell in order to reach the brain,” explains Dr. Radbruch. She adds: “It is likely, however, that the virus is also transported via the blood vessels, as evidence of the virus was also found in the walls of blood vessels in the brain.” SARS-CoV-2 is far from the only virus capable of reaching the brain via certain routes. “Other examples include the herpes simplex virus and the rabies virus,” explains Dr. Radbruch. The researchers also studied the manner in which the immune system responds to infection with SARS-CoV-2. In addition to finding evidence of activated immune cells in the brain and in the olfactory mucosa, they detected the immune signatures of these cells in the cerebral fluid. In some of the cases studied, the researchers also found tissue damage caused by stroke as a result of thromboembolism (i.e. the obstruction of a blood vessel by a blood clot). “In our eyes, the presence of SARS-CoV-2 in nerve cells of the olfactory mucosa provides good explanation for the neurologic symptoms found in COVID-19 patients, such as a loss of the sense of smell or taste,” explains Prof. Heppner. “We also found SARS-CoV-2 in areas of the brain which control vital functions, such as breathing. It cannot be ruled out that, in patients with severe COVID-19, presence of the virus in these areas of the brain will have an exacerbating impact on respiratory function, adding to breathing problems due to SARS-CoV-2 infection of the lungs. Similar problems might arise in relation to cardiovascular function.”

Bone regeneration is seen as a model template for scarless healing. A new Collaborative Research Centre (SFB), entitled ‘Directed Cellular Self-Organisation for Advancing Bone Regeneration’ and led by Charité – Universitätsmedizin Berlin, will study which factors and mechanisms are important to allow a scarless regeneration and how they change as we age. It is hoped the findings will help us to understand the precise processes involved in bone regeneration and enable these processes to continue into old age. The underlying principles may serve as blueprint for regeneration also in other, even more challenging, clinical settings. Funded by the German Research Foundation (DFG), this collaborative research project will receive an initial grant of more than €12 million over four years. Bone is one of the few tissues with the capacity for scar-free healing, meaning it is capable of complete regeneration of both structure and function. This makes bone an ideal model for understanding the general principles involved in cellular self-organization and the body’s ability to heal itself. While these healing processes generally work well in young and healthy individuals, they become impaired in older people and those with pre-existing conditions. Increasing age, lack of physical exercise, chronic inflammation and metabolic disorders all lead to changes in bone healing, which is why musculoskeletal disorders are more commonly found in older people. However, while regenerative potential can vary greatly between patients, standard care is so far remarkably uniform. A deeper understanding of how the body’s regenerative potential changes in response to age, metabolic disorders or an altered immune response (known as immunoaging) remains largely elusive. A greater understanding of these issues, however, is crucial for a personalized approach to treatment. “The beginning of the healing process is crucial for long-term success”, explains SFB Spokesperson Prof. Dr. Georg N. Duda, who is also Director of Charité’s Julius Wolff Institute for Biomechanics and Musculoskeletal Regeneration and BIH Chair for Engineering Regenerative Therapies. He adds: “If the healing process is derailed early on, this will result in its delay or even failure. Key components of successful healing are a well-controlled immune response, adequate quantities of all supplies needed, and the structural integrity of the surrounding tissue.” Until now, these three aspects – inflammation, metabolism and mechanics – had only been studied in isolation. The aim of new SFB 1444 ‘Directed Cellular Self-Organisation for Advancing Bone Regeneration’ is to help improve our understanding of the relevant mechanisms and the coordinated manner of their interactions. Using bone regeneration as an example, the SFB’s researchers will undertake a detailed study of the fundamental mechanisms which determine whether the physical healing process ends in success or failure. The researchers hope to decipher how relevant interactions are controlled and regulated and how these might adapt throughout the normal aging process to ensure the body retains its ability to regenerate into old age. This large collaborative project brings together leading experts in basic and clinical research from Charité, the Berlin Institute of Health (BIH), the Max Delbrück Center for Molecular Medicine (MDC), Freie Universität Berlin, the Zuse Institute Berlin (ZIB), the Max Planck Institute of Colloids and Interfaces and the German Institute of Human Nutrition in Potsdam. The collaboration comprises 28 researchers working across 16 projects. The project will be launched on 1 January 2021. In his role of Spokesperson, Prof. Duda is supported by Deputy Spokesperson Prof. Dr. Hans-Dieter Volk, who is Director of the Institute of Medical Immunology and Spokesperson of the BIH Center for Regenerative Therapies (BCRT). “Our long-term goal is to influence the interactions between inflammation, metabolism and mechanics in a way that will enable physical regeneration even under challenging conditions,” says SFB Research Coordinator PD Dr. Katharina Schmidt-Bleek. It is hoped this will create the conditions needed for improved risk assessments and personalized treatment approaches.

Joint press release by the Christiane Herzog Foundation, Charité – Universitätsmedizin Berlin and the Berlin Institute of Health (BIH) Dr. Simon Gräber, an assistant physician in Charité’s Department of Pediatric Pulmonology, Immunology and Critical Medicine and a fellow in the BIH Charité Clinician Scientist Program sponsored by Stiftung Charité, is the 2020 Christiane Herzog Award winner of the Christiane Herzog Foundation. With the prize money of €50,000, Dr. Gräber will establish a care and research infrastructure at Charité – Universitätsmedizin Berlin to examine cystic fibrosis patients who have rare mutations. His goal is to find an effective therapy for these patients by individually testing approved drugs on the patients’ cells, along with CFTR modulators currently being developed in the laboratory. In the long term, the aim is to establish personalized medicine to treat cystic fibrosis (CF). Cystic fibrosis is a rare hereditary disease caused by genetic changes in what is known as the CFTR gene, coding for an ion channel in the cell membrane. Patients do not necessarily show the same changes. Depending on which section of the gene is mutated, the symptoms can be more or less pronounced. Recently, an international clinical study co-led by Prof. Dr. Marcus Mall, BIH Professor and Director of Charité’s Department of Pediatric Pulmonology, Immunology and Critical Medicine, demonstrated the effectiveness of a new triple therapy that helps about 90 percent of all cystic fibrosis patients. Dr. Gräber is now working on a solution for the remaining 10 percent. “We plan to include a total of at least 50 cystic fibrosis patients with rare mutations in our project,” says Dr. Gräber, who conducts research at Charité’s Christiane Herzog Centre. The patients are being recruited at Charité and from surrounding centers and will be comprehensively examined. In this process, doctors and scientists want to measure lung function or visualize the lung with modern imaging techniques and record the activity of the CFTR channel in laboratory medical tests. “In addition, we are primarily relying on ‘ex vivo’ tests on tiny organoids, which we cultivate individually from the patients’ cell samples,” explains Dr. Gräber. “These enable us to test drugs for their efficacy, individually for each patient.” The substances used are already approved drugs, but modulators currently under development are also available to the research group through cooperation partners. With his doctoral thesis in 2008, Dr. Gräber started his career as a CF researcher, which he continued along with his work as a doctor in cystic fibrosis care. Through his work, he shows that “bench to bedside” care is possible for patients. He has always oriented his research on CF care requirements, and he also generates new research questions from his daily work in the hospital. Since September 2018, Dr. Gräber has been supported by the BIH Charité Clinician Scientist Program, which is co-financed by Stiftung Charité. Prof. Dr. Duska Dragun, director of both the BIH Charité Clinician Scientist Program and the BIH Biomedical Innovation Academy, is pleased about her successful participant: “Dr. Gräber covers the entire translational process with his scientific and clinical activities and works in extremely integrative fashion in his daily routine. In this way, he epitomizes an exemplary clinician scientist.”

A joint press release by Charité – Universitätsmedizin Berlin and Berlin Institute of Health (BIH) As part of an international project, scientists from Charité – Universitätsmedizin Berlin and Berlin Institute of Health (BIH) have genetically examined all cells of the human pancreas to determine their exact location within the organ and shed light on the relationships between individual cells. In doing so, they discovered previously unknown cell types that help to explain how this important organ functions and how pancreatic diseases develop. The project is part of the global Human Cell Atlas initiative, which aims to analyze all cells of the human body. The researchers have now published their results in the journal Gastroenterology*. “We wanted to create a resource for all researchers with an interest in the pancreas,” explains Prof. Dr. Roland Eils, head of the international pancreas project and, as BIH Chair, founding director of the BIH and Charité Digital Health Center. “Our results will help those who study the endocrine component of the pancreas, which produces insulin and is responsible for the development of diabetes. But our findings are also relevant for scientists studying the gland’s exocrine component, which produces and releases digestive enzymes into the small intestine and is affected by pancreatitis or pancreatic cancer.” Obtaining and examining pancreatic tissue is extremely difficult, as the digestive enzymes are very active and the organ runs the risk of digesting itself. It was therefore important for the scientists to prepare the tissue as gently and quickly as possible. Here, Prof. Eils and his team relied on international cooperation. “We received high-quality samples from colleagues in Stanford and Munich,” explains Dr. Christian Conrad, whose lab hosted the experiments and who is joint last author of the study together with Prof. Eils. “We then developed new protocols specifically for pancreatic tissue in our laboratory, which enabled us to obtain this type of data for the first time.” Dr. Luca Tosti, researcher in Dr. Conrad’s lab and lead author of the study, applied various single-cell technologies in this mammoth project. “One technique involved isolating cell nuclei from frozen biopsies and measuring gene activity in each nucleus individually,” explains Dr. Tosti. “In total, we analyzed more than 120,000 cell nuclei. In addition, we performed so-called in-situ sequencing on the frozen tissue. This method tells us not only which genes are active in the various cells, but also how the cells are organized spatially and what relationships exist between the different cells.” During their investigations, the team was able to divide exocrine pancreatic cells into three subtypes. A comparison of adult tissue with that of newborns showed an astonishing change in cell composition during development. “We were surprised to find that an organ previously regarded as relatively homogeneous has such a complex structure,” reports Prof. Eils. “By combining various biological and computational techniques, we have gained insight into intercellular communication in the human pancreas to an extent that has not previously been possible.” Next, the researchers want to analyze samples from patients with diabetes or pancreatic tumors in order to better understand the causes of pancreatic diseases and to develop new diagnostic and therapeutic approaches. The European Union is supporting the Horizon 2020 project ESPACE to the tune of €5 million, with €1 million going to the BIH Digital Health Center in Berlin. The project kicked off on January 1, 2020.The pancreas project is a sub-project of the global Human Cell Atlas initiative, in which researchers around the world have joined forces to profile every single cell in the human body. The aim is to understand the processes in a healthy body in order to be able to better diagnose, treat and prevent diseases. “The Human Cell Atlas project is certainly one of the most promising projects in the life sciences field,” says Prof. Eils. “Our vision is to make a significant contribution to understanding how human life functions.” The pancreas project is the only one of the six European Human Cell Atlas initiatives that is being coordinated in Germany.

A group of researchers from Charité – Universitätsmedizin Berlin have confirmed Germany’s first-ever case of animal-to-human transmission involving a specific species of virus known as the ‘Seoul virus’. Working alongside colleagues from Friedrich-Loeffer-Institut (FLI), the researchers were able to confirm the presence of the virus in a young female patient and her pet rat. Their findings, which have been published in Emerging Infectious Diseases*, may influence the way in which we deal with both wild and domesticated rats. Following multiple outbreaks earlier in the 21st century, hantavirus disease syndromes have gained increasing levels of public attention and were made notifiable in Germany in 2001. The Puumala and Dobrava-Belgrade viruses, for instance, which are common across central Europe and can be spread by numerous types of mice, usually cause acute fever. Occasionally, infection may result in HFRS (hemorrhagic fever with renal syndrome), an illness characterized by fever, low blood pressure and acute kidney failure. The Seoul virus, in contrast, which is mainly found in Asia and transmitted exclusively by rats, is far more likely to cause severe disease. Even outside Asia, however, there have been numerous reports of rat-to-human transmission of this highly virulent virus. For the first time, a team of researchers led by Prof. Dr. Jörg Hofmann, Head of the National Consultant Laboratory for Hantaviruses at Charité’s Institute of Virology, has been able to describe an autochthonous (i.e. acquired in Germany) case of Seoul virus infection transmitted by a rat. Working in close collaboration with a team of researchers led by Prof. Dr. Rainer G. Ulrich at the Friedrich-Loeffler-Institut (FLI) in Greifswald and colleagues at both local and regional health authorities, the researchers were able to identify the virus in samples from a young female patient from Lower Saxony and her pet rat. “The virus originally comes from Asia and was probably carried to Europe by wild rats on ships. However, it had not previously been observed in Germany,” says the study’s first author, Prof. Hofmann. The infected rat, which had been bred for domestic life, is likely to have been imported from a different country. After developing symptoms of acute kidney failure, the young patient required intensive care treatment and was hospitalized for several days. Serology testing quickly confirmed a suspected diagnosis of hantavirus infection. The species of hantavirus responsible, however, remained unclear. Working at Charité’s specialist hantavirus laboratory, Prof. Hofmann and his team of researchers developed a special molecular diagnostic technique capable of identifying the Seoul virus in samples collected from the patient. Using the same technique, experts at the Friedrich-Loeffler-Institut were able to confirm that the patient’s pet rat had been infected by the same virus. Explaining the results, Prof. Hofmann says: “Both viral sequences – the patient’s and the rat’s – were identical. This confirms that the disease was transmitted by an animal to a person – which means it is a zoonotic disease.” “Until now, only contact with mice would result in a suspected diagnosis of hantavirus infection. It will now be necessary to consider the possibility of infection after contact with either wild or domesticated rats as well,” caution the study’s authors. “The fact that this pathogen has been confirmed in a pet rat also means that the virus is capable of being exported, via the trade in these animals, practically anywhere in the world.” Those keeping rats are therefore advised to exercise caution.

Heart attacks strike suddenly and have a range of different triggers. Researchers from Charité – Universitätsmedizin Berlin and the German Centre for Cardiovascular Research (DZHK) were able to uncover a further underlying cause. Studying arterial deposits (plaque) in patients with acute coronary syndrome, the researchers found that, in some patients, these were characterized by activated immune cells which, as a result of altered flow conditions within the vessel, had accumulated on the interior arterial wall, causing damage to the arterial lining. The researchers’ report on this novel immune system-mediated pathophysiological mechanism has been published in the European Heart Journal*. Acute coronary syndrome (also known as heart attack) is a life-threatening condition which is characterized by impaired blood flow to the heart and is caused by a blockage or narrowing of the coronary arteries. Arterial deposits (known as plaque) represent a major contributing factor, as they can give rise to blood clots, which can detach and block the coronary arteries. What triggers the formation of blood clots – and thus the subsequent heart attack – remains to be fully elucidated. For a long time, researchers had thought that these blood clots were exclusively caused by damage to the fibrous cap, a connective tissue layer which surrounds the deposit and whose rupture results in the release of debris. More recent data, however, suggest that blood clots can also originate from plaques whose fibrous cap remains intact. For the first time, researchers from Charité’s Department of Cardiology on Campus Benjamin Franklin and from DZHK have shown the manner in which this type of ‘plaque erosion’ can help trigger heart attack. As part of the OPTICO-ACS study program, the research teams – led by study lead Prof. Dr. David M. Leistner and Head of Department Prof. Dr. Ulf Landmesser – investigated a total of 170 patients with acute coronary syndrome. The researchers found that, in approximately 25 percent of patients, the acute coronary syndrome had been caused by plaque erosion rather than plaque rupture. “Our study is the first to elucidate the manner in which plaque erosion can trigger heart attack. Areas of plaque erosion were characterized by the presence of special, activated immune cells known as T-lymphocytes. Altered arterial blood flow enables these cells to accumulate in the coronary artery wall, causing damage to the inner lining,” says first author Prof. Leistner. Using special high-resolution imaging technology known as optical coherence tomography (OCT), the researchers were able to visualize the heart attack-causing plaques for classification into the ‘plaque rupture’ and ‘plaque erosion’ trigger categories. Using an aspiration catheter, the researchers then removed the blood clots for analysis. They also collected blood samples, which were tested for immune cells and markers of inflammation. Blood clot analysis revealed altered immune cell ratios in approximately one quarter of blood clots, namely those which had originated from sites of plaque erosion. These showed increased levels of CD4+ and CD8+ lymphocytes and their effector molecules, a finding which suggests an inflammatory response that causes damage to endothelial cells in the arterial wall. In these patients, the culprit blood clots were also found near sites of arterial branching, an environment which is known to create altered blood flow patterns. Prof. Leistner adds: “In the hope of reinforcing our patient-based observations – and in keeping with our translational approach – we also used cell culture experiments, which enabled us to confirm our findings.” What this means is that heart attacks can have different pathophysiological causes. One of the key features of this newly described mechanism is a misguided adaptive immune response. Summing up the significance of the research, Prof. Landmesser (also BIH Professor) says: “Given that the use of immunomodulation has proven to be both safe and effective within cardiovascular medicine, this certainly holds great promise in terms of research into more personalized treatments for different forms of acute coronary syndrome which may even be able to prevent clinical complications.” In pursuit of the ability to influence the immune system in a targeted manner, the researchers plan to conduct a more detailed study of the precise role of the T-lymphocytes involved and how they accumulate inside blood vessels.

Joint press release by Charité – Universitätsmedizin Berlin and Tel Aviv University. Over the next six years, research groups at Charité – Universitätsmedizin Berlin and Tel Aviv University will study how invasive fungal pathogens are able to evade treatments and develop tolerance to antifungal drugs. In addition to generating fundamental knowledge of fungal pathogens, this large project aims to provide new insights into fungal cell metabolism. This joint endeavor is supported by a European Research Council ERC Synergy Grant worth approximately € 9.7 million. While fungal infections are extremely common, they are not usually life-threatening. Invasive fungal infections, however, are an exception, as they can lead to sepsis, a severe condition caused by an extreme systemic response to uncontrolled infection. Fungal infections of this kind can have a mortality of up to 50 percent, are often difficult to treat, and are responsible for at least 1.6 million deaths per year. While bacterial infections can be treated with a range of antimicrobial drugs, only three classes of drugs (azoles, echinocandins and polyenes) have been shown to be effective against invasive fungal infections. Reasons for the paucity of effective drugs include the fact that fungal and human (and other mammalian) cells are very similar, which leaves very few pathogen-specific drug targets to choose from. In addition to the dearth of antifungals, the situation is further exacerbated by the declining efficacy of these drugs. For instance, the drug of choice in the treatment of invasive candidiasis, fluconazole, is ineffective in approximately half of all invasive infections caused by Candida albicans, the most common human pathogen (better known as the organism responsible for thrush). Treatment failures such as these are, in part, explained by pathogen tolerance, a phenomenon which allows fungal cells to continue growing in the presence of an antifungal drug. Under the leadership of Prof. Dr. Markus Ralser (Director of Charité’s Institute of Biochemistry and Group Leader of the ‘Biochemistry and Metabolic Systems Biology’ research group) and Prof. Dr. Judith Berman (head of the Judith Berman Lab at Shmunis School of Biomedical and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University) a leading expert in fungal pathogens, the research teams are hoping to identify the precise mechanisms responsible for these treatment failures. One of their key hypotheses is that the explanation may be found in metabolic processes. “Our previous observations revealed that different types of cells work together. This collaboration involves the exchange of metabolites such as nutrients and results in the cells jointly developing tolerance” explains Prof. Ralser. He adds: “This metabolic collaboration makes cells heterogeneous. We have evidence that this metabolic heterogeneity may be a key factor in drug tolerance. Furthermore, inhibitors of metabolic pathways appear to influence the stress survival mechanisms in some of these cells.” Both the Berlin and Tel Aviv research teams will now study the underlying biological mechanisms in great detail. “The situation regarding invasive fungal pathogens is fundamentally different from that involving antibiotic-resistant bacteria,” explains Prof. Berman. She adds: “In problematic bacterial infections, pathogens often acquire mutations which render them resistant to antibiotics. In fungal pathogens, however, resistance is far less common and spreads less rapidly. Rather, what we find is that fungal cells become heterogeneous and adapt to their immediate environment. A proportion of cells continue to grow slowly, even in the presence of an antifungal drug. An examination of these growing cells shows that the growth exhibited by both drug-tolerant and non-tolerant cells is similar to that of the original strains. Cellular tolerance is therefore a phenotypic trait; it is not caused by mutations akin to those seen in bacterial resistance.” Their highly interactive work program will see Prof. Berman and Prof. Ralser work together to test thousands of fungal strains, establishing their drug tolerance levels and comparing their metabolic characteristics. To do so, they will work with clinicians and biologists from across Europe, Canada and the United States. Their common aim is to identify the molecular pathways which explain drug tolerance in fungal pathogens. The researchers also hope to develop new concepts and drugs which will be effective in preventing fungal pathogens from developing increased tolerance to antifungal drugs. The researchers are hopeful that their work will contribute to the development of new antifungal agents and new combination antifungal therapies which will be effective against life-threatening invasive fungal infections.

Joint press release by Charité – Universitätsmedizin Berlin, the Max Planck Institute for Molecular Genetics, and the Max Delbrück Center for Molecular Medicine Female moles not only have ovarian, but also testicular tissue that produces male sex hormones – which lets them diverge from the categorization into two sexes. A team led by Berlin researchers Prof. Dr. Stefan Mundlos and Dr. Darío Lupiáñez describes in Science* which genetic modifications contribute to this singular development. Moles are special creatures that roam in an extreme habitat. As mammals that burrow deep into the earth, they have forepaws with an extra finger and exceptionally strong muscles. What’s more, female moles are intersexual while retaining their fertility. Typical for mammals, they are equipped with two X chromosomes, but they simultaneously develop functional ovarian and testicular tissues. In female moles, both tissue types are united in one organ, the ovotestis – something that is unique among mammals. The testicular tissue of the female mole does not produce sperm, but large amounts of the sex hormone testosterone, meaning the females have similarly high levels as the males. Presumably this natural “doping” makes the female moles aggressive and muscular, an advantage for life underground, where they have to dig burrows and fight for resources. In a study in the journal Science, Berlin scientists are now reporting on the genetic peculiarities that lead to this characteristic sexual development in moles. According to the study, it is primarily changes in the structure of the genome that lead to altered control of genetic activity. In addition to the genetic program for testicular development, this also stimulates enzymes for male hormone production in the females. The study was conducted by an international team co-led by Prof. Dr. Stefan Mundlos, Director of Charité’s Institute of Medical Genetics and Human Genetics and Research Group leader at the Max Planck Institute for Molecular Genetics (MPIMG), and by Dr. Darío Lupiáñez, Research Group Leader at the Berlin Institute for Medical Systems Biology (BIMSB), which is part of the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC). “Since Darwin, it has been generally accepted that the different appearances of living organisms are the result of gradual changes in genetic makeup that have been passed onto subsequent generations,” says Prof. Mundlos. “But how are DNA changes and their manifestations in the appearance of an organism related in concrete terms, and how can we uncover such changes?” To pursue this question, the researchers have completely sequenced the genome of the Iberian mole (Talpa occidentalis) for the first time. Moreover, they examined the three-dimensional structure of the genome within the cell. In the nucleus, genes and their associated control sequences form regulatory domains – relatively isolated “neighborhoods” consisting of large regions where DNA sections interact frequently with each other. “We hypothesized that in moles, there are not only changes in the genes themselves, but particularly in the regulatory regions belonging to these genes,” says Prof. Mundlos. In the course of the moles’ evolution, then not only would individual letters of the DNA have changed, also larger pieces of the genome would have shifted, says the researcher. If segments of DNA move from one location to another, completely new or reorganized regulatory domains can emerge and thus activate new genes and enhance or attenuate their expression. “The sexual development of mammals is complex, although we have a reasonably good idea on how this process takes place,” says Dr. Lupiáñez. “At a certain point, sexual development usually progresses in one direction or another, male or female. We wanted to know how evolution modulates this sequence of developmental events, enabling the intersexual features that we see in moles.” In fact, when comparing the genome to that of other animals and humans, the team discovered an inversion – i.e., an inverted genomic segment – in a region known to be involved in testicular development. The inversion causes additional DNA segments to get included in the regulatory domain of the gene FGF9, which reorganizes the control and regulation of the gene. “This change is associated with the development of testicular tissue in addition to ovarian tissue in female moles,” explains Dr. Francisca Martinez Real, lead author of the study and scientist at the MPIMG as well as the Institute of Medical Genetics and Human Genetics at Charité. The team also discovered a triplication of a genomic region responsible for the production of male sex hormones (androgens), more specifically the androgen production gene CYP17A1. “The triplication appends additional regulatory sequences to the gene – which ultimately leads to an increased production of male sex hormones in the ovotestes of female moles, especially more testosterone,” says Dr. Real. The highly territorial moles cannot be kept in the laboratory, which particularly challenged the work of the researchers. “We had to do all our research on wild moles,” says Dr. Lupiáñez. He and Real spent months in southern Spain collecting samples for their experiments. “However, this drawback also became a strength in our study. Our results are not limited to laboratory animals, but extend our knowledge to wild animals.” The research group proved that the two genome mutations actually contribute to the special sexuality of female moles by creating a mouse model in which they mimic the genomic changes observed in moles. Of the altered animals, the female mice had androgen levels that were as high as in normal male mice. They were also significantly stronger than their unaltered conspecifics. With moles, the sexes are not that clearly delimited from one another; instead, females move on a spectrum between typically female and typically male phenotypes, i.e., they are intersexual. “Our findings are a good example of how important the three-dimensional organization of the genome is for evolution,” says Dr. Lupiáñez. “Nature makes use of the existing toolbox of developmental genes and merely rearranges them to create a characteristic such as intersexuality. In the process, other organ systems and development are not affected.” “Historically, the term intersexuality has caused considerable controversy,” says Prof. Mundlos. “There was and continues to be a tendency to characterize intersexual phenotypes as pathological conditions. Our study highlights the complexity of sexual development and how this process can result in a wide range of intermediate manifestations that are a representation of natural variation.”

Initiated and coordinated by Charité – Universitätsmedizin Berlin, the new national academic research network dedicated to COVID-19 (Forschungsnetzwerk der Universitätsmedizin zu Covid-19) combines and enhances existing strengths. The aim is to optimize the speed at which knowledge about this new disease becomes available. The infrastructure for a nationally coordinated program of COVID-19 research is now in place. 13 large collaborative projects have been designed, which will be conducted under the leadership of different university hospitals. Charité will lead on two of these large projects and act as co-lead on a further three. Researchers from Charité – Universitätsmedizin Berlin will also make major contributions to a further seven collaborations. The research network has been allocated a total of €150 million in funding by the Federal Ministry of Education and Research (BMBF). Preventing infections, optimizing patient care, and safeguarding health care services. The COVID-19 pandemic has been characterized by the need to implement strategy switches at very short notice. Researchers from across 36 university hospitals have joined forces to pool and strengthen relevant research efforts. Charité will act as the central coordinating hub for the new academic research network, which is also known as ‘Netzwerk Universitätsmedizin’ (literally Network of University Medicine) or NUM. Co-initiator of the NUM and Charité’s Chief Executive Officer, Prof. Dr. Heyo K. Kroemer, said: “As part of this initiative, which brings together nearly all German university hospitals as well as other networks, researchers will be working across partner sites to optimize treatment options, to address issues from the fields of health services research and pandemic response, and to develop evidence-based approaches. The guiding principle which underpins this endeavor is what sets this initiative apart. The idea is to promote the involvement and collaboration of the largest possible number of stakeholders rather than encourage competition between individuals – because what we need now is prompt access to knowledge.” The new academic research network promotes the systematic and comprehensive exchange of knowledge between research partners. In close consultation with the National Task Force (and coordinated by Charité), a total of more than 280 concepts submitted to the network have been organized into 13 large-scale projects. Individual project implementation plans take into account local research strengths at participating sites and aim to pool the relevant expertise from across the country. The consortia thus created are led by one or more of the participating sites. Five of these projects will see Charité either act as overall project lead or share this responsibility with other university hospitals. Charité will also have involvement in a further seven projects. These include the establishment of an emergency department registry, the design of testing strategies which take account of infection levels, and the development and refinement of specific apps. The following collaborative projects are either led or co-led by Charité: National COVID-19 Research Data Platform/Nationale Forschungsdatenplattform Covid-19 (FoDaPla) COVID-19 research needs a comprehensive, standardized database to underpin research efforts on a wide range of issues. The aim of the project is to develop a nationwide, standardized and data protection-compliant infrastructure which enables the storage of COVID-19 research-related data sets. Plans include a centralized data platform, data collection tools, use and access protocols and a data trust. Lead Coordinator is Prof. Dr. Roland Eils, Founding Director of the Digital Health Center which is operated by the Berlin Institute of Health (BIH) and Charité. He said: “We want to create an infrastructure capable of processing data from multiple COVID-19 research data sets, including clinical data, imaging data and biomaterials data, providing pseudonymized, patient-specific information to researchers across multiple sites. This infrastructure will be centrally available to all researchers and link up the various university hospitals.” The infrastructure for the research database platform is being provided by the German Centre for Cardiovascular Research (Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK) e.V.) and the Medical Informatics Initiative (die Medizininformatik-Initiative). The plan is to create a platform which can be further expanded and adapted for use during future pandemics. Overall coordination: Charité – Universitätsmedizin Berlin. Institutions involved: Medizinische Hochschule Hannover, Universitätsmedizin Greifwald, Universitätsklinikum Köln, Universitätsklinikum Schleswig-Holstein, Universitätsmedizin Göttingen, Charité – Universitätsmedizin Berlin, Universitätsklinikum Erlangen, Universitätsmedizin Dresden, Universitätsmedizin Mannheim, Universitätsklinikum Leipzig, Universitätsklinikum Aachen, Universitätsklinikum Ulm, Universitätsklinikum Frankfurt, Universitätsklinikum Bonn, Ludwigs-Maximilian-Universität München, Friedrich-Alexander-Universität Erlangen-Nürnberg, Technische Universität München, Eberhard Karls Universität Tübingen. Non-university partners: Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK), Deutsches Zentrum für Infektionsforschung (DZIF), TMF e.V., Gesellschaft für wissenschaftliche Datenverarbeitung Göttingen GmbH (GWDG), Hochschule Heilbronn. National Pandemic Cohort Network/Nationales Pandemie Kohorten Netz (NAPKON) This large-scale project aims to establish a network for the collection and collation of high-quality clinical data, including biosamples and imaging data. The purpose of this endeavor is to create strong foundations for future research studies. The project is closely linked with the development of the National Research Data Platform for COVID-19 (FoDaPa), which will also include NAPKON-generated data. Prof. Dr. Martin Witzenrath, Consortium Co-coordinator and Deputy Head of Charité’s Department of Infectious Diseases and Respiratory Medicine, said: “We are providing the field of COVID-19 research with a centrally coordinated resource which will offer rapid and efficient access to a myriad of high-quality data and biomaterials. By doing so, we are enabling robust research based on comprehensive and up-to-date data sets. With access to suitable cohorts, for instance, researchers would be able to study the long-term effects of COVID-19 in a systematic way, taking into account data from all health care sectors.” The network will consist of essential infrastructures and cohort platforms and bring together German university hospitals as well as other stakeholders such as non-university hospitals, private medical practices, and other health care facilities. Project leadership: Charité – Universitätsmedizin Berlin, Universitätsklinikum Frankfurt, Universitätsklinikum Hannover, Universitätsklinikum Schleswig-Holstein, Universitätsklinikum Würzburg. Institutions involved: Universitätsklinikum Carl Gustav Carus Dresden, Universitätsklinikum Köln. All German university hospitals are invited to join NAPKON. Non-university partners: Non-university hospitals, private medical practices, and other health care facilities. Determining and using immunity to SARS-CoV-2 (COVIM)/Bestimmung und Nutzung von SARS-CoV-2 Immunität (COVIM) Protective immunity can prevent infections and play a decisive role in controlling the SARS-CoV-2 pandemic. The ability to identify markers of immunity is therefore crucial, as is the ability to reliably determine individual and population-level immunity. This is why the COVIM consortium is addressing the following questions: Which individuals have protective immunity to SARS-CoV-2, how is this achieved and how long does it last? How can the protective immunity of a few individuals be transferred to a large number of people without such immunity? Project Co-coordinator Prof. Dr. Leif Erik Sander of Charité’s Department of Infectious Diseases and Respiratory Medicine, said: “In order to find answers to these questions, we are pooling existing expertise in immunology, virology, bioinformatics, epidemiology and infectious disease medicine from across Germany. We will study both collective and individual immunity in order to capture as full a picture of anti-SARS-CoV-2 immunity within the German population as possible”. The researchers plan to use an interdisciplinary ‘ImmunoHub’ to combine the data collated by members of the COVIM consortium and analyze them using computer-assisted learning. By working in close collaboration with the NAPKON project, the COVIM project aims to help advance the search for measures aimed at protecting the population against COVID-19. Project leadership: Charité – Universitätsmedizin Berlin, Universitätsklinikum Köln. Institutions involved: Universitätsklinikum Düsseldorf, Universitätsklinikum Erlangen, Universitätsklinikum Freiburg, Ludwig-Maximilians-Universität München, Technische Universität München, Medizinische Hochschule Hannover, Universitätsklinikum Köln, Universitätsklinikum Hamburg-Eppendorf, Universitätsklinikum Frankfurt, Universitätsklinikum Gießen und Marburg. Organ-specific stratification in COVID-19 (Organo-Strat)/Organspezifische Stratifikation bei Covid-19 (Organo-Strat) The name ‘Organo-Strat’ (short for ‘organ-specific stratification’) highlights the fact that COVID-19 is not merely a disease of the respiratory system. Rather, the disease can also affect other organ systems, such as the heart, brain, kidneys, gastrointestinal tract, and blood vessels. Our understanding of both the type and extent of organ involvement remains limited, yet they exert a direct impact on individual prognoses and treatment options. What we currently lack is meaningful, clinically relevant data on disease development, disease progression and organ-specific manifestations. There is a similar lack of robust models for use in the preclinical testing of potential drug candidates. Project Co-coordinator Prof. Dr. Andreas C. Hocke of Charité’s Department of Infectious Diseases and Respiratory Medicine, said: “Our aim is to establish a network of university hospitals and other university and non-university partners. The purpose is to develop standards for human organ models and their targeted infection, as well as for comparative analyses involving ex vivo and postmortem tissue samples. Structured quality and data management processes will help establish an agreed process chain, which will be dedicated to increasing our understanding of COVID-19”. Using COVID-19 data, Organo-Strat will create a modular and flexible network structure which will facilitate research into other emerging pathogens. As such, it will be able to form part of future Pandemic Preparedness efforts by providing information on organ-specific disease involvement and supporting the rapid testing of potential drug treatments. Project leadership: Charité – Universitätsmedizin Berlin. Institutions involved: The nine initial sites are the following university hospitals: Aachen, Berlin, Hamburg, Heidelberg, Jena, Gießen/ Marburg, Münster, Tübingen and Würzburg. (Non-) university partners: Freie Universität Berlin, Helmholtz-Institut für RNA-basierte Infektionsforschung (HIRI, Julius-Maximilians-Universität Würzburg, Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtz-Gemeinschaft, Robert Koch-Institut. COVID-19 Pandemic Radiological Cooperative Network (RACOON)/Radiological Cooperative Network zur Covid-19 Pandemie (RACOON) Early on in the COVID-19 pandemic, it became clear that radiology would play a crucial role in the management of this new disease. Lung CT scans continue to play a key role in diagnosing the disease and, above all, in predicting disease progression. The analysis of radiology findings is therefore one of the major objectives – and key to an effective pandemic response approach. One of the obstacles to systematic and quantitative analyses of imaging data is the lack of standardized reporting. Traditional prose reports in particular are often not accessible to computer-assisted methods of analysis. Over the past few years, radiology has therefore witnessed the emergence of itemized reporting. Individual findings and measurements are linked to meta data which can be used to identify in a clear and reproducible manner how a specific finding was obtained, quantified, or deduced from other data. As the first project of its scope, the RACOON network will establish a nationwide infrastructure for the standardized collection of COVID-19-related imaging data and use them to fight the pandemic. Co-Project Lead Prof. Dr. Bernd Hamm, Head of Charité’s Department of Radiology, said: “RACOON enables us to collate the findings and data on pneumonia cases with suspected COVID-19 and use them for research purposes. It will be the first time that such large quantities of highly structured data will be made available to inform relevant decision-making processes in epidemiological studies, situational assessments, and early warning mechanisms”. Another aim is to make the data available for use with epidemiological early warning systems and medical assistance systems (including artificial intelligence-based systems). Project leadership: Charité – Universitätsmedizin Berlin, Universitätsklinikum Frankfurt. Institutions involved: All German university hospitals. (Non-) university partners: Technical University of Darmstadt, German Cancer Research Center (DKFZ), Heidelberg, Fraunhofer Institute for Digital Medicine MEVIS, Bremen.

Joint Press Release Charité – Universitätsmedizin Berlin and German Center for Neurodegenerative Diseases Researchers at the German Center for Neurodegenerative Diseases (DZNE) and Charité - Universitätsmedizin Berlin have identified highly effective antibodies against the coronavirus SARS-CoV-2 and are now pursuing the development of a passive vaccination. In this process, they have also discovered that some SARS-CoV-2 antibodies bind to tissue samples from various organs, which could potentially trigger undesired side effects. They report their findings in the scientific journal Cell*. Initially, the scientists isolated almost 600 different antibodies from the blood of individuals who had overcome COVID-19, the disease triggered by SARS-CoV-2. By means of laboratory tests, they were able to narrow this number down to a few antibodies that were particularly effective at binding to the virus. Next, they produced these antibodies artificially using cell cultures. The identified so-called neutralizing antibodies bind to the virus, as crystallographic analysis reveals, and thus prevent the pathogen from entering cells and reproducing. In addition, virus recognition by antibodies helps immune cells to eliminate the pathogen. Studies in hamsters – which, like humans, are susceptible to infection by SARS-CoV-2 – confirmed the high efficacy of the selected antibodies: “If the antibodies were given after an infection, the hamsters developed mild disease symptoms at most. If the antibodies were applied preventively - before infection - the animals did not get sick,” said Dr. Jakob Kreye, coordinator of the current research project. The DZNE scientist is one of the two first authors of the current publication. Treating infectious diseases with antibodies has a long history. For COVID-19, this approach is also being investigated through the administration of plasma derived from the blood of recovered patients. With the plasma, antibodies of donors are transferred. “Ideally, the most effective antibody is produced in a controlled manner on an industrial scale and in constant quality. This is the goal we are pursuing,” said Dr. Momsen Reincke, also first author of the current publication. “Three of our antibodies are particularly promising for clinical development,” explained Prof. Dr. Harald Prüss, a research group leader at the DZNE and also a senior physician at the Clinic for Neurology with Experimental Neurology at Charité - Universitätsmedizin Berlin. “Using these antibodies, we have started to develop a passive vaccination against SARS-CoV-2.” Such a project requires cooperation with industrial partners. That is why the scientists are collaborating with Miltenyi Biotec. In addition to the treatment of patients, preventive protection of healthy individuals who have had contact with infected persons is also a potential application. How long the protection lasts will have to be investigated in clinical studies. “This is because, unlike in active vaccination, passive vaccination involves the administration of ready-made antibodies, which are degraded after some time,” Prof. Prüss said. In general, the protection provided by a passive vaccination is less persistent than that provided by an active vaccination. However, the effect of a passive vaccination is almost immediate, whereas with an active vaccination it has to build up first. “It would be best if both options were available so that a flexible response could be made depending on the situation.” Kreye, Reincke, Prüss and colleagues usually deal with autoimmune diseases of the brain, in which antibodies erroneously attack neurons. “In the face of the COVID-19 pandemic, however, it was obvious to use our resources also in other ways,” said Prof. Prüss. For the current project, the researchers benefit from a project funded by the Helmholtz Association: the “BaoBab Innovation Lab”. Within this framework, they are developing and refining technologies for the characterization and production of antibodies, which they are now applying. “Now, we are working with our industrial partner to establish the conditions that will allow for the most effective large-scale production of the antibodies we have identified,” said Prüss. “The next step is clinical trials, that is testing in humans. However, this can not be expected before the end of this year at the earliest. The planning for this has already started.” During their investigations, the researchers made a further discovery: some of the particularly effective antibodies against the coronavirus specifically attached to proteins of the brain, heart muscle and blood vessels. In tests with tissue samples from mice, several of the neutralizing antibodies exhibited such a cross-reactivity. Thus, they were excluded from the development of a passive vaccination. “These antibodies bind not only to the virus, but also to proteins in the body that have nothing to do with the virus. Future research is needed to analyse whether the associated tissues could potentially become targets of attacks by the own immune system,” said Prof. Prüss. Whether these laboratory findings are relevant for humans cannot be predicted at present. “On the one hand, we need to be vigilant in order to detect any autoimmune reactions that may occur in the context of COVID-19 and vaccinations at an early stage. On the other hand, these findings can contribute to ensure the development of an even safer vaccine,” the scientist said. For the current studies, the DZNE research group lead by Prof. Prüss collaborated closely with the Department of Infectious Diseases and Respiratory Medicine at the Charité and the Institute of Virology at the Campus Charité Mitte. The Institutes of Virology and Veterinary Pathology at the Freie Universität Berlin and the Scripps Research Institute in the US were also significantly involved.

Alexei Navalny, who had been receiving treatment at Charité – Universitätsmedizin Berlin since August 22, 2020, was yesterday discharged from inpatient care. The patient’s condition had improved sufficiently for him to be discharged from acute inpatient care. Alexei Navalny had been receiving treatment at Charité for a total of 32 days, of which 24 days were spent in intensive care. Based on the patient’s progress and current condition, the treating physicians believe that complete recovery is possible. However, it remains too early to gauge the potential long-term effects of his severe poisoning. The decision to make details of Mr. Navalny’s condition public was made in consultation with the patient and his wife.

A team of researchers from Charité – Universitätsmedizin Berlin and the Deutsches Rheuma-Forschungszentrum (DRFZ) Berlin, a Leibniz Institute, have successfully treated two patients with the autoimmune disease systemic lupus erythematosus. Using daratumumab, a monoclonal antibody which targets specific immune cells known as plasma cells, the researchers were able to modulate the abnormal immunological memory processes found in these patients. Treatment induced sustainable clinical responses and resulted in a reduction in systemic inflammation. The results of this research have been published in the New England Journal of Medicine*. The body’s immunological memory enables the immune system to respond more rapidly and effectively to pathogens that have been encountered before. This immune response is mediated by both memory T lymphocytes and antibodies, which are produced by cells known as ‘plasma cells’. Mature memory plasma cells reside in special niches in the bone marrow and are able to produce large amounts of antibodies for decades or even life-time. In autoimmune diseases, the immune system mistakes part of the body as foreign and considers it a danger. In a process that is assisted by the body’s immunological memory, the immune system mounts a response using ‘autoantibodies’. Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease in which antibodies are produced against components of the body’s cellular nuclei. This autoimmune response is associated with inflammation that may affect the skin, joints, or internal organ systems such as the kidneys, heart or central nervous system. Traditionally, treatments have relied on the long-term suppression of the immune response. Until now, however, they have not been targeted at mature memory plasma cells. For the first time – and working alongside colleagues from the DRFZ (led by Prof. Dr. Andreas Radbruch) – Charité researchers, led by Dr. Tobias Alexander, have studied the effectiveness and tolerability of a plasma cell-specific treatment in two lupus patients who failed to respond to conventional therapies. “In a certain proportion of patients, the disease cannot be controlled using currently available treatments. As a result, there is a desperate need for novel and targeted treatment approaches,” explains study lead Dr. Alexander, who is Head of Rheumatology Outpatient Services at Charité’s Department of Rheumatology and Clinical Immunology and also conducts research at the DRFZ. The researchers focused their efforts on the monoclonal anti-CD38 antibody daratumumab, which has been used for years to successfully treat patients with plasma cell cancer. The role of plasma cells in autoimmune diseases has been a major focus of the work conducted by the research group led by Dr. Alexander and his co-author, Prof. Dr. Falk Hiepe. “CD38 surface protein is considered a classic plasma cell marker. However, our preliminary investigations have shown that, in patients with lupus, increased levels of this marker can also be detected in other active immune cells such as memory T lymphocytes, as well as in the blood and urine,” explains Dr. Alexander. This makes CD38 an ideal target for treatment, which aims to eliminate the pathologically altered immune cells. The recipients of this new treatment were two female patients with life-threatening lupus, whose symptoms included inflammation of the heart and kidneys and antibody-induced anemia. Weekly administrations of daratumumab over four weeks resulted in a rapid and significant improvement in symptoms, which remained stable for several months. The patients also showed a marked decline in serum autoantibody levels. Using state-of-the-art immunological techniques – including single-cell sequencing – the researchers were furthermore able to show that daratumumab has a positive effect on active T lymphocytes, which are thought to play an important role in disease development. No relevant side effects were recorded. Although testing revealed a decline in protective antibodies in the blood, this was not associated with increased susceptibility to infections. “The promising results seen in SLE may be transferable to other autoimmune diseases in which autoantibodies play a role,” says first author Lennard Ostendorf, a doctoral student at the DRFZ. The next step, however, will be to test the safety and efficacy of daratumumab in a larger group of lupus patients. For this, the researchers are planning to conduct a pilot clinical study, which will be led by Dr. Alexander and conducted at Charité.

The EMPAIA project, which is led by Charité – Universitätsmedizin Berlin, has been crowned one of the winners of the AI Innovation Competition organized by the Federal Ministry for Economic Affairs and Energy (BMWi). The project, which will now enter its implementation stage, aims to build a platform for AI-assisted solutions within the field of diagnostic medical imaging. The consortium has been awarded a total of € 11.4 million over three years, of which € 4.6 million will go to Charité. In an effort to provide patients with more personalized treatments, physicians are relying on increasingly complex clinical diagnostics. This development is seen in a range of disorders but is particularly pronounced in the diagnosis of cancer. The processes involved in evaluating imaging data (such as MRIs) and tissue sections are particularly time-consuming and complex. By speeding up image analysis, artificial intelligence-based methods can help deliver relevant information faster – such as whether a cancer has metastasized. “Artificial intelligence holds enormous potential; it has the capacity to revolutionize all areas of diagnostic medical imaging over the coming years,” says Prof. Dr. Peter Hufnagl of Charité’s Institute of Pathology. The coordinator of the EMPAIA Consortium (Ecosystem for Pathology Diagnostics with AI Assistance) adds: “This potential is almost impossible to realize at the moment because we lack both infrastructure and standards, as well as clarity regarding the relevant legal framework.” For this reason, Prof. Hufnagl is working alongside the Distributed Artificial Intelligence (DAI) Laboratory at Technische Universität Berlin, the Fraunhofer Institute for Digital Medicine MEVIS, vitagroup AG and Qualitätssicherungs-Initiative Pathologie QuIP GmbH to develop a platform which will make it easier for physicians to access approved and validated AI-based apps. The researchers want to enable users to compare how different programs solve a specific problem. At the same time, they want developers of AI-based algorithms to be able to access imaging data which they need in order to validate their software. In order to speed up the certification of diagnostic algorithms, the platform will also bring together developers, reference institutes and certification bodies. “The rules under which this marketplace operates will of course be guided by current data protection and medical devices legislation,” emphasizes Prof. Hufnagl. He adds: “By creating this marketplace within a clearly defined legal framework, we want to enable physicians to routinely use approved AI-based solutions within diagnostic imaging.” During the development process, the consortium plan to initially focus on the analysis of tissue sections before switching their focus to imaging data. The EMPAIA Consortium will hold a kickoff meeting on Friday, 25 September, 10 AM to 5 PM. Media representatives are invited to attend this digital event. To register, please contact empaia(at)charite.de.

The condition of Alexei Navalny, who has been receiving treatment at Charité – Universitätsmedizin Berlin since August 22, 2020, continues to improve. The patient has been successfully removed from mechanical ventilation. He is currently undergoing mobilization and is able to leave his bed for short periods of time. The decision to make details of Mr. Navalny’s condition public was made in consultation with the patient and his wife. Relaxed through pregnancy 2020-09-11T08:27:00+02:00 2020-09-11T08:27:00+02:00 https://www.charite.de/en/service/press_reports/artikel/detail/relaxed_through_pregnancy/ Charité-Redaktion webteam@charite.de © Charité – Universitätsmedizin Berlin

A group of researchers from Charité – Universitätsmedizin Berlin have been able to show that maternal psychological wellbeing during pregnancy has a positive effect on newborn infants. Increased telomere length suggests a reduced rate of cell aging, which could have an effect on children’s future health. Results from this study have been published in the American Journal of Psychiatry*. A variety of pregnancy-related factors can have an impact on child development. Until now, researchers had primarily focused on the negative effects of stress, excess weight and poor nutrition – and how these might affect, say, placental function, premature birth and children’s general health. At the cellular level, various pregnancy-related factors can have a direct impact on ‘telomeres’, cellular structures which protect the ends of chromosomes during cell division and can be lengthened by the enzyme telomerase. Telomere length is a molecular biology marker of cell aging which is linked to life expectancy and a range of age-related disorders. Although the effects of maternal stress have been widely studied, data on protective maternal factors and their positive effects on child development remain limited. A group of researchers led by Prof. Dr. Sonja Entringer of Charité’s Institute of Medical Psychology have been able to show that the mother’s ability to cope with stress during pregnancy – her ‘psychological resilience’ – is linked to telomere length. The more positive a mother’s attitude during pregnancy, the longer the children’s telomeres. “Positive maternal psychological characteristics are biologically embedded and have a protective effect on the fetus,” says Prof. Entringer. In an earlier study, the researchers examined the way in which maternal stress during pregnancy affects telomere length in their offspring. The current study, which saw Prof. Entringer’s team work with a team of researchers led by Nobel Laureate Elizabeth Blackburn of the University of California and colleagues in Finland, had access to a large study population comprising 650 mother and child pairs. Telomere length was determined at birth, using cells from cord blood. Positive attitude in the face of stress was determined using a ‘resilience index’, which also took into account the pregnant women’s psychological wellbeing and perceived social support. “This study underlines the importance of maternal psychological wellbeing during pregnancy in terms of the developmental programming of lifelong health and disease, and the significance of improved psychosocial support measures during pregnancy,” explains Prof. Entringer, who is also an Associate Professor at the University of California. Prof. Entringer was awarded a European Research Council ‘Starting Grant’ in 2016, which enabled her to set up and develop her own research group. The researchers are currently conducting more detailed investigations into the molecular mechanisms underlying the biological embedding of psychosocial effects in the cells of unborn children. As a next step, they are planning to conduct an interventional study on stress reduction in the day-to-day lives of pregnant women.

The condition of Alexei Navalny, who has been receiving treatment at Charité – Universitätsmedizin Berlin since August 22, 2020, has improved. The patient has been removed from his medically induced coma and is being weaned off mechanical ventilation. He is responding to verbal stimuli. It remains too early to gauge the potential long-term effects of his severe poisoning. The treating physicians remain in close contact with Mr. Navalny's wife. After consultation with the patient's wife, Charité is reassured that the decision to make details of the patient’s condition public would be in accordance with his wishes. In pursuit of the origin and role of ecDNA 2020-09-03T11:30:00+02:00 2020-09-03T11:30:00+02:00 https://www.charite.de/en/service/press_reports/artikel/detail/in_pursuit_of_the_origin_and_role_of_ecdna/ Charité-Redaktion webteam@charite.de © Charité – Universitätsmedizin Berlin

A team of pediatric oncologists led by PD Dr. Anton G. Henssen has set out to further improve our understanding of the mechanisms involved in cancer development and disease progression. PD Dr. Henssen, a researcher at the Experimental and Clinical Research Center (ECRC) – a facility jointly operated by Charité – Universitätsmedizin Berlin and the Max Delbrück Center for Molecular Medicine (MDC) – suspects genome-level adaptations as the driving force behind these mechanisms. The aim of the CancerCirculome project is to improve our understanding of ecDNA – ring-shaped sections of DNA which are found inside our cells but do not form part of our normal genetic information. The objective is to use cancer cell-specific characteristics of these DNA sections to inform treatment, diagnosis and clinical prognosis. The European Research Council (ERC) has allocated a total of approx. €1.5 million for the establishment of this new research group. 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 PD Dr. Henssen, who 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 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 PD Dr. 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 PD Dr. 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 PD Dr. 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.

Alexei Navalny has been receiving treatment at Charité – Universitätsmedizin Berlin since 22 August 2020. He remains in a serious condition. The patient, whose symptoms were the result of cholinesterase inhibition following a confirmed poisoning event, continues to improve. The reason for this improvement is the gradual recovery of cholinesterase activity. Alexei Navalny continues to be treated in an intensive care unit and remains on a ventilator. Recovery is likely to be lengthy. It is still too early to gauge the long-term effects which may arise in relation to this severe poisoning. The treating physicians remain in close contact with Mr. Navalny's wife. After consultation with the patient's wife, Charité is reassured that the decision to make details of the patient’s condition public would be in accordance with his wishes. COVID-19 high-risk groups: Why the immune system is less effective at fighting the virus 2020-09-02T11:30:00+02:00 2020-09-02T11:30:00+02:00 https://www.charite.de/en/service/press_reports/artikel/detail/covid_19_high_risk_groups_why_the_immune_system_is_less_effective_at_fighting_the_virus/ Charité-Redaktion webteam@charite.de © Charité – Universitätsmedizin Berlin

Older people and people with underlying medical conditions are at particular risk of severe COVID-19. A group of researchers from Charité – Universitätsmedizin Berlin have discovered one possible reason for this vulnerability. While these risk groups produce greater quantities of an important type of immune cell known as ‘T-helper cells’, their T-helper cells show impaired function. This ‘molecular brake’ on the immune system could serve as a potential new treatment target in patients with severe COVID-19. The researchers’ findings have been published in the Journal of Clinical Investigation*. Soon after the emergence of COVID-19, medical experts from across the globe reported the same phenomenon. They found that older people and people with underlying medical conditions (such as cardiovascular disease and diabetes) were more likely to develop severe disease. There is likely an array of medical reasons why advancing age or health problems should make it more difficult for our bodies to fight an infection with SARS-CoV-2. One of the factors suspected of playing a major role in this regard was the immune system. An interdisciplinary team of researchers from Charité has collated findings which support this hypothesis. As part of their study, the researchers collected blood samples from 39 COVID-19 patients who had been admitted to Charité for treatment. The researchers used these blood samples to isolate immune cells which they then stimulated with specially synthesized fragments of the SARS-CoV-2 virus. Using specific dyes to make them visible, the researchers then counted T-helper cells which had reacted to the viral fragments. As a last step, the researchers tested whether there might be a link between the number of activated T-helper cells and the patients’ risk factors. The researchers were able to show a positive correlation between the frequency of virus-specific T-helper cells and the patients’ age. The same positive correlation was found to exist in relation to the ‘Comorbidity Index’, a compound measure expressing the severity of 19 different underlying medical conditions: the higher the patient’s Comorbidity Index, the higher the number of SARS-CoV-2-specific T-helper cells in their blood. However, the team also found that advancing age and overall comorbidity scores were linked to a decrease in the proportion of cells producing the messenger substance ‘interferon gamma’ (IFN?). Cells normally release this molecule when they have recognized a virus; it is used to stimulate other components of the body's immune response which are needed to fight the pathogen. “Some of the SARS-CoV-2-specific T cells which we found in the blood of COVID-19 patients with risk factors no longer function properly,” explains leading co-first author Dr. Arne Sattler, a researcher in the Translational Immunology Research Group at Charité's Department of General, Visceral and Vascular Surgery. Summing up the study's findings, Dr. Sattler says: “One might say that these T-helper cells are being slowed down in people with risk factors. We believe this has the potential to hamper the body's ability to mount an effective response against the pathogen.” One substance known to act as a molecular ‘brake’ on the immune system is the protein PD-1. Found on the surface of T cells, this protein normally ensures an appropriate immune response and prevents the immune system attacking the body. Notably, the Charité researchers were able to show that the virus-specific T-helper cells produced significantly more PD-1 in patients with acute infection than in patients who had recovered from relatively mild symptoms. “Seen in combination with the findings from other researchers, our data suggest that PD-1 could be partly responsible for the fact that, in some people with COVID-19, the immune system produces insufficient quantities of messenger substances to be able to fight the pathogen,” says Dr. Sattler. He adds: “COVID-19 patients may therefore benefit from treatments which aim to release this type of ‘immune system brake’. However, many more studies will be needed in order to clarify this matter.”

Alexei Navalny has been receiving treatment at Charité – Universitätsmedizin Berlin since last weekend. His condition is stable. There has been some improvement in the symptoms caused by the inhibition of cholinesterase activity. Mr. Navalny continues to be treated in an intensive care unit, where he is being kept in a medically induced coma and on a ventilator. While his condition remains serious, there is no immediate danger to his life. However, due to the severity of the patient’s poisoning, it remains too early to gauge potential long-term effects. The treating physicians remain in close contact with Mr. Navalny's wife. After consultation with the patient's wife, Charité is reassured that the decision to make details of the patient’s condition public would be in accordance with his wishes. Statement by Charité: Clinical findings indicate Alexei Navalny was poisoned 2020-08-24T15:29:00+02:00 2020-08-24T15:29:00+02:00 https://www.charite.de/en/service/press_reports/artikel/detail/statement_by_charite_clinical_findings_indicate_alexei_navalny_was_poisoned/ Charité-Redaktion webteam@charite.de © Charité – Universitätsmedizin Berlin

Since his admission at the weekend, Alexei Navalny has been receiving treatment at Charité – Universitätsmedizin Berlin. The patient is being treated in intensive care and remains in a medically induced coma. While his condition is serious, it is not currently life-threatening. Following his admission, Mr. Navalny underwent extensive examination by a team of Charité physicians. Clinical findings indicate poisoning with a substance from the group of cholinesterase inhibitors. The specific substance involved remains unknown, and a further series of comprehensive testing has been initiated. The effect of the poison – namely, the inhibition of cholinesterase in the body – was confirmed by multiple tests in independent laboratories. As a result of this diagnosis, the patient is now being treated with the antidote atropine. Alexei Navalny’s prognosis remains unclear; the possibility of long-term effects, particularly those affecting the nervous system, cannot be excluded. The treating physicians remain in constant contact with Mr. Navalny’s wife. After close consultation with the patient’s wife, Charité is reassured that the decision to make details of the patient’s condition public would be in accordance with his wishes.

Charité – Universitätsmedizin Berlin can confirm that Alexei Anatolievich Navalny has been admitted for medical treatment. The patient is currently undergoing extensive diagnostic evaluation. Following completion of their evaluation and consultation with the patient's family, the treating physicians will make a statement regarding Mr. Navalny's condition and further treatment. Diagnostic evaluation is expected to take some time. We would therefore ask for your patience. We shall provide a further update as soon as new information becomes available. Extended opening hours at airport testing stations 2020-08-19T16:44:00+02:00 2020-08-19T16:44:00+02:00 https://www.charite.de/en/service/press_reports/artikel/detail/extended_opening_hours_at_airport_testing_stations/ Charité-Redaktion webteam@charite.de © Charité – Universitätsmedizin Berlin

All travelers returning from coronavirus risk areas are obliged to observe a 14-day quarantine. Travelers have the option of undergoing COVID-19 testing to reduce the length of quarantine required. Mandatory testing for travelers returning from risk areas has been in place since 8 August. Both Tegel and Schönefeld Airports offer air passengers the option of undergoing testing upon arrival. From tomorrow, the two airport testing stations, which are operated by Charité and Vivantes, will remain open until 10 PM. The airport-based testing service is exclusively aimed at returning travelers who do not display symptoms of COVID-19. The introduction of mandatory testing and the RKI’s decision to expand its list of designated risk areas have resulted in a sharp increase in testing. “Since the beginning of the pandemic, we have been reviewing our measures and procedures on a regular basis and adapting them to fit the rapidly developing situation. The implementation of the new testing stations has seen us establish – at extremely short notice – well-functioning structures which will enable us to produce highly accurate estimates of infection levels,” says Charité’s Chief Medical Officer Prof. Dr. Ulrich Frei. Out of the approximately 18,000 people who have been tested since airport screening was introduced in late July, around 250 tested positive. Approximately 8,000 of these tests were performed only last week – producing 90 positives. This increased testing volume needs to be supported by adequate processing times. A positive test results in automatic notification of the relevant public health department. This mirrors arrangements in place for tests conducted at other testing sites and family practices. Operated by Charité and Vivantes, the testing stations for travelers returning from risk areas offer a fully digitized service, meaning those wishing to undergo testing register digitally and receive their results in electronic format. Opting for a fully digitized service was a conscious decision aimed at removing the susceptibility to human error associated with manual data entry. Explaining the reasons behind this decision, Prof. Frei says: “An increase in testing volume meant there was a need to optimize the system in operation. Processes in place at the testing stations were not affected by this change. Occasionally, there were minor delays in the transmission of negative test results. Positive results remained unaffected. The direct transmission of positive test results to the relevant public health department was guaranteed at all times.” Airport-based testing forms part of the comprehensive testing strategy developed by Charité on behalf of the Senate of Berlin.

Using highly complex analytical techniques, a group of researchers from Charité – Universitätsmedizin Berlin were able to observe in detail how different metals are released from joint implants and accumulate in the surrounding bone tissue. Findings showed a steady release of metals from various implant components. In contrast to previous assumptions, this was not related to the degree of mechanical stress involved. The researchers’ findings, which have been published in Advanced Science*, will help to optimize the materials used in implants and enhance their safety. Modern joint implants restore pain-free mobility of patients with chronic degenerative joint disease, thereby drastically enhancing their quality of life. To ensure long-term mechanical stability, artificial joints are made from materials containing a range of different metal alloys. A crucial factor in determining an implant’s long-term effectiveness, however, is its integration into the surrounding bone tissue. Previous studies on implant stability show that friction between the articulating surfaces (bearing surfaces) can result in the formation of metal debris. This wear debris can lead to osteolysis – the destruction of bone around the implant – which can result in premature loosening of the implant. The possibility of a steady release of metal from other parts of the prosthesis had not previously received much attention. A group of researchers led by Dr. Sven Geißler of Charité’s Julius Wolff Institute of Biomechanics and Musculoskeletal Regeneration and BIH Center for Regenerative Therapies has now studied the spatial distribution and local toxicokinetics of metallic wear and corrosion products within the surrounding bone tissue. For their detailed analysis, the researchers used a unique synchrotron-based X-ray fluorescence imaging setup. “Our work has enabled us to show, for the first time, that both particulate and dissolved metals released from arthroplasty implants are present in the surrounding bone and bone marrow at supraphysiological levels,” says Dr. Geißler. “Therefore, the collagen-rich layer which encapsulates the implant after surgery does not separate these metals from human tissue to the extent previously assumed.” The researchers collected minute bone and bone marrow samples from 14 patients undergoing either a hip or knee arthroplasty procedure. The researchers then determined the qualitative and quantitative composition of the samples using a technique known a X-ray fluorescence. This technique provides unique insights into the concentration, distribution, location and accumulation of metallic degradation products like cobalt, chromium or titanium in adjacent bone and bone marrow. The extremely bright and intensively focused X-ray beam required was achieved by the synchrotron radiation source at the European Synchrotron Radiation Facility (ESRF). The ESRF, which is located in Grenoble, France, is the only particle accelerator in the world to offer a spatial resolution of up to 30 nanometers. Summing up the researchers’ achievements, the study’s first author, Dr. Janosch Schoon, says: “Our work therefore addresses an issue of enormous clinical relevance with a highly complex experimental setup.” “Our study has made a major contribution to the improvement of the risk-benefit evaluation of medical devices. It has shown that these evaluations should not only comprise biocompatibility testing of raw materials; rather, biocompatibility testing should also extend to wear and corrosion products. The data from this study will therefore prove instrumental in keeping implant safety at the highest possible level,” explains Dr. Geißler. Based on their findings, the researchers plan to conduct additional studies which will investigate the biological consequences of metal release on bones and bone marrow. At the same time, the researchers will develop new approaches which will facilitate the reliable preclinical testing of implant materials using both human cells and engineered tissues.

Joint press release of Charité, the University of Bonn, the German Center for Neurodegenerative Diseases, the Helmholtz Centre for Infection Research, and the German Center for Infection Research Contrary to what has been generally assumed so far, 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. Experts from Charité – Universitätsmedizin Berlin, the University of Bonn, the German Center for Neurodegenerative Diseases (DZNE), the Helmholtz Centre for Infection Research (HZI) and the German Center for Infection Research (DZIF), along with colleagues from a nationwide research network, present these findings in the scientific journal Cell*. Most patients infected with the novel coronavirus SARS-CoV-2 show mild or even no symptoms. However, 10 to 20 percent of patients develop pneumonia during the course of COVID-19 disease, some of them with life-threatening consequences. "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 indicate an ineffective immune response. This is a contradiction," says Prof. Dr. Joachim Schultze of the University of Bonn and the DZNE. "We therefore assumed that immune cells are produced in large quantities, but that their function is defective. Therefore, we analyzed the blood of patients with varying degrees of COVID-19 severity," explains Leif Erik Sander of 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) - meaning that the analysis and interpretation of the data was spread across various teams and sites. Prof. Schultze was centrally involved in coordinating the project. The blood samples were derived 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 used to determine, for example, the gene activity and the amount of proteins on the level of individual cells – thus with very high resolution. Using this data, the scientists characterized the properties of immune cells in the blood – so-called white blood cells. "Applying bioinformatics methods to this very extensive data set of the gene activities of each individual cell, allowed us to gain a comprehensive view of the activities of white blood cells," explains Prof. Dr. Yang Li of the Centre for Individualised Infection Medicine (CiiM) and Helmholtz Centre for Infection Research (HZI) in Hannover. "Combining sequencing with the detection of important proteins on the surface of the immune cells, allowed us to decipher the changes in the immune system of patients with COVID-19," adds Prof. Dr. Birgit Sawitzki of the Institute of Medical Immunology on Campus Virchow-Klinikum. The human immune system comprises a broad arsenal of cells and other defense mechanisms that closely interact with each other. The current study focused on so-called myeloid cells, which include neutrophils and monocytes. These are immune cells that are at the forefront of the immune response, i.e. they are mobilized at a very early stage to defend against infections. These cells also impact subsequent responses including formation of antibodies and other cells that contribute to immunity, placing the myeloid cells in a key position. "We found that neutrophils and monocytes were 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 Dr. Antoine-Emmanuel Saliba of the Helmholtz Institute for RNA-based Infection Research (HIRI) in Würzburg. In contrast, the situation is different in severe cases of COVID-19, explains Prof. 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." Prof. Sander adds: "This phenomenon can also be observed in other severe infections, although the reason for this is unclear. The findings indicate that the immune system stands in its own way during severe courses of COVID-19. This possibly leads to an insufficient immune response against the coronavirus, while severe inflammation in the lung tissue proceeds.“ The current findings could point to new therapeutic options, says Dr. Anna Aschenbrenner of 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 normally aim to suppress the immune system. "In the case of excessive dysfunctional immune cells, as our study shows, one would however very much wish to suppress or reprogram such cells." Prof. Dr. Jacob Nattermann of the Medical Clinic I of the University Hospital Bonn and the DZIF, further explains: "Drugs that act on the immune system might be helpful. But this is a delicate balancing act. After all, it is 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. We can possibly learn from cancer research. There is experience with therapies that target these cells." In view of the many people involved, Prof. 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 analysis. 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 shared openly, and cooperation is based on trust. This is extremely important, especially in the current crisis. “

Is the long-term use of glucocorticoids essential in people with chronic inflammatory diseases such as rheumatoid arthritis, or can early discontinuation prevent characteristic side effects? How can these drugs be discontinued without giving rise to glucocorticoid withdrawal syndrome? These were the questions addressed by the SEMIRA study, a large European trial led by Charité – Universitätsmedizin Berlin. According to the trial’s findings, continuous glucocorticoid regimens were better at controlling disease activity. However, discontinuation also proved successful in the majority of cases, and could be used to prevent the long-term side effects associated with glucocorticoid treatment. Results from this trial have been published in The Lancet.* Glucocorticoids, such as cortisone, are highly effective in controlling inflammatory diseases. Their long-term use, however, is associated with severe side effects, including cardiovascular disorders, osteoporosis and infections. These drugs also suppress the adrenal glands, thereby impairing the body's ability to produce its own cortisone. This can lead to fatigue, nausea and low blood pressure, and can even prove life-threatening. An appropriate period of gradual dose reduction – known as tapering – is essential to enable the body to adapt to a reduced supply of this substance and prevent withdrawal syndrome. Tapering glucocorticoids without triggering a recurrence of inflammation is a common challenge faced by many medical specialties. “We had not previously had access to data from double-blind, randomized, placebo-controlled trials which compared a tapering regimen for low-dose prednisone – the most common glucocorticoid used – with continued use of low-dose prednisone. In the SEMIRA trial, our comparative analysis focused on rheumatoid arthritis, a condition commonly treated with glucocorticoids,” explains the article’s first author, Prof. Dr. Gerd-Rüdiger Burmester, Head of the Medical Department, Division of Rheumatology and Clinical Immunology on Campus Charité Mitte. He and his Deputy Head of Department, Prof. Dr. Frank Buttgereit, form part of the team responsible for conducting the Steroid Elimination In Rheumatoid Arthritis (SEMIRA) study, a trial including more than 250 participants recruited from close to 40 trial centers in six different countries. All recruited patients had been receiving glucocorticoids for a minimum of six months, meaning their disease-related inflammation was well-controlled. Patients in the control group continued to receive prednisone at a similar dose for a duration of six months, while patients on the dose reduction regimen had their treatment tapered down to zero over the course of four months. Both groups received the anti-interleukin-6 receptor antibody tocilizumab as adjunctive therapy. Treatment successfully prevented disease flare-ups in 77 percent of patients on the continued prednisone regimen. The same outcome was achieved in 65 percent of patients on the tapering regimen. Fortunately, neither of the two groups had to contend with clinically relevant changes in their laboratory parameters, disease-related inflammation or other severe problems. “The fact that glucocorticoid tapering was associated with a treatment success rate of 65 percent is of enormous significance for shared decision-making involving patients. It will now be possible to decide, on a case-by-case basis, whether glucocorticoid treatment should continue or whether tapering should be attempted,” says Prof. Burmester. He adds: “Our results also set the scene for studies to investigate glucocorticoid tapering in other clinical settings – for instance in the fields of allergology, neurology and dermatology – where these drugs are also used, and where there is a certain level of uncertainty regarding the risks and benefits of discontinuing treatment.”

A study led by Charité – Universitätsmedizin Berlin and the Max Planck Institute for Molecular Genetics (MPIMG) shows that some healthy individuals possess immune cells capable of recognizing the novel coronavirus, SARS-CoV-2. The reason for this might be found in prior infections with ‘common cold’ coronaviruses. Whether or not this cross-reactivity has a protective effect on the clinical course in individuals infected with SARS-CoV-2 will now be addressed by the ‘Charité Corona Cross’ study. Why is it that some people develop severe symptoms following infection with the novel coronavirus, while others hardly notice the infection? The answer to this question is multilayered and is the subject of intensive research. One potentially crucial factor has now been identified by a team of researchers from Charité and the MPIMG: prior exposure to harmless ‘common cold’ coronaviruses. This insight is based on research involving T-helper cells, a type of specialized white blood cell which is essential to the regulation of our immune response. The researchers found that one in three people with no prior exposure to SARS-CoV-2 nonetheless have T-helper cells capable of recognizing the virus. The likely reason for this is that SARS-CoV-2 shares certain structural similarities with coronaviruses which are responsible for the common cold. For their study, the researchers isolated immune cells from the blood of 18 COVID-19 patients receiving treatment at Charité and confirmed PCR positive for SARS-CoV-2. They also isolated immune cells from the blood of 68 healthy individuals who had never been exposed to the novel coronavirus. The researchers then stimulated these immune cells using small, synthetic fragments of SARS-CoV-2 ‘spike proteins’, the characteristic, crown-like protrusions on the outer surface of coronaviruses which enable the virus to enter human cells. The researchers subsequently tested whether the T-helper cells would be activated by contact with these protein fragments. They found that this was the case in 15 out of 18 patients with COVID-19 (85%). “This was exactly what we had expected. The immune system in these patients was in the process of fighting this novel virus, and therefore showed the same reaction in vitro,” explains one of the study’s three lead authors, Dr. Claudia Giesecke-Thiel, head of the Flow Cytometry Facility at the MPIMG. She adds: “The fact that not all patients with COVID-19 showed this T-helper cell response to viral fragments is probably due to fact that T cells cannot be activated outside the human body during an acute or particularly severe phase of an illness.” The team were, however, surprised to find memory T-helper cells capable of recognizing fragments of SARS-CoV-2 in the blood of healthy individuals. They were found in a total of 24 out of 68 healthy individuals tested (35%). In fact, the researchers noticed that the immune cells of COVID-19 patients reacted to different fragments of the viral envelope than the immune cells of healthy individuals. While the T-helper cells of patients recognized the spike protein in its full length, the T-helper cells isolated from healthy individuals were primarily activated by sections of the spike protein which showed similarity to corresponding sections found in the spike proteins of harmless ‘common cold’ coronaviruses. “This suggests that the T-helper cells of healthy individuals react to SARS-CoV-2 because of previous exposure to the endemic ‘common cold’ coronaviruses,” says Dr. Giesecke-Thiel. She goes on to explain: “One of the characteristics of T-helper cells is that they are not only activated by a pathogen with an ‘exact fit’, but also by pathogens with ‘sufficient similarity’.” Notably, the researchers were able to show that the T-helper cells isolated from healthy participants who reacted to SARS-CoV-2 were also activated by various ‘common cold’ coronaviruses – displaying what is known as ‘cross-reactivity’. What effects this cross-reactivity might have on a previously healthy person infected with SARS-CoV-2 was not addressed in the current study. “Generally speaking, it is possible that cross-reactive T-helper cells have a protective effect, for instance by helping the immune system speed up its production of antibodies against the novel virus,” explains co-lead author Prof. Dr. Leif Erik Sander of Charité’s Medical Department, Division of Infectious Diseases and Respiratory Medicine. He adds: “In this case, a recent bout of the common cold would probably result in less severe COVID-19 symptoms. However, it is also possible that cross-reactive immunity could lead to a misdirected immune response and potentially negative effects on the clinical course of COVID-19. We know this can occur with dengue fever, for instance.” Prospective studies will be needed in order to conclusively determine whether previous ‘common cold’ coronavirus infections confer protection against subsequent infection with SARS-CoV-2 – and whether this might explain the high variability in clinical manifestations. One such study, which will be led by Charité and conducted in collaboration with Technische Universität Berlin and the MPIMG, has just been launched. Funded by the Federal Ministry of Health (BMG) and the Federal Institute for Drugs and Medical Devices (BfArM), the ‘Charité Corona Cross Study’ will investigate the impact of cross-reactive T-helper cells on the course of COVID-19. In Germany, coronaviruses are responsible for up to 30 percent of all seasonal colds, says Prof. Dr. Andreas Thiel, a Charité researcher based at both the Si-M (‘Der Simulierte Mensch – literally ‘The Simulated Human’, a joint research space of Charité and Technische Universität Berlin) and the BIH Center for Regenerative Therapies (BCRT). “Current estimates suggest that the average adult will contract an infection caused by one of the four endemic coronaviruses approximately every two to three years,” explains Prof. Thiel, who is the article’s third co-lead author and responsible for coordinating the Charité Corona Cross Study. He adds: “If we assume that these cold viruses are capable of conferring a certain level of immunity against SARS-CoV-2, this would mean that people who have had frequent exposure to such infections in the past, and who test positive for cross-reactive T-helper cells, should have better protection. This group of people will therefore be a particular focus of the ‘Charité Corona Cross Study’.” The researchers will simultaneously follow COVID-19 risk populations over several months. Ultimately, the study aims to help predict the clinical course of COVID-19, both in people with and without previous SARS-CoV-2 infections. “This is of paramount importance, both in terms of people’s day-to-day lives and the treatment of patients,” explains Prof. Thiel. The study includes a comprehensive immunological investigation of child daycare staff, pediatric practice staff and care home residents, which will last well into next year. Swabs collected from participants will be tested for SARS-CoV-2 using PCR-based testing. Additional tests will include tests for antibodies against the virus and for T cell reactivity. Should study participants subsequently contract SARS-CoV-2, the researchers will be able to establish links between the course of the disease and individual patients’ immunological parameters. The researchers also plan to collect blood samples from a minimum of 1,000 recovered COVID-19 patients. These will then be tested for a range of immunological factors in order to study how they correlate with symptoms. The team hope to be able to identify other potential parameters which influence COVID-19 severity and clinical course. The researchers are currently looking for individuals who were confirmed cases of COVID-19 and subsequently recovered from the illness. They would also like to hear from individuals who, at some point over the past few years, developed infections subsequently confirmed as caused by ‘common cold’ coronaviruses like 229E, C43, NL63 or HKU1. Those interested should contact the research team on 030/314 279 12 (Mondays to Fridays between 10 AM and 5PM) or email studie(at)si-m.org.

Joint Press Release of Freie Universität Berlin, Humboldt-Universität zu Berlin, Technische Universität Berlin, and Charité – Universitätsmedizin Berlin The Berlin University Alliance and the University of Oxford are taking forward their research partnership with the establishment of a Centre for Advanced Studies. The Centre for Advanced Studies funds cooperating groups consisting of up to ten fellows working together. These cooperating groups are to conduct research on topics relating to the Berlin University Alliance’s Grand Challenge Initiatives. The Grand Challenge Initiatives will be examining particularly relevant global challenges, such as the current issues of Global Health and Social Cohesion. The Centre is funded under the Excellence Strategy of the Federal Government and the Länder by the Berlin University Alliance and improves the parameters for making Oxford/Berlin collaborative research partnership more flexible from an organizational point of view and strengthening the exchange of expertise across national borders. The cooperating groups should collaborate on an interdisciplinary basis and develop joint research ideas. The first group will be starting as a virtual group in 2020 and will focus on questions related to Social Cohesion. There are plans for a total of three cooperation groups for which the Berlin University Alliance will provide up to 300,000 euros each. The funding is intended to provide financial support for fellows of the centre and their research, as well as to enable summer schools and final conferences. The format is intended to provide maximum organizational flexibility for each cooperation, the structure of which can be chosen by the collaborating groups themselves. Flexible funding opportunities should also promote mobility for researchers and graduate students from Berlin and Oxford working on joint projects. Governing Mayor and Senator for Higher Education and Research Michael Müller says: “I am delighted to see how the cooperation between Berlin and Oxford has grown and evolved in recent years and how researchers are working together to take on the big issues of our time, such as social cohesion and global health. Both Berlin and Oxford are centers of science and research, and they are retaining their close ties regardless of the United Kingdom’s withdrawal from the European Union. Their strong relationship makes an important contribution to German-British cooperation. By the Oxford/Berlin partnership, we are bolstering our city as an international research hub.” Prof. Dr. Günter M. Ziegler, President of Freie Universität Berlin and spokesperson for the Berlin University Alliance, highlights: "Oxford and Berlin are a better match than it might seem at first glance: in top research, diversity of subjects, infrastructure of museums and collections, and at both universities, many outstanding researchers full of enthusiasm for collaborative work and creative exchange – in short, a ‘match made in heaven’. I am pleased that the Oxford/Berlin partnership is now taking this next big step towards long-term cooperation.” Prof. Louise Richardson, Vice-Chancellor of the University of Oxford says: “Oxford University has always valued its status as an international university and, now - possibly more than ever before - we must reaffirm the importance of maintaining international links between academics, researchers and students. Oxford's partnership with the Berlin University Alliance has already delivered important advances in research and scholarship, and the formation of a Centre for Advanced Studies promises to achieve much more. We are extremely grateful to our partners in Berlin for taking the lead on the establishment of the Centre and look forward to the participation of Oxford colleagues in its activities over the coming years.”

The smallpox virus circulated in northern Europe as early as the seventh century. Evidence for this was found in DNA fragments obtained from Viking skeletons and analyzed by Researchers from Charité – Universitätsmedizin Berlin, the University of Cambridge, and the University of Copenhagen. This is the first time researchers have produced scientific proof that the smallpox virus has been infecting humans for at least 1,400 years. The unexpected level of genetic diversity displayed by the virus may also be of relevance in the future. The variola virus, which causes smallpox, is usually considered the deadliest virus in the world. During the twentieth century alone, the virus, which has a mortality of up to 30 percent, claimed an estimated 300 to 500 million lives. Following a global vaccination program, the human smallpox virus was declared eradicated in 1980. Even today, however, Central and West Africa sees cases of monkeypox, a disease which occurs when a close relative of the smallpox virus is transmitted from animals to humans. Monkeypox produces similar symptoms to true smallpox but has a lower mortality rate. One question which has remained unanswered is just how long the human smallpox virus had been circulating prior to its eradication. Historical documents suggest that smallpox may have existed more than 3,000 years ago. However, the oldest skeleton in which the virus had previously been identified was only around 360 years old. “We effectively had a discrepancy of almost 3,000 years between what we had surmised about the history of the smallpox virus and what we actually know,” explains the bioinformatics expert Dr. Terry Jones, Research Group Leader at Charité’s Institute of Virology on Campus Charité Mitte, and joint research lead of the study, alongside colleagues from the University of Copenhagen’s Lundbeck Foundation GeoGenetics Centre and the University of Cambridge. “Using modern molecular biology techniques, we set out to find scientific evidence that would corroborate written records indicating an earlier presence of smallpox,” says Dr. Jones. Their approach proved successful. The researchers discovered the variola virus in up to 1,400-year-old skeletal remains from Viking burial sites in Denmark, Norway, Sweden, Russia, and England. For their analysis, the researchers studied the DNA of almost 1,900 skeletons, between 150 and 30,000 years old, which had been found at various sites across Europe and America. In 13 cases, the researchers managed to isolate fragments of DNA from teeth and/or sections of the temporal bone. The age and authenticity of the DNA samples was confirmed by the presence of specific DNA damage which is associated with age-related degradation. Eleven of these individuals lived between approximately 600 and 1050 AD, i.e. during the Viking Age (793 to 1066 AD). “Ours is therefore the first study to provide molecular biology-based evidence that even Vikings were infected with the smallpox virus,” says the article’s first author, Dr. Barbara Mühlemann, a researcher from the German Center for Infection Research (DZIF) at Charité’s Institute of Virology on Campus Charité Mitte. “We were therefore able to reduce the current discrepancy between historical anecdotes and direct evidence of smallpox by approximately 1,000 years. However, we consider it likely that infections occurred much earlier than that.” The new research findings contradict a range of previous assumptions which posited that the smallpox virus was first introduced into Europe by, for example, returning crusaders between the eleventh and thirteenth centuries. Summarizing their findings, Dr. Jones, who is both a DZIF researcher and a Senior Research Associate at the University of Cambridge, says that: “Based on these recently confirmed smallpox cases in northern Europe and the historical reports of suspected cases in southern and western Europe, we assume that the smallpox virus must have been circulating widely within Europe from at least the end of the Viking Age.” Some of the samples were so well preserved that the researchers were able to use computers to reconstruct the complete viral genome sequence from the extracted fragments. Their sequence analysis revealed that the smallpox virus which was in circulation during the Viking Age differs significantly from the variola virus of the twentieth century, and that it shares more similarities with the poxvirus strains found in camels and gerbils. The ancient virus displayed a very different pattern of active and inactive genes. “Some of these genes determine, among other things, the degree of specificity which the smallpox virus shows for its host,” explains Dr. Mühlemann. She adds: “Judging by the activity pattern of the Viking Age smallpox virus, it is possible that, at the time, the virus was not only capable of infecting humans but animals as well.” It is, however, impossible to deduce either the mortality rate of the ancient virus or the nature of the symptoms it might have produced – even if the researchers’ genetic data suggest that the virus may have caused a fever in its Viking Age hosts. “We did not expect this degree of genetic diversity in the human smallpox virus. It really did take us by surprise,” says Dr. Jones. “The evolution of the smallpox virus is clearly more complex than we had assumed. The history of the human smallpox virus shows that it followed very diverse genetic paths. Given this history, it is feasible that other poxviruses, currently circulating in animals, could have had similarly diverse evolution – and this could have consequences for the transmission of the disease from animals to humans. In the future, we should therefore keep a closer eye on animal poxviruses.”

The Outpatient, Translation and Innovation Center (Ambulanz-, Translations- und Innovationszentrum – ATIZ) is currently being built in Berlin-Mitte, directly adjacent to Charité’s main patient care facility. The existing building, which formerly housed surgical, intensive care and emergency units, was gutted for reconstruction and will in the future be used jointly by the Berlin Institute of Health and Charité – Universitätsmedizin Berlin. All project milestones have been met despite the coronavirus pandemic. Federal Research Minister Anja Karliczek and Governing Mayor of Berlin and Senator for Science and Research Michael Müller paid tribute to the successful progress of the construction work at a topping-out ceremony. Almost exactly a year ago, Federal Minister of Education and Research Anja Karliczek and Governing Mayor of Berlin and Senator for Science and Research Michael Müller paid a visit to Campus Charité Mitte. On that day – July 10, 2019 – they signed an administrative agreement on the integration of the BIH into Charité. Returning to the same site for the topping-off ceremony of the ATIZ building, they got a first-hand look of how the two Berlin health institutions’ contractually agreed-upon cooperation is being put into place on the ground. “Our idea for integrating the BIH into Charité facilitates the further advancement of the BIH’s innovative and cutting-edge translational health research, which transfers basic research findings into clinical practice,” said Research Minister Anja Karliczek. Governing Mayor of Berlin and Senator for Science and Research Michael Müller, added: “Berlin is the right place to create the medicine of tomorrow. The state-of-the-art ATIZ facility shows that step by step we are implementing our plan to not only combine world-class medical research with the best in patient care, but also to transform our city into a leading international healthcare hub. I am pleased that we have been able to work in unison with the federal government and wish everyone involved in the building project continued success.” The Executive Board members of the BIH and Charité thanked the federal government and the State of Berlin for generously funding the structural restoration of Charité’s former surgery and intensive care wing and transforming it into a modern and spacious research, innovation and patient center. Prof. Dr. Heyo K. Kroemer, Chairman of the Executive Board of Charité, emphasized: “The past months of the coronavirus pandemic have shown the tremendous importance of combining basic research with the practical clinical application of research results. The ATIZ brings together the translational medical research of Charité and the BIH and gives the BIH’s integration a face.” “This building will enable leaders in medical research and clinical practice to work together under one roof,” said a delighted Prof. Dr. Axel R. Pries, interim Chairman of the BIH Executive Board and Dean of Charité, adding that “this will make the interaction between translational medicine at the BIH and the clinical centers and research institutes at Charité tangible. Only when all partners work closely together can we turn research into health.” Astrid Lurati, the Chief Financial and Infrastructure Officer at Charité, praised in particular the constructive collaboration on this ambitious building project: “The BIH has put €49 million toward the development of the ATIZ, while the State of Berlin has contributed an additional €32 million through Charité. This highlights the special cooperation and also reflects the connecting function of the building.” The modern six-story research building, which contains 14,875 square meters of floor space, will unite the BIH’s innovative patient-centric translational research and Charité’s medical care under one roof. It plans to house a joint translation center for international research groups, complete with state-of-the-art spaces for labs, offices and technology facilities; an innovation center with dedicated space for biomedical technology transfer; and a patient center of the BIH Clinical Research Unit equipped with examination and treatment rooms for clinical trials. Charité will have complementary research spaces in ATIZ, which will be used for overarching studies. Patients will also receive care there outside of studies, such as in the Oncological Outpatient Department and Day Case Unit as well as in the Skin Care Center of the Department of Dermatology and its surgical and functional units. In addition, the Simulation and Training Center will provide training to physicians within and outside Charité on how to use next-generation technologies and methods. The architect Dr. Alexander Gyalokay, from the architectural firm Heinle, Wischer and Partners, used a model of the ATIZ building to explain how the concept of translational medicine was implemented from an architectural standpoint. “The central idea behind our proposal was to bring medical research and clinical practice as close together as possible and to make the processes on both sides transparent. The close vicinity of the ATIZ building to Charité Bettenhaus Mitte, the main patient care facility, enables a direct connection between the two areas, which is also achieved through ample spaces for communication. The two-story entrance lobby provides a space for the public to encounter and experience the techniques used and discoveries made by the clinicians and scientists working in the ATIZ building.” In a moderated discussion, researchers from BIH and Charité presented a number of translational research projects investigating the coronavirus. Prof. Dr. Christof von Kalle, BIH Chair for Clinical Translational Sciences and Director of the BIH Clinical Study Center at Charité, reported on the challenge of coordinating, on very short notice, all the studies being conducted on the novel coronavirus and COVID-19. As spokesperson of the COVID-19 Research Board of Charité and BIH, Prof. von Kalle, together with Prof. Dr. Sylvia Thun, BIH Professor for eHealth and Interoperability, prepared a consensus data set for COVID-19 patients in all German university hospitals. The data set, which is subject to rigorous data protection standards, contains all relevant information, starting with personal data like age, gender, height, and weight, followed by lab results like blood pressure readings or cholesterol levels, risk factors, medication use, as well as symptoms and therapeutic procedures performed. Data from research labs are also recorded in a standardized way and then shared on servers specifically reserved for this purpose. Prof. Dr. Christine Goffinet, BIH Professor for Virology at Charité, described her experience as an AIDS researcher who suddenly found herself thrust into coronavirus research and how she keeps up with hundreds of inquiries from the public and policymakers without neglecting her research into the virus. And Prof. Dr. Roland Eils, Chair and Founding Director of the BIH Digital Health Center, reported on exciting insights from the analysis of single cells taken from the respiratory tract of COVID-19 patients. All are looking forward to the day when they will be able to work together under one roof at the ATIZ. A second building for BIH researchers is currently being built in Berlin-Buch, in cooperation with the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC). The Käthe Beutler Building on the Buch campus will house research groups working in translational vascular medicine. Prof. Dr. Thomas Sommer, interim Scientific Director of the MDC, is excited about the start of research operations in the Käthe Beutler Building in early 2021: “Through the collaboration between the MDC and the BIH, an outstanding research cluster is emerging in Berlin in this very promising field.” In the topping-out address, Mehmet Coskun, the lead builder, summed up the delight of everyone involved over the successful completion of the shell construction: “Proud, modern and always with new ideas, Over there we behold thee, Charité. On your existing foundation, known far and wide among the medical profession, a new venue is being created, where knowledge and practice will soon be fused. Wonderfully united in the ATIZ are the BIH and Charité. The first stage is now complete, May the building soon shine in new splendor.”

A group of researchers from Charité – Universitätsmedizin Berlin have further refined the use of deep brain stimulation in the treatment of obsessive-compulsive disorder. By accurately localizing electrode placement in the brains of patients, the researchers were able to identify a fiber tract which is associated with the best clinical outcomes following deep brain stimulation. The researchers’ findings, which have been published in Nature Communications*, may be used to improve the treatment of obsessive-compulsive disorder. A person with obsessive compulsive disorder (OCD) experiences unwanted thoughts and behaviors, the urge for which they find difficult or impossible to resist. More than 2 percent of people are affected by obsessive thoughts and compulsive behaviors which severely impair daily activities. A treatment option for severe cases is deep brain stimulation, a technique which is also used in other disorders, such as Parkinson’s disease. Deep brain stimulation involves the implantation of tiny electrodes into structures deep inside the brain. After implantation, these electrodes deliver very weak electric currents to help rebalance brain activity. By stimulating different areas of the brain, such as a fiber tract within the internal capsule or the subthalamic nucleus, this technique can help improve clinical symptoms in some cases. Treatment success depends on the accurate placement of electrodes and requires millimeter-level precision. The optimal stimulation target for patients with obsessive-compulsive disorders had not previously been identified. For the first time, a team of researchers – led by Dr. Andreas Horn of Charité’s Department of Neurology with Experimental Neurology – has been able to identify a specific nerve bundle which appears to be the optimal target for stimulation. The researchers studied 50 patients with obsessive-compulsive disorder who received treatment at a number of centers around the world. Using magnetic resonance imaging technology both before and after electrode placement, the researchers were able to visualize surrounding fibre tracts and test to see which of these the electrodes were selectively stimulating. “Our analysis shows that optimal results are linked to a very specific nerve bundle. Reliable evidence for this link was found across the cohorts of patients examined in Cologne, Grenoble, London and Madrid,” explains Dr. Horn. The researchers initially examined two cohorts of patients, both of which received deep brain stimulation to the internal capsule or the subthalamic nucleus. These brain structures have a variety of connections to other areas of the brain. And yet, a specific tract situated between the prefrontal cortex and the subthalamic nucleus was identified as a suitable target for stimulation in both of these groups. Precise electrode localizations allowed the researchers to reliably predict treatment outcomes in both of these groups. These results were then replicated in two further, independent cohorts. When comparing their results with other studies, the researchers showed that the target areas described were also located within the tract-target identified in this study. Describing the way in which these findings could help with electrode implantation, the study’s first author, Ningfei Li, says: “Our results do not alter the original target area, they simply helped us to define it more precisely. What this means is that: so far, we have had to steer our boat toward an island which was shrouded in fog. Now, we can make out the island itself and perhaps even the pier, so we can aim for it with greater accuracy.” All 3D structural analysis data have been made publicly available to researchers around the world. No Charité patients with obsessive-compulsive disorder are receiving treatment using this invasive method of deep brain stimulation. However, the participating research centers continue to share their knowledge and are developing protocols for additional studies to test the newly defined target areas.

A joint press release by Charité – Universitätsmedizin Berlin and Deutsche Gesellschaft für Internationale Zusammenarbeit (GIZ) GmbH Working alongside colleagues from the German development agency ‘Deutsche Gesellschaft für Internationale Zusammenarbeit (GIZ) GmbH’, a team of experts from Charité – Universitätsmedizin Berlin is supporting Latin American efforts to set up diagnostic procedures for COVID-19. In addition to delivering laboratory reagents and other equipment, the team’s Spanish-speaking experts from Charité’s Institute of Virology will train local laboratory staff in conducting diagnostic testing. Support missions during the current pandemic have seen the German Epidemic Preparedness Team (SEEG) visit the West African country of Benin, as well as Colombia and Ecuador. Missions to other countries will follow. The SEEG was established by the Federal Ministry for Economic Cooperation and Development (BMZ) in collaboration with the Federal Ministry of Health (BMG). The BMZ provides approximately € 1 million in funding per year to support the SEEG’s work. Charité’s experts are also involved in establishing and maintaining an open dialog with countries in Latin America and the Caribbean. The Federal Foreign Office is supporting their efforts with € 200,000. For more than five years, SEEG teams have been supporting German development cooperation partner countries in ensuring the early detection and prompt containment of infectious disease outbreaks. Commissioned by the BMZ and BMG, the SEEG group of experts was established during the Ebola epidemic (2014 to 2016). Current COVID-19 deployments focus on countries in Latin America and Africa, where the spread of the novel coronavirus (SARS-CoV-2) affects wide swathes of the population, including numerous indigenous groups. The early and widespread detection of COVID-19 is key to breaking chains of infection. The earlier this is done, the faster outbreaks will be contained – both locally and ultimately worldwide. Success primarily relies on comprehensive outbreak detection systems, well-equipped and functional laboratories and health care facilities, as well as qualified and dedicated specialist staff. A team of experts from Charité and the GIZ is currently on deployment across Ecuador, Peru and other Latin American countries, delivering testing material and training laboratory staff in diagnostic techniques. Following a ‘train the trainer’ concept, the team’s efforts are enabling trained staff to pass on their knowledge and expertise to staff working in local laboratories. The team of experts, led by Prof. Dr. Jan Felix Drexler, Head of the Institute of Virology’s ‘AG Drexler – Virus Epidemiology Unit’ on Campus Charité Mitte, and Dr. Michael Nagel, the SEEG’s Head of Deployment Operations, can tap into a wealth of experience, gained through years of working together. For instance, the team were responsible for establishing Zika diagnostic testing in the Peruvian tropical rainforest, a region severely affected by the virus. These types of deployments and the ability to rely on infrastructure elements developed and tested during previous epidemics mean that the experts are able to respond quickly to the current situation. “Now that Latin America has become the global COVID-19 epicenter, we can provide particularly effective support, not only because we have been active in the region for some time, but also because of the work we did with our Latin American partners during the recent Zika outbreak,” says Prof. Drexler, GIZ’s Project Partner at Charité. In addition to close contacts with Salvador University in the Brazilian state of Bahia and local experts in Tropical Medicine, the team also boasts many members who speak fluent Spanish. “A good level of knowledge of the countries and their languages helps us to provide support to local reference laboratories and advice to local decision-makers,” emphasizes Prof. Drexler. Over the past three months, the team has been able to provide the equipment needed to establish a total of ten laboratories, develop three reference laboratories and train large numbers of local staff to handle the virus safely. Since the launch of the project in the West African country of Benin, SEEG has increasingly responded to requests for assistance from Latin America. Following trips to Colombia and Ecuador, the team of experts plans deployments to Peru, Costa Rica and Honduras. Argentina and Chile have also expressed an interest. The GIZ’s Epidemic Preparedness Team will initially provide logistics support for the delivery of up to 100,000 test reagents and essential laboratory equipment, including large devices. Explaining details of these plans, Head of Deployment Operations, Dr. Michael Nagel, says: “We will start by delivering reagents needed for lab-based diagnostic testing. By doing so, we will help to solve the Gordian Knot of diagnostic testing problems in these countries. Once testing is more efficient and staff have been adequately trained, it will be possible to identify and isolate suspected cases. This is absolutely key, and of crucial importance for vulnerable and indigenous people.” At a later stage, the field mission teams will provide advice on follow-on measures, such as diagnostic strategies. The aim of these efforts, which form part of a wider pandemic-related dialog being promoted by the German Foreign Office, will be to enable partner countries to better manage the epidemiological situation. Entering into a scientific dialog with countries in this region will promote the sharing of knowledge on how to best manage the current pandemic and inform decisions regarding future measures. Acting as reliable partners in a crisis, the teams will provide specialist advice which will target specific areas of need within the region. Recommendations for action will be issued based on the experts’ experiences and assessments of local developmental needs.

A large international study coordinated by Charité – Universitätsmedizin Berlin and University Hospital Regensburg has demonstrated the safety of new cell therapy approaches for use in kidney transplant recipients. Transplant recipients were shown to require lower levels of immunosuppression in order to prevent organ rejection. This reduces the risk of side effects such as viral infections. Results from this study have been published in The Lancet.* Transplant recipients usually receive immunosuppressants to prevent organ rejection. However, these drugs cannot provide an absolute guarantee that rejection will not occur at a later stage. Furthermore, immunosuppression is often associated with severe side effects such as intolerances, infections, or other problems. Cell therapy offers an alternative treatment approach. This involves the use of specific immune cells, which are isolated and expanded in vitro. Known as ‘regulatory cell products’, these cells are then infused into the transplant recipient in order to restore their immune system. Charité was one of a number of institutions involved in the international ONE Study consortium, which was led by Prof. Dr. Edward K. Geissler of University Hospital Regensburg. The Berlin-based members of the consortium were primarily responsible for testing the safety and efficacy of cell therapy in kidney transplant recipients as well as effects on their immune system. Research centers based in several different countries worked to a standardized protocol to develop a range of regulatory cell products, which were then tested in clinical trials. These therapies, which were administered to transplant recipients either before or after their surgery, comprised regulatory T cell and macrophage products, as well as products made of dendritic cells, which produce anti-inflammatory messengers. Results were then combined and compared with a reference patient group who had received standard-of-care immunosuppression. Patients were then followed up for a further 60 weeks. “The new cell therapy was able to reduce the need for immunosuppression in approximately 40 percent of patients, thereby minimizing the risk of side effects,” says the study’s first author, Prof. Dr. Birgit Sawitzki of the Institute for Medical Immunology on Campus Virchow-Klinikum. The regulatory cells were shown to be just as safe as the drugs used in standard treatment and did not result in higher rejection rates. “Particularly remarkable was the fact that none of the patients given regulatory cells developed herpes infections, which often lead to dangerous complications in transplant recipients,” notes Prof. Sawitzki. Prof. Sawitzki’s team was primarily responsible for the development and implementation of standardized immune monitoring, i.e. the monitoring of immune cell populations in the blood. “Before transplantation, patients showed altered immune cell composition, and regulatory cells were better than standard therapy at restoring normal composition,” explains Prof. Sawitzki. She adds: “This means there are new, safe treatment options which can help to reduce the dose of conventional immunosuppressants and the risk of viral infections.” There are plans for further, larger studies to confirm the efficacy of regulatory cell therapy.

Joint press release by Senate Chancellery – Higher Education and Research and Charité The testing strategy for educational facilities comprises multiple elements: Charité will start by testing random samples of staff from 24 schools and 24 kindergartens for SARS-CoV-2. This will mark the beginning of a comprehensive coronavirus testing strategy*, which was developed at Charité in response to a request by the Senate of Berlin. From next week, Charité will schedule individual testing time slots for asymptomatic staff from the 48 selected educational facilities (12 primary schools, 12 secondary schools and 24 child care centers). The next step will see Charité launch its school-based study** in mid-June. This will involve mobile Charité teams conducting testing drives of 24 randomly selected schools. At each primary and secondary school, 20 children and adolescents, as well as five adults, will undergo regular testing over a period of 12 months. The aim of this stepwise approach is to study the developing situation and identify potential risks as educational facilities gradually return to normal operations. This will provide the data needed for an epidemiological evaluation of the unfolding situation and subsequently inform future planning. Emphasizing the significance of the plans, Michael Müller, Berlin’s Governing Mayor and Senator for Higher Education and Research, says: “It has taken real strength and endurance for all of us to drastically reduce the spread of coronavirus in our city. We need to continue to work together to protect what is a hard-won and fragile achievement. Thanks to the expertise at Charité, we are now implementing a clever testing strategy, which will establish a comprehensive and multi-faceted early warning system for infections and enables us to learn more about the virus. Testing drives in educational institutions, hospitals, nursing homes and many other areas within the public arena, such as transport, legal services, and even the catering trade, are an important foundation on which to construct a cautious return to normal life in Berlin. Explaining details of the testing strategy, Charité’s Chief Executive Officer, Prof. Dr. Heyo K. Kroemer, says: “We developed the concept guided by current scientific standards and went on to integrate the options currently available for managing the pandemic. As we still do not have access to rapid testing, we decided to use a risk-adapted random testing approach. Using results from the selected group of participants and mapping them onto the general population will help us to get a picture of the status of the pandemic in Berlin.” He adds: “The current collaboration of Charité and Vivantes, with various partners from within the public health care sector and government agencies, illustrates our plans for Berlin as a center of research and the degree of networking we aim to achieve.” The Berlin testing strategy also comprises plans for: the screening of members of staff and patients at hospitals across the city; infection surveillance in care homes; and the risk-adapted random testing of other groups. The aim is to develop a response to the pandemic, one which is both effective and preventive in focus, and to prevent and contain new clusters of infection. This will enable a return to normal life which does not expose people to uncontrollable risks.

Researchers from Charité – Universitätsmedizin Berlin and the Francis Crick Institute have identified 27 proteins which are present at different levels in the blood of COVID-19 patients, depending on the severity of their symptoms. These biomarker profiles could be used to predict disease progression and make it easier for doctors to decide which type of treatment to use. The work has been published in Cell Systems*. People respond very differently to infection with the novel coronavirus (SARS-CoV-2). While some patients develop no symptoms at all, others will develop severe disease and may even die. For this reason, there is an urgent need for ‘biomarkers’, quantifiable biological characteristics which could provide a reliable means of predicting disease progression and severity. A research team led by Prof. Dr. Markus Ralser (Director of Charité’s Institute of Biochemistry, holder of an Einstein Professorship and Group Leader at the Francis Crick Institute) used state-of-the-art analytical techniques to rapidly determine the levels of various proteins in the blood plasma. This approach enabled the researchers to identify various protein biomarkers in the blood plasma of patients with COVID-19 which were linked to the severity of their disease. The researchers developed a precise, high-throughput mass spectrometry platform capable of analyzing the patients’ proteomes – the compendium of proteins found in biological material – at a rate of 180 samples per day. Using this technology, the team analyzed blood plasma samples from 31 men and women who were receiving treatment at Charité for COVID-19 of varying degrees of severity. The researchers were able to identify 27 proteins in the blood which varied in quantity depending on disease severity. The researchers then validated these molecular signatures by analyzing samples from another group of 17 COVID-19 patients and 15 healthy people. Protein expression signatures were able to precisely classify patients according to the World Health Organization’s coding criteria for COVID-19. “These results lay the foundations for two very different applications. One possible future use would be for disease prognosis,” explains Prof. Ralser, who is also group leader at the Francis Crick Institute in London. “An early blood test would enable the treating physician to predict whether or not a patient with COVID-19 will develop severe symptoms. This could potentially save lives: the sooner physicians know which patients will require intensive care, the faster they can make use of the available treatment options.” In order to get closer to this goal, the researchers will now study how the biomarker signatures change over the course of the disease. “Another possible future use would be as an in-hospital diagnostic test, which could provide clarity regarding a patient’s condition – regardless of how they themselves describe it,” explains the biochemist. He adds: “In some cases, a patient's symptoms do not appear to provide an accurate picture of their true health status. An objective evaluation, based on their biomarker profile, could be extremely valuable in this regard.” The research team now plan to test their new method in a larger number of patients in the hope of getting closer to developing a diagnostic test.

Many neurological disorders are associated with impaired movement. Neuromodulation, the targeted electrical stimulation of nerve cells, can help to control altered neuronal network activity. A new Transregional Collaborative Research Center (SFB/Transregio) will now study the nature of the neuromodulation mechanisms which are responsible for a range of conditions. A joint undertaking of Charité – Universitätsmedizin Berlin and the University Hospital of Würzburg, the new SFB/Transregio (‘Retuning dynamic motor network disorders using neuromodulation’) aims to contribute to the development of innovative treatment strategies for people with currently untreatable movement disorders. Funded by the German Research Foundation (DFG), this collaborative research project will receive an initial grant of €10 million over four years. Impaired movement is often a sign of impaired communication between different motor networks in the brain. These ‘motor network disturbances’, which can occur after stroke or brain trauma and in patients with neurodegenerative diseases, can cause severe disruption to everyday life. Neuromodulation offers new treatment options. Using both invasive and non-invasive electrical or magnetic stimulation to influence neuronal network activity, this method is capable of restoring normal brain function. A technique known as deep brain stimulation (DBS), which uses a pacemaker-like device to stimulate the brain, has been used with great success in patients with Parkinson’s disease, dystonia, tremors and other movement disorders. Until now, however, these successes have not been replicated in many other brain disorders. The aim of the new SFB/Transregio – TRR 295 ‘RETUNE’ – is to find potential neuromodulation targets and identify disease-specific changes for a range of neurological disorders. This collaborative project will see international experts from both basic and clinical research at Charité and the University Hospital of Würzburg work alongside colleagues from the Hebrew University of Jerusalem, Heinrich Heine University Düsseldorf, the Max Planck Institute for Human Cognitive and Brain Sciences in Leipzig, the University of Potsdam, and the University of Rostock. “It is our vision to develop neuromodulation methods for use in clinical practice, which can be used in a network-specific manner to treat complex clinical syndromes,” says Prof. Dr. Andrea Kühn, the project’s spokesperson and Head of the Movement Disorders and Neuromodulation Unit at Charité’s Department of Neurology with Experimental Neurology. She adds: “We want to use minimally invasive techniques to selectively target specific network nodes in the brain to suppress altered brain activity.” The planned research will focus on the development of demand-driven pacemaker systems, which are only to be activated when symptoms occur. In order to selectively target disturbances, the researchers plan to decode the characteristic brain signals associated with both normal and impaired movements. They will also study fundamental mechanisms of brain stimulation using models of movement disorders. Clinical and experimental findings will then be used to develop computer models which will be able to predict person-specific, optimized stimulation algorithms. This research will contribute to an improved understanding of the complex symptoms of various movement disorders and help researchers to develop specific treatments. “Thanks to the coordinated collaboration between internationally renowned experts from basic science, digital medicine and clinical practice – with the aim of rapidly translating research findings into improved treatments – this collaborative undertaking is truly unique,” explains Prof. Dr. Jens Volkmann, Head of the University of Würzburg’s Department of Neurology and co-initiator of the new Transregional Collaborative Research Center (SFB/Transregio). The sites involved in the project will also establish structures needed to support early career researchers.

A joint press release by Charité – Universitätsmedizin Berlin, Universitätsmedizin Mainz and Verband der Universitätsklinika Deutschlands e.V. Charité – Universitätsmedizin Berlin and Universitätsmedizin Mainz will act as joint hosts for the launch of this year’s Healthcare Hackathon on 18 May 2020. Due to the current situation, the launch of the 2020 season of interactive events will be held almost exclusively online. Aimed specifically at university hospitals, the Hackathon will bring together experts from all over Germany. The objective is to work together to address challenges created by the current pandemic and develop digital solutions for implementation in all relevant hospitals. The Hackathon is one of the first projects realized under the auspices of the new German academic research network. The kick-off event will be opened by video message from both Anja Karliczek, the Federal Minister of Education and Research, and Jens Spahn, the Federal Minister of Health. The Healthcare Hackathon is dedicated to endeavors in the fields of digital care, artificial intelligence, quantum computing, chatbot systems, emergency medicine and prevention, as well as the development of apps for use by patients and physicians. This year’s event has one additional focus: Projects which support efforts pertaining to the COVID-19 pandemic. Participants from 23 university hospitals will use the agile Healthcare Hackathon format to meet online to develop a concept for pooling multiple locally developed digital solutions. The event is supported by co-organizer Verband der Universitätsklinika Deutschland e.V. (VUD) - the association representing German university hospitals. The VUD sees the event’s online format as a chance for participants to join forces to develop digital solutions for subsequent cross-site implementation. The current crisis has certainly demonstrated how many areas of Germany have benefited from the use of fully developed digital solutions, and how these can help address crisis-related challenges quickly and flexibly. “Whether these involve smart information systems for patients and staff or enable the app-based collection of important research data, a fully developed digital strategy and a network of connected hospitals could help alleviate local pressures and play an important role in medical care delivery. Data collection, apps and networking represent important building blocks of the academic research network for which Charité acts as coordinator,” says Charité’s Chief Executive Officer, Prof. Dr. Heyo K. Kroemer. He adds: “I am delighted that this project has been able to attract experts from so many university hospitals.” As part of the Berlin Hackathon’s kick-off event, participants will have the opportunity to choose five different sessions dedicated to COVID-19-related apps and data collection strategies . Participants will also be provided with essential information on the next two Hackathon events in Kiel and Mainz. The Healthcare Hackathon is of interest to physicians, developers and clinical staff, providing an opportunity to critically review and optimize long-standing and often outdated processes. “The implementation of an overarching digital network which connects different hospitals is of particular importance during a crisis,” says PD Dr. Christian Elsner, Business Director of Universitätsmedizin Mainz. Summing up his conclusions, he says: “Each and every hospital stands to benefit if different institutions wave goodbye to isolated digital solutions in favor of digital collaboration.” The Healthcare Hackathon, which will be based at Charité, will take place on 18 May 2020, between 10 AM and 4 PM. The event is open to university hospitals and interested parties from other sectors. For further information and to register for the event: www.healthcare-hackathon.info/hh-berlin.

According to a study by Charité – Universitätsmedizin Berlin, the northern Italian city of Nembro recorded more deaths during March 2020 than between January and December 2019. However, only approximately half of all deaths recorded this spring were classified as confirmed COVID-19 deaths. The study shows that the health impacts of the COVID-19 pandemic may go far beyond official COVID-19 death counts. It also shows the important role of all-cause mortality in quantifying the full impact of the pandemic. The study’s findings have been published in The BMJ*. During the current pandemic, the northern Italian region of Lombardy has been one of the most severely affected areas in Europe. Despite high death counts officially attributed to COVID-19 during the worst part of the pandemic, doubts were soon raised over the accuracy of these data. Official figures did not appear to reflect actual, observable pressures on the health care system. This was also the case in Nembro, a small town in the Bergamo province of Lombardy, which has a population of 11,500. In order to quantify the true impact of the pandemic on the local health care system, a team of researchers led by Tobias Kurth, MD, ScD, Director of Charité’s Institute of Public Health (IPH), studied overall mortality figures, looking at all deaths regardless of their cause. Working alongside colleagues from the Centro Medico Santagostino in Milan, the researchers found the following: During the height of the pandemic in the spring of 2020, the number of all-cause deaths was approximately double that of confirmed COVID-19-related deaths. In order to accurately quantify mortality rate regardless of cause of death – known as all-cause mortality – the researchers used data for the period between January 2012 and mid-April 2020. They obtained data from several sources: the Italian National Institute of Statistics (ISTAT), Nembro’s registration office, and the Lombardy region COVID-19 dashboard. “Nembro is a small town with a very stable population and very little immigration and emigration over time,” explains Prof. Kurth. He adds: “Given its size and the availability of quality data sources, this town provided the ideal conditions for a robust, descriptive epidemiological study to quantify the impact of the current COVID-19 pandemic as well as its impact on the health of this local community.” According to the researchers’ analyses, in recent years the town typically recorded all-cause death counts just over 100 per year. In 2018 and 2019, for instance, the town recorded 128 and 121 deaths, respectively. This contrasts sharply with the 194 deaths seen during the three-and-a-half-month period between 1 January 2020 and 11 April 2020; of these, 151 occurred in March 2020 alone. This corresponds to a monthly all-cause mortality of 154 deaths per 1,000 person years for March 2020, nearly eleven times the rate recorded for the same month of the previous year (14 deaths per 1,000 person years). The largest increase in mortality recorded during the pandemic was seen among people aged 65 and over, with men disproportionately affected. 14 deaths involved people younger than 65. “In the light of Nembro’s otherwise extremely stable all-cause mortality figures, the massive increase in mortality seen during March 2020 can only be interpreted as a consequence of the coronavirus pandemic”, says the study’s first author, Marco Piccininni, who is a researcher at the IPH. Out of a total of 166 deaths recorded during the pandemic (late February to early April 2020), only 85 had tested positive and were subsequently recorded as deaths from COVID-19. “This represents an enormous discrepancy and shows that the pandemic’s impact on the health of the population was significantly more pronounced than the official COVID-19 death count would suggest,” explains Piccininni. The study’s authors believe there are two main reasons for this discrepancy. Firstly, it is likely that not all infected people were identified as such. This is probably attributable to a shortage of materials needed for testing and the fact that not all suspected cases were tested. Secondly, this could be due to people with non-COVID-related conditions having impaired access to health care, either because health system capacities had been exhausted by COVID-19 cases or because of individuals’ reluctance to visit the hospital for fear of infection. “If we are to accurately quantify the health impact of the pandemic, we must not rely on confirmed COVID-19 deaths as the sole metric,” emphasizes Prof. Kurth. “To better adapt containment measures to the local situation, consideration should also be given to current data on all-cause mortality from within the relevant region. Unfortunately, it is not always possible to access up-to-date all-cause mortality data. I am pleased that Germany has recently started to make preliminary figures available.”

Working alongside colleagues in Mainz, Bern, Hannover and Bonn, researchers from Charité – Universitätsmedizin Berlin, the Berlin Institute of Health (BIH) and the German Rheumatism Research Center Berlin (DRFZ) were able to show how the microbiome helps to render the immune system capable of responding to pathogens. If absent, relevant mediators are not released, resulting in a failure to activate metabolic processes in certain immune cells. According to the researchers’ report, which has been published in Cell*, this leaves the relevant cells without the necessary fuel to mount an immune response. Residing in environmental interfaces, the body’s epithelial tissues represent potential gateways for pathogens. These tissues are also naturally colonized by a complex community of bacteria, viruses, fungi and parasites, and this is known as the microbiome. It is likely that, during the course of evolution, permanent interactions with these microorganisms resulted in the development of robust signaling pathways which help to protect the body. A team of researchers led by Prof. Dr. Andreas Diefenbach, Director of Charité’s Institute of Microbiology, Infectious Diseases and Immunology, have been studying the microbiome’s role in the body’s immune response against harmful pathogens and the resulting effects on signaling pathways. Presence of an infection triggers the body’s immune response. A key role in this process is played by ‘conventional dendritic cells’ (cDCs). These form part of the body’s innate immune system and carry a range of pattern recognition receptors, which enable them to quickly detect invading pathogens. The cells’ initial response involves the release of cytokines, signaling proteins which attract immune cells to the site of infection. At the same time, these cells also use phagocytosis to engulf and digest invasive pathogens, after which they present individual particles as antigens on their cell surface.This, in turn, leads to the activation of T cells (which form part of the adaptive immune system) and results in a targeted immune response. In contrast, when T cell activation is triggered by cDCs presenting endogenous antigens, this leads to a faulty and undesirable immune response and results in autoimmune diseases. The team of researchers led by Prof. Diefenbach found that cDCs are incapable of triggering immune responses in sterile conditions (i.e., in germ-free mice). The researchers concluded that cDCs must receive information while the cell is in its ‘basal state’ (which is characterized by the absence of infection) and that this information must derive from the microbiome. These microbiome-derived signals prime cDCs for a future response against pathogens. “We want to understand the nature of the microbiome’s continuous effects on cDC function,” says Prof. Diefenbach, who also holds an Einstein Professorship in Microbiology and leads the DRFZ’s Mucosal Immunology Research Group. “In this study, we were able to show that, in their basal state, these specialist immune cells are subject to the uninterrupted microbiome-controlled signaling of type I interferons (IFN-I).” Interferons are cytokines, i.e. special signaling molecules which are known to play a role in antiviral activity. “Until now, we had known only little about the role of IFN-I in the basal state. cDCs, which do not receive this IFN-I signaling during the basal state, cannot fulfill the physiological functions which they perform as part of the body’s fight against pathogens,” explains the microbiologist. Study results suggest that the microbiome controls our immune system's fitness. It exerts this control by bringing the immune system to a state of ‘readiness’ in order to speed up its response to pathogens. The researchers used various animal models in order to gain insight into the manner in which the microbiome-controlled IFN-I primes basal-state cDCs for future combat. Using sequencing technology, the researchers were able to compare the epigenomes and transcriptomes of cDCs from germ-free animals with those of control animals and animals deficient in IFN-I receptors. The researchers wanted to know what happens at the molecular level in cDCs when they are no longer exposed to IFN-I. Describing the researchers’ observations, the study’s first author, Laura Schaupp, says: “Interestingly, when we looked at cDCs from germ-free animals and those without IFN-I signaling, we were able to observe low levels of expression among genes involved in the mitochondrial respiratory chain.” The Charité researcher adds: “Further analyses revealed that the cellular metabolism of cDCs from germ-free animals is dysfunctional, making them unable to initiate an immune response. The cells effectively lack the fuel needed to respond to pathogens.” This suggests that the microbiome is of crucial importance to the functioning of cDCs. It appears essential to the ability of cDCs to mount an effective response to bacterial or viral infections, including responses mediated by T cells. The researchers’ findings may contribute to the development of new therapeutic approaches. Many autoimmune diseases, such as systemic lupus erythematosus, are caused by an increased production of IFN-I. Other studies have shown that the microbiome influences the effectiveness of checkpoint inhibitors in cancer immunotherapies. “These phenomena will continue to be of great interest to us,” says Prof. Diefenbach. “For instance, is it possible to change the composition of the microbiome in such a way as to reduce the availability of IFN-I, thereby exerting a positive influence on autoimmune diseases? Or might it be possible to improve responses to cancer immunotherapies by exerting a positive influence on the underlying IFN-I production?” The team of researchers now plan to conduct further studies which will explore these questions.

A joint press release by Charité – Universitätsmedizin Berlin, Berlin Institute of Health and the German Center for Lung Research Working alongside research groups from Heidelberg, researchers from Charité – Universitätsmedizin Berlin have elucidated the novel disease processes involved in the development of pulmonary fibrosis. They were able to show that the protein known as NEDD4-2 plays a key role in lung health and that loss of this crucial regulatory molecule has a significant impact on various mechanisms involved in the development of chronic progressive lung disease. These new insights make it easier to further investigate the precise mechanisms involved in the development and progression of pulmonary fibrosis. The researchers’ findings, which have been published in Nature Communications*, will enable researchers to develop new therapeutic approaches. Pulmonary fibrosis is a serious lung disease which mainly affects older people; there are virtually no effective treatments. The disease is characterized by progressive tissue changes which lead to scarring of the lung. However, its causes are largely unknown, and the cellular mechanisms involved in its development remain poorly understood. The term ‘mucociliary clearance’ refers to a self-cleaning mechanism which relies on ciliated cells in the lung epithelium propelling inhaled pathogens and other particles trapped in mucus out of the airways. We know that changes in the epithelium are associated with the production of excess mucus. They are also associated with the impaired clearance of this mucus and its primary structural components (known as ‘mucins’). NEDD4-2 is involved in the degradation of a range of other proteins which in turn are responsible for using these processes to regulate lung epithelial function. This means NEDD4-2 is a key protein with a central role in the pathogenesis of pulmonary fibrosis. Working alongside colleagues from the German Center for Lung Research (DZL), Heidelberg University Hospital and the German Cancer Research Center, the team of researchers led by Prof. Dr. Marcus Mall (Director of Charité’s Department of Pediatric Pulmonology, Immunology and Critical Medicine as well as Einstein and Berlin Institute of Health [BIH] Professor) succeeded in developing a novel animal model of idiopathic pulmonary fibrosis (IPF). As NEDD4-2 is crucial for early development, the researchers only deleted the relevant encoding gene in lung epithelial cells once the animals had reached adulthood. The researchers examined the animals once they had reached a stage roughly comparable to the point at which the disease would be diagnosed in a human patient. Oxygen saturation measurements taken at that stage revealed a level of lung function impairment which is characteristic of the disease. Using tissue sections and CT imaging to examine the lungs, the researchers also found evidence of patchy scarring, a type of structural abnormality which is indicative of fibrosis. The researchers found further evidence of the significance of NEDD4-2 in the pathogenesis of IPF: lung tissue biopsy samples of patients with IPF contained significantly reduced levels of both transcripts and proteins. Using mass spectrometry, the researchers then performed what is known as ‘protein profiling’, an analysis of the complete set of proteins produced in the lungs. This revealed a high degree of overlap between the proteins found to be expressed differently in the lungs of patients with IPF and in the animals used in this study. “Our findings can help researchers to further investigate the pathogenesis and progression of this lung disease and develop new treatments. This model could prove useful for the preclinical testing of compounds with therapeutic potential, or to develop markers for the early detection of the disease,” says Prof. Mall. When studying the underlying disease mechanisms, the researchers discovered that reduced levels of NEDD4-2 in epithelial cells result in epithelial remodeling in the airways. Not only are the different cell types present in different proportions, the cells also produce increased amounts of certain mucins. When combined with changes in epithelial sodium transport and the resultant reduction in the volume of airway surface liquid, this will lead to impaired mucociliary clearance. Lack of NEDD4-2 also causes increased activity of the TGFβ signaling pathway, which promotes the formation of fibrosis. Summing up the findings of the study, the study's first author, Dr. Julia Dürr, says: “This means we were able to establish that a lack of NEDD4-2 is directly linked with mucociliary clearance dysfunction and the dysregulation of the TGFβ signaling pathway. According to current state of knowledge, both of these play a role in the pathogenesis of IPF.” Anti-fibrotic drugs have been used to treat pulmonary fibrosis for some years. While these drugs usually succeed in slowing the development of scarring, they cannot wholly replace lung transplants as a last resort treatment option. “Using our model and an already licensed anti-fibrotic agent, we were able to confirm that this type of treatment can slow disease progression but does not constitute a curative treatment.” By way of explanation, Prof. Mall adds: “We hope that, by providing an improved preclinical testing model, we can help speed up the development of new therapeutic options.” As a next step, the researchers plan to test predictive biomarkers which might aid in early diagnosis. They also plan to test the effectiveness of potential new drugs which could be used to treat pulmonary fibrosis.

Prof. Dr. Christian Drosten, Director of Charité’s Institute of Virology, has been awarded the ‘Special Award for Outstanding Achievements in Scientific Communication during the COVID-19 Pandemic’. Presented by the German Research Foundation (DFG) and ‘Stifterverband’ (Donor’s Association), the award carries a prize of €50,000. The prize, which recognizes Prof. Drosten's outstanding achievements in the field of science and in the promotion of the public understanding of science, was awarded by the DFG and Stifterverband. Commenting on their decision, the awarding committee emphasized the significance of Prof. Drosten’s unique position as an advocate for science and the role it must play during the COVID-19 pandemic. More than any other scientist, Prof. Drosten has succeeded in convincing the public of the need to accept science as the most reliable means of navigating the current crisis. His highly accessible, transparent and fact-based approach has enabled Prof. Drosten to explain the state of current scientific knowledge, elucidate how various scientific processes work and outline areas where uncertainty remains. Prof. Drosten has also actively countered the emergence of hypotheses not based in evidence, confronted the limits of his own knowledge, and repeatedly emphasized that science requires us to constantly question what we do and do not know, and to revise what we previously held to be certain. This approach has enabled the winner of this Special Award to gain widespread acceptance and trust, including in the field of politics, where he is currently one of the most important advisers. According to the DFG and Stifterverband, Prof. Drosten’s communications provide an outstanding example of the potential role of science in shaping politics and society, including during a crisis. In addition to his role as Director of the Institute of Virology on Campus Charité Mitte, Prof. Drosten also holds a Professorship at the Berlin Institute of Health (BIH) and conducts research at the German Center for Infection Research (DZIF). Expressing his delight at the award, he says: “This pandemic represents a set of highly exceptional circumstances for our country. Our ability to meet the challenges involved will, in my view, depend on how well the public is informed about the state of the outbreak and the biological mechanisms underpinning it. It is therefore of particular importance to me that the current state of knowledge regarding the SARS-2 virus – including areas where uncertainty remains – should be communicated to the public as promptly and as comprehensively as possible. Only by doing so will people feel enabled to make up their own minds, to overcome their fears, and to make decisions in their daily lives which will have an impact on the spread of the infection.” Prof. Dr. Heyo K. Kroemer, Charité’s Chief Executive Officer, says: “Charité is delighted that Prof. Drosten’s achievements in scientific communication should be formally recognized. His characteristically proactive approach to the communication of knowledge involves an enormous amount of additional effort on the part of the scientist and should not be underestimated. The Award also reaffirms that, in addition to its role in treating patients with COVID-19 and conducting research into the novel coronavirus, Charité also plays a major role in public information.” Created as a one-time award by the DFG and Stifterverband, the Special Award will not replace but complement the 2020 Communicator Prize.

For the first time, researchers from Charité – Universitätsmedizin Berlin have shown that a unicellular parasite commonly found in the mouth plays a role in both severe tissue inflammation and tissue destruction. Most patients with severe and recurrent periodontitis (gum disease) showed an increased presence of the amoeba Entamoeba gingivalis inside their oral cavities. The effect of this amoeba is similar to that of Entamoeba histolytica, the parasite responsible for causing amebiasis. Once the parasite has invaded the gingival tissue, it feeds on its cells and causes tissue destruction. According to the researchers’ findings, which have been published in the Journal of Dental Research*, the two amoebae show similar mechanisms of tissue invasion and elicit a similar immune response in the host. Periodontitis, or gum disease, is an inflammation of the gums and supporting structures of the teeth. It is one of the most common chronic diseases in the world. In Germany, approximately 15 percent of people are affected by a particularly severe form of this disease. If left untreated, periodontitis will lead to tooth loss. The disease also increases the risk of arthritis, cardiovascular disease and cancer. In patients with periodontitis, a decrease in the diversity of the oral flora coincides with an increase in the frequency of E. gingivalis. A team of researchers, led by Prof. Dr. Arne Schäfer, Head of the Periodontology Research Unit at Charité’s Institute of Dental and Craniofacial Sciences, was able to show that oral inflammation is associated with colonization by the oral parasite E. gingivalis. Scientists have long been aware of the virulence potential of this genus of amoebae. The gastrointestinal parasite E. histolytica, for instance, causes a disease known as amebiasis, one of the most common causes of death from parasitic diseases worldwide. “We have shown that an amoeba like E. gingivalis, which colonizes the oral cavity, will invade the oral mucosa and destroy gingival tissue. This enables increased numbers of bacteria to invade the host tissue, which further exacerbates inflammation and tissue destruction,” says Prof. Schäfer. The international team of researchers was the first to describe precise roles of E. gingivalis in the pathogenesis of inflammation. During their analysis of inflamed periodontal pockets, the researchers detected evidence of the amoeba in approximately 80 percent of patients with periodontitis, but in only 15 percent of healthy subjects. Their observations revealed that, after invading the gums, the parasites move within the tissue, feeding on and killing host cells. Cell culture experiments showed that infection with E. gingivalis slows the rate at which cells grow, eventually leading to cell death. The researchers concluded that the amoeba’s role in inflammation shows distinct parallels to the pathogenesis of amebiasis. “E. gingivalis actively contributes to cell destruction inside the gingival tissue and stimulates the same host immune response mechanisms as E. histolytica during its invasion of the intestinal mucosa,” explains Prof. Schäfer. “This parasite, which is transmitted by simple droplet infection, is one potential cause of severe oral inflammation.” Treatment success is often short-lived in patients with periodontitis. This might be due to the high virulence potential of this previously unnoticed, yet extremely common amoeba. Summing up the results of the research, Prof. Schäfer says: “We identified one infectious parasite whose elimination could improve treatment effectiveness and long-term outcomes in patients with gum disease.” He adds: “Current treatment concepts for periodontitis fail to consider the possibility of infection by this parasite or its successful elimination.” A clinical trial is underway to determine the extent to which the elimination of this amoeba might improve treatment outcomes in patients with periodontitis.

A joint press release by Charité and the MDC A new diagnostic test to quickly and easily monitor kidney transplant patients for infection and rejection relies on a simple urine sample and a powerful partner: the gene-editing technology CRISPR. This was shown by Dr. Michael Kaminski, who leads a new Emmy-Noether Independent Juniour Research Group at Charité – Universitätsmedizin Berlin and the Max Delbrueck Center for Molecular Medicine in the Helmholtz Association (MDC). The study has been published in the journal Nature Biomedical Engineering*. The new test screens for two common viruses infecting kidney transplant patients, cytomegalovirus (CMV) and BK polyomavirus (BKV), and CXCL9 mRNA, whose expression increases during acute cellular kidney transplant rejection. “Most people think of gene editing when they think of CRISPR, but this tool has great potential for other applications, especially cheaper and faster diagnostics,” said Dr. Kaminski, who heads the Kidney Cell Engineering and CRISPR Diagnostics Lab at the MDC and Charité. He spearheaded the test’s development while at the lab of Prof. Dr. James Collins at the Massachusetts Institute of Technology (MIT). Since 2020 Kaminski, who is a medical doctor at Charité’s Medical Department, Division of Nephrology and Internal Intensive Care Medicine, started a new lab at the Berlin Institute for Medical Systems Biology (BIMSB) from MDC. Kidney transplant patients are on medications suppressing their immune systems to reduce the chance the organ will be rejected. But this increases their risk of getting sick from infections. Closely monitoring patients for both infection and rejection is critical and guides the delicate balance of care. Usually this is done via blood tests and kidney biopsies, which are time-consuming, more invasive and expensive. While affordable urine-based diagnostic tests are available for a variety of biomarkers, from diabetes to pregnancy, they have not been widely adapted for nucleic acids, such as DNA or RNA. That’s where CRISPR comes in. CRISPR technology is able to find very small segments of a DNA or RNA sequence guided by a complimentary piece of RNA. It works in tandem with certain types of Cas proteins, which cut the target sequence, as well as a fluorescent reporter molecule. This so-called collateral cleavage releases fluorescence, indicating presence of a target. Many labs have been investigating CRISPR’s diagnostic potential on synthetic material, but few have tested real clinical samples. “The challenge is getting down to concentrations that are clinically meaningful,” Dr. Kaminski said. “It really makes a huge difference if you are aiming for a ton of synthetic target in your test tube, versus if you want to get to the single molecule level in a patient fluid.” The test kit, formally called an assay, uses a two-step process. First, viral target DNA in a urine sample must be amplified – copied enough times so CRISPR can detect it even if there is just one target molecule present. The team used a specific CRISPR-Cas13 protocol known as SHERLOCK to optimize the process for viral DNA. The results are conveyed much like a home pregnancy test. When a paper strip is dipped in the prepared sample, if only one line appears on the strip, the result is negative, while two lines indicates a virus is present. “It’s exciting to see the results appear on the test strips,” said Robert Greensmith, a PhD student in Dr. Kaminiski’s Lab and paper co-author. The researchers used a similar process for the rejection marker CXCL9. There, mRNA was isolated and amplified, followed by CRISPR-Cas13 mediated target detection. For very low target concentrations, often a pale second line appears on the test strip, which could cause confusion. So, the team developed a smartphone app that unbiasedly analyzes pictures of the test strip and renders the final call based on the line’s intensity. After a lot of work to optimize the technique, the researchers used their assay to analyze more than 100 samples from kidney transplant patients. The assay was very accurate even with low levels of BKV or CMV infection, and correctly detected signs of acute cellular transplant rejection. Dr. Kaminski is interested in larger clinical studies comparing the assay to conventional monitoring methods. He would also like to investigate ways to make the test even more streamlined. Right now, the test requires multiple steps. While it could be used in a hospital setting, it’s not quite ready for at-home testing. The ultimate goal is a one-step process that can quantitatively measure multiple parameters. That way, patients can measure specific changes against their individual baselines.

Skin rash combined with head and joint pain: these are the symptoms which patients with familial (hereditary) cold urticaria develop when exposed to temperatures below 15 °C. Researchers from Charité – Universitätsmedizin Berlin have discovered a new, previously unknown form of this inflammatory skin disorder. In addition to explaining why conventional treatments are ineffective in some people with the disorder, their findings also point to potential alternatives. The results of this research have been published in Nature Communications*. When exposure to cold temperatures causes itchy hives to appear on the skin, this is referred to as cold urticaria. In many people, this disorder will develop suddenly, but gradually lessen and disappear again after a number of years. Why it appears at all remains unknown. A small proportion of sufferers inherit the disorder from their parents. In these people, the immune system response to cold temperatures is due to a genetic defect which, in addition to a skin rash, will cause signs of systemic inflammation, including fever and joint pain. Researchers led by PD Dr. Karoline Krause of the Department of Dermatology, Venereology and Allergology on Campus Charité Mitte have now discovered a new form of cold urticaria which is caused by a previously unknown mutation in the ‘Factor 12’ gene. The name proposed for this new hereditary disorder is ‘Factor XII-associated cold autoinflammatory syndrome’, or FACAS. “Our report relates to several members of the same family seen in our department. At least one person in each generation of this family reported identical symptoms, which they had suffered from birth,” explains PD Dr. Krause. She adds: “These individuals all developed a burning skin rash after 30 minutes of exposure to temperatures below 15°C (59°F). The rash was exacerbated by windy weather and humid conditions, and only resolved several hours after the individual returned to a warmer room.” The patients also reported other symptoms like chills, fatigue, headache and joint pain. In contrast to people who develop cold urticaria spontaneously, these patients did not respond to a cold provocation test known as the ‘ice cube test’. Their symptoms also failed to respond to antihistamines, which are normally an effective treatment for cold urticaria. “The family's symptoms were clearly indicative of a hereditary form of cold urticaria,” says the dermatologist. “We therefore studied the affected individual’s genetic information, looking for mutations which are known to cause the disorder's hereditary form; but to no avail. What we found instead was a previously unknown defect in the Factor 12 gene.” The researchers were then able to show that this defect leads to the activation of the contact system pathway, and that the hives are produced as a result of the subsequent release of inflammatory mediators. “Interestingly, defects in the Factor 12 gene had previously been known to cause a very different condition which we refer to as hereditary angioedema,” explains PD Dr. Krause. Hereditary angioedema is characterized by sudden attacks of severe and painful swelling in the deeper tissues. “While the symptoms reported by FACAS patients are those of hereditary cold urticaria, the underlying mechanisms causing these symptoms are entirely different. These patients therefore qualify for treatment with drugs normally used in hereditary angioedema.” Interestingly, one of the FACAS patients showed an immediate response when given icatibant, a drug normally used to treat acute attacks of hereditary angioedema. Upon administration, the patient's cold-induced symptoms resolved quickly and almost completely. The study's findings could help researchers discover the causes of currently unexplained cases: people with hereditary cold urticaria of unknown origin, in whom conventional drugs such as antihistamines are ineffective, can undergo genetic testing for FACAS. “We also plan to conduct a small clinical study in order to test whether lanadelumab can provide long-term relief in our group of adult FACAS patients,” explains the study’s lead investigator. Lanadelumab is a type of antibody which is primarily used as a preventive long-term treatment in hereditary angioedema.

Charité – Universitätsmedizin Berlin has today unveiled its new intensive care building for patients with COVID-19. The now repurposed Charité Campus-Klinik (CCK) will offer 135 intensive care beds, all of which are equipped with ventilators. Michael Müller, Governing Mayor of Berlin and Chair of Charité’s Supervisory Board, visited the building to find out what is being done to prepare for the expected increase in COVID-19 patients. Charité’s step-by-step increase in intensive care capacity at the CCK guarantees the strict physical segregation of infected and non-infected patients. It also ensures that Charité will be able to meet the needs of COVID-19 patients even once case numbers start to increase. Thanks to the CCK beds, Charité’s overall capacity of intensive care beds will be increased from 364 today to 499. From the very beginning, Charité has been committed to actively containing the current pandemic. In early March, Charité launched Berlin’s first coronavirus examination unit on Campus Virchow-Klinikum. Intended to inspire others to follow suit, the unit has since welcomed a total of 120 to 150 persons a day. In addition to providing specialist advice, the unit also triages for testing in accordance with official selection criteria. The unit is complemented by Charité’s CovApp and its coronavirus video consultation service. Charité also launched further examination units on its three clinical campuses for use by members of staff. Michael Müller, Governing Mayor of Berlin and Chair of Charité’s Supervisory Board, explains: “I was very impressed today by how quickly and professionally Charité has been able to ramp up its capacities for coronavirus patients. Charité responded promptly and effectively. All of the technology and equipment needed for the treatment and ventilation of critical coronavirus patients is here and ready. I am immensely grateful to the entire team at Charité, including those working in the background, for making this possible.” “One important role Charité has taken on is that of Berlin-wide coordinator for the allocation of intensive care beds using the ‘SAVE’ concept. As part of this initiative, we are also involved in the remote care of intensive care patients at other hospitals,” says Prof. Dr. Heyo K. Kroemer, Charité Chief Executive Officer. This telemedicine-based intervention replicates the concept of the Innovation Fund-funded ERIC (Enhanced Recovery after Intensive Care) project. Prof. Dr. Ulrich Frei, Charité’s Chief Medical Officer, adds: “Medically speaking, the treatment of critically ill and ventilated COVID-19 patients is complex and challenging. This remote care concept enables our intensive care physicians and specialist nursing staff to use telemedicine-based solutions to support and provide expert consultations to other hospitals.” Efforts are currently underway to expand the existing network of eleven hospitals within the Berlin-Brandenburg region. This will give a total of 30 hospitals access to this network and Charité’s services.

A joint press release by Freie Universität Berlin, Humboldt-Universität zu Berlin, Technische Universität Berlin and Charité – Universitätsmedizin Berlin A new Berlin-based collaborative research project is laying the foundations for comprehensive research into the novel coronavirus, SARS-CoV-2. Funded by the Berlin University Alliance, the project entitled ‘Coronavirus Pre-Exploration Project’ will receive €1.8 million over one year. The project will see researchers from Freie Universität Berlin, Humboldt-Universität zu Berlin, Technische Universität Berlin and Charité – Universitätsmedizin Berlin work together to test drugs, develop potential vaccines and explore health economics consequences which might arise from the current crisis. The ‘pre-exploration project’ will serve as a pilot project for the Berlin University Alliance competition this summer, which will invite proposals pertaining to the area of ‘global health’. The Berlin University Alliance is committed to addressing some of the big challenges of our globalized world. The current crisis represents a clear mandate for action from the outstanding research alliance which comprises Berlin's three big universities and Charité. Country-specific responses aimed at containing the spread of SARS-CoV-2 have resulted in major restrictions on public life and have created significant challenges for the affected countries’ economies and health care systems. Researchers from the Berlin University Alliance's member institutions will be working with colleagues from the Leibniz Institute for Molecular Pharmacology (FMP) and the Robert Koch Institute to develop tools for the long-term control and prevention of the infection caused by SARS-CoV-2. The project is divided into six subject areas, which will be addressed separately by small teams of researchers. The teams will focus on the synthesis and testing of antiviral therapy options for the treatment and prevention of the infection, the use of two- and three-dimensional human tissue models, and the use of animal and surrogate models of SARS-CoV-2 infection. Research will also focus on: the development of long-lasting vaccines; the study of disease course, disease stages and ‘predictive markers’; and the modeling of the spread and consequences of the SARS-CoV-2 pandemic. “The aim is to use this preliminary collaborative work to submit another joint project proposal after one year, and to secure public and private funding for the implementation of the most promising options. This approach will provide ongoing support for research into what is a health topic of global significance,” says Prof. Dr. Rainer Haag, Project Lead at Freie Universität Berlin. The pilot phase of the research – the ‘Coronavirus Pre-Exploration Project’ – will be funded as part of the Berlin University Alliance’s Grand Challenge Initiative. One of the overarching aims of the Alliance’s member institutions is to tackle the big global challenges (Grand Challenges) through a collaborative approach. The Berlin Alliance has dedicated the initial stage of this initiative to the issue of ‘Social Cohesion’. The current project forms part of the second Grand Challenge – ‘Global Health’ – which will be launched in the summer. The project is led by Prof. Dr. Rainer Haag (Freie Universität Berlin), Prof. Dr. Christian Hackenberger (Humboldt-Universität zu Berlin and Leibniz Institute for Molecular Pharmacology), Prof. Dr. Jens Kurreck (Technische Universität Berlin) and Prof. Dr. Christian Drosten (Charité – Universitätsmedizin Berlin).

A joint press release by Charité, München Klinik Schwabing and the Bundeswehr Institute of Microbiology In early February, research teams from Charité – Universitätsmedizin Berlin, München Klinik Schwabing and the Bundeswehr Institute of Microbiology published initial findings describing the efficient transmission of SARS-CoV-2. The researchers’ detailed report on the clinical course and treatment of Germany’s first group of COVID-19 patients has now been published in Nature*. Based on these findings, criteria may now be developed to determine the earliest point at which COVID-19 patients treated in hospitals with limited bed capacity can be safely discharged. In late January, a group of patients in the Starnberg area near Munich became Germany’s first group of epidemiologically linked cases of COVID-19. Nine patients from this ‘Munich cluster’ subsequently received treatment at München Klinik Schwabing. “At that point time, we really knew very little about the novel coronavirus which we now refer to as SARS-CoV-2,” says one of the study’s lead authors, Prof. Dr. Christian Drosten, Director of the Institute of Virology on Campus Charité Mitte. He adds: “Our decision to study these nine cases very closely throughout the course of their illness resulted in the discovery of many important details about this new virus.” “The patients treated at our hospital were all young to middle-aged. Their symptoms were generally mild and included flu-like symptoms like cough, fever and a loss of taste and smell,” explains the other lead author, Prof. Dr. Clemens Wendtner, Head of the Department of Infectious Diseases and Tropical Medicine at München Klinik Schwabing, a teaching hospital of LMU Munich. “In terms of scientific significance, our study benefited from the fact that all of the cases were linked to an index case, meaning they were not simply studied based on the presence of certain symptoms. In addition to getting a good picture of how this virus behaves, this also enabled us to gain other important insights, including on viral transmission.” All nine patients underwent daily testing using both nasopharyngeal (nose and throat) swabs and sputum samples. Testing continued throughout the course of their illness and up to 28 days after the initial onset of symptoms. The researchers also collected stool, blood and urine samples whenever possible or practical. All of the samples collected were then tested for SARS-CoV-2 by two separate laboratories working independently of each other: the Institute of Virology on Campus Charité Mitte in Berlin and the Bundeswehr Institute of Microbiology, an institution which forms part of the German Center for Infection Research (DZIF). According to the researchers’ observations, all COVID-19 patients showed a high rate of viral replication and shedding in the throat during the first week of symptoms. Sputum samples also showed high levels of viral RNA (genetic information). Infectious viral particles were isolated from both pharyngeal (throat) swabs and sputum samples. “This means that the novel coronavirus does not have to travel to the lungs to replicate. It can replicate while still in the throat, which means it is very easy to transmit,” explains Prof. Drosten, who is also affiliated with the DZIF, and is a professor at the Berlin Institute of Health (BIH). Due to genetic similarities between the new virus and the original SARS virus, the researchers initially assumed that, just like the SARS virus, the novel coronavirus would predominantly target the lungs – thus making human-to-human transmission more difficult. “However, our research involving the Munich cluster showed that the new SARS coronavirus differs quite considerably in terms of its preferential target tissue,” says the virologist, and adds: “Naturally, this has enormous consequences for both viral transmission and spread, which is why we decided to publish our initial findings in early February.” In most cases, viral load decreased significantly during the first week of symptoms. While viral shedding in the lungs also decreased, this decline happened later than in the throat. The researchers were no longer able to obtain infectious virus particles from day 8 after the initial onset of symptoms. However, levels of viral RNA remained high in both the throat and lungs. The researchers found that samples with fewer than 100,000 copies of viral RNA no longer contained any infectious viral particles. This allowed the researchers to draw two conclusions: “A high viral load in the throat at the very onset of symptoms suggests that individuals with COVID-19 are infectious very early on, potentially before they are even aware of being ill,” explains Colonel PD Dr. Roman Wölfel, Director of the Bundeswehr Institute of Microbiology and one of the study’s first authors. “At the same time, the infectiousness of COVID-19 patients appears to be linked to viral load in the throat and lungs. In hospitals with limited bed capacity and the resultant pressure to expedite patient discharge, this is an important factor when it comes to deciding the earliest point at which a patient can be safely discharged.” Based on these data, the study’s authors suggest that COVID-19 patients with less than 100,000 viral RNA copies in their sputum sample on day 10 of symptoms could be discharged into home-based isolation. The researchers’ work also suggests that SARS-CoV-2 replicates in the gastrointestinal tract. However, the researchers were unable to isolate any infectious virus from patients’ stool samples. None of the blood and urine samples tested positive for the virus. Serum samples were also tested for antibodies against SARS-CoV-2. Half of the patients tested had developed antibodies by day 7 following symptom onset; antibodies were detected in all patients after two weeks. The onset of antibody production coincided with a gradual decrease in viral load. The Munich- and Berlin-based research groups plan to conduct additional research on the development of long-term immunity against SARS-CoV-2, both within the first German cluster and in other patients. This type of research will also play an important role in the development of vaccines.

The fifth Charité Supervisory Board was constituted last Friday. Due to the current situation, the meeting was held by video conference. Supervisory Board members provided detailed information on measures taken to combat the corona crisis and expressed their gratitude for the commitment and dedication of Charité staff. The composition of the brand new Charité Supervisory Board will remain in place for the next five years. The Board presently consists of thirteen voting and four non-voting advisory members. In his capacity as Senator for Science and Research as well as Chairman of the Supervisory Board, the Governing Mayor of Berlin, Michael Müller stressed: "The Charité’s diverse and comprehensive medical expertise means that it plays a leading role both within Berlin’s science and healthcare scene and across the whole of Germany. This is evident on a daily basis but particularly now in the midst of the current corona crisis. Only recently, the German Federal Government entrusted the Charité with the coordination of the new National Research Alliance For Combating COVID-19. This decision once again underscores the crucial national role played by the Charité. All the more reason for me to thank all members of the new Supervisory Board for their willingness to support this truly outstanding institution on its path to becoming an internationally prominent university hospital in teaching, research and healthcare. I look forward to our continued cooperation". On Friday, Supervisory Board members elected Irmtraut Gürkan, former Managing Director of Heidelberg University Hospital and an experienced expert on the German university medicine system, to the position of Deputy Chairperson of the Supervisory Board: "As the institution at the forefront of German university medicine, the Charité plays a crucial role beyond the frontiers of Berlin and indeed of Germany. This is particularly clear in the context of the current pandemic. Reports presented at the Supervisory Board meeting highlight the Charité's numerous initiatives to tackle coronavirus and the tireless commitment of its staff. This is very impressive. As members of the Supervisory Board, we wish to play our part in supporting Charité wherever we can". In its constituent meeting on Friday, the Supervisory Board passed numerous resolutions ensuring Charité's organizational structure and economic capacity will allow it to continue its work to combat coronavirus. Members of the Supervisory Board Berlin Senate Members: Michael Müller, Governing Mayor of Berlin and Senator for Science, Chairman of the Supervisory Board Dr. Matthias Kollatz, Berlin’s Senator for Financial Affairs External experts appointed by the Berlin Senate: Prof. Dr. Michael Baumann, Professor at the Dresden University of Technology, Chairman and Scientific Director of the German Cancer Research Center (DKFZ) Irmtraut Gürkan, Political Economist, most recently Hospital Business Director of Heidelberg University Hospital Prof. Dr. Denise Hilfiker-Kleiner, University Professor and Dean of Research of Hannover Medical School (MHH), Member of the German Council of Science and Humanities Prof. Dr.-Ing. Reimund Neugebauer, University Professor at the Chemnitz University of Technology, President of the Fraunhofer-Gesellschaft e. V. Stefan Oelrich, Member of The Bayer AG Board of Management and Head of the Pharmaceuticals Division, Member of the Supervisory Board of the Berlin Institute of Health (BIH) A recent change in law means that two university professors appointed by the Charité Faculty Council as well as one jointly appointed President of Freie Universität Berlin and Humboldt-Universität zu Berlin now also belong to the AR: Prof. Dr. Martin E. Kreis, Medical Director Department of General, Visceral and Vascular Surgery, Campus Benjamin Franklin Prof. Dr. Adelheid Kuhlmey, Science Director CharitéCenter Health and Human Sciences CC1, Director of the Institute of Medical Sociology and Rehabilitation Science Prof. Dr.-Ing. Sabine Kunst, President of Humboldt-Universität zu Berlin In addition, the Supervisory Board has three members who are elected by direct secret ballot by full-time Charité employees. The elected representatives are: Ulla Hedemann, Department of Pediatrics, Division of Pulmonology, Immunology and Critical Care Medicine Prof. Dr. Jörg-Wilhelm Oestmann, Department of Radiology (including Pediatric Radiology) Campus Virchow-Klinikum Dr. Paul Ritschl, Department of Surgery Campus Charité Mitte / Campus Virchow-Klinikum In addition, Charité’s Central Counsellor for Women’s Affairs and Equal Opportunities, a member of the General Staff Council, a member of Charité’s Disabled Persons' Representative Body (for the first time) as well as a member of the Faculty Council Students’ Group serve as non-voting advisory members of the Supervisory Board: Dr. Christine Kurmeyer, Women's and Equal Opportunities Commissioner at the Charité Bernd Marquardt, Chair of the Central Staff Committee Dr. Ulrike Pohling, Person of trust of the representation of severely disabled persons Raphael Raspe, Member of the Group of Students of the Faculty Council

Even during the COVID-19 pandemic, heart attack and stroke will continue to affect both men and women. Berlin records more than 12,000 strokes and approximately 10,000 heart attacks every year. Thanks to modern treatments, the past few years have seen dramatic improvements in the prognosis of patients with either heart attack or stroke. However, for patients with either of these conditions, every minute counts. Charité – Universitätsmedizin Berlin is now appealing to the citizens of Berlin to take any potential symptoms seriously and to immediately contact the emergency services by calling 112. Both conditions represent acute emergencies. This is why affected patients will continue to receive the care they need, even during the current COVID-19 pandemic. Patients with COVID-19 are treated on entirely separate wards. Since the start of the pandemic, Charité has recorded a drop in the numbers of patients with heart attack and stroke. Similar observations have been made elsewhere in Germany and in other areas of Europe. The data suggest that affected individuals are unsure as to whether a visit to the hospital is advisable in the current situation. Patients affected by these conditions tend to belong to groups of individuals considered at increased risk from COVID-19 – and will naturally be worried as a result. However, it is important to remember that patients with heart attack and stroke must receive hospital treatment without delay. Failure to seek immediate help may result in adverse consequences such as heart failure, arrhythmias and paralysis, or may even lead to death.

Charité is ramping up capacity for an expected increase in COVID-19 patients requiring intensive care. Key measures from its Pandemic Response Plan include the repurposing of individual rooms, wards, beds and outpatient areas, which will be used exclusively for patients affected by the pandemic. As part of these measures, Charité Campus-Klinik (CCK) will be gradually converted into a dedicated intensive care building with an additional 135 beds. The first ward will be ready to accept patients from tomorrow. The launch of the first 24-bed intensive care unit for COVID-19 patients on level 3 of the CCK building will be the first step in a gradual process aimed at ensuring Charité has and continues to have sufficient capacity for patients with intensive care needs. These beds will add to Charité’s existing capacity of 364 intensive care beds. All of Charité’s intensive care beds offer life-saving ventilation equipment. This additional intensive care capacity will ensure the continued and strict physical separation of infected and non-infected patients, enabling Charité to meet the needs of all intensive care patients as case numbers increase. Although the extra capacity of this new facility is not yet required, the unit will be ready to accept intensive care patients if and when this becomes necessary.

Gemeinsame Pressemitteilung der Charité – Universitätsmedizin Berlin und der Einstein Stiftung Berlin Einstein Student Support for Corona Medical Emergency Einstein Foundation launches aid program to support medical care in Berlin The Einstein Foundation Berlin has launched an aid program to fund the temporary deployment of student helpers at Charité – Universitätsmedizin Berlin. As part of its ‘Einstein Student Support for Corona Medical Emergency’ program, the Einstein Foundation will provide €300,000 to boost basic medical services. Over the next three months, this will enable Charité to pay up to 100 students a salary of €1,000 per month. The program is intended to address a predicted shortage of nursing staff which is expected as a result of the coronavirus pandemic. The Einstein Foundation hopes to use this initiative to help Charité to better meet the medical and nursing challenges ahead. By supporting students, we also wish to recognize and encourage the social commitment of our young people,” says Günter Stock, Chief Executive Officer of the Einstein Foundation. “We very much welcome this initiative. Over the coming days and weeks, a large number of patients will require treatment. During this time, both medical and nursing students will have the opportunity to make a real difference. Many of these students gained nursing experience or completed relevant training before starting their studies,” says Heyo K. Kroemer, Chief Executive Officer of Charité – Universitätsmedizin Berlin. Applications are invited from students of Charité and Alice Salomon Hochschule. The application process is simple. Interested students will need to complete the volunteer form and email this to stud-freiwillige(at)charite.de. Non-Charité students will also need to attach proof of university enrollment. Resumés/CVs, transcripts or other documents will not be required. Successful applicants will be selected and deployed based on their suitability for a particular role. Students will be able to decide the duration of their deployment and arrange their work schedules to fit around other commitments.

The novel coronavirus (SARS-CoV-2) continues to spread, including in Berlin. More and more people need to be examined and the demand for SARS-CoV-2 testing increases. Charité – Universitätsmedizin Berlin is launching its ‘CovApp’ in an effort to further improve the services provided by its dedicated Examination Unit. Charité is committed to ensuring that, even during the current dynamic situation, patients continue to receive optimal medical care. To this end, it has been working with the Potsdam-based nonprofit organization Data4Life to develop its new CovApp. The CovApp uses a questionnaire-based risk assessment, which can be completed at home. It helps the user decide whether or not they should visit the Examination Unit and whether they should be tested for SARS-CoV-2. The responses provided as part of this assessment can then be sent to Charité via a QR code, which is anonymous, with the relevant information processed and stored on the user’s device. The CovApp also provides the user with information on how to reduce their risk of infection. “The CovApp helps us to protect both our patients and our staff. Given the high level of demand experienced by our Examination Unit, it is vital that individuals with symptoms not indicative of SARS-CoV-2 are not placed at risk. Similarly, it is essential that patients in need of testing are swabbed as quickly as possible,” explains Prof. Dr. Ulrich Frei, Charité’s Chief Medical Officer. The CovApp is a browser-based application and can be accessed via https://covapp.charite.de/. Explaining the reasons behind his organization’s involvement, Data4Life CEO Christian-Cornelius Weiß says: “As a nonprofit organization, it is both our privilege and our duty to provide our expertise and resources at a time of such pressing need, and to do our utmost to help both improve the situation facing us as a result of the current pandemic and minimize the risks involved.” He adds: “We are extremely pleased to be working with Charité, one of largest and most important university hospitals in Europe.”

A group of researchers from Charité – Universitätsmedizin Berlin has discovered a new mechanism of long-lasting pain relief. The cell-signaling protein interleukin-4 induces a specific type of blood cell to produce endogenous opioids at the site of inflammation. The researchers’ findings have been published in the Journal of Clinical Investigation (JCI) Insight*. Peripheral nerve inflammation can lead to chronic pain. The inflammatory response is mediated by a number of blood-derived immune cells. These produce cytokines, cell-signaling proteins which either enhance or reduce inflammation and pain. Thanks to its anti-inflammatory properties, one of these cytokines – known as interleukin-4 (IL-4) – is already being used to treat pain. The team, led by Prof. Dr. Halina Machelska from Charité's Department of Experimental Anesthesiology on Campus Benjamin Franklin, used an animal model of sciatic pain to study the analgesic mechanisms of IL-4. Initially, a single injection of IL-4 near the inflamed nerve produced pain relief which only lasted for several minutes. When repeated daily, however, injections reduced pain for up to eight days, even in the absence of further IL-4 injections. This resulted from the IL-4-induced accumulation of M2 macrophages, a type of immune system scavenger cell which produces opioids and thereby reduces pain. Prof. Machelska proposes that not general inhibition of inflammation, but fostering the beneficial properties of the M2 macrophages is most promising to tackle pathological pain. “Our findings are relevant to many immune-mediated diseases, ranging from arthritis to neurodegenerative diseases and cancer.” The M2 macrophages were then isolated from the inflamed nerve and transferred into a different animal, where they also reduced pain. When the researchers studied the isolated cells in greater detail, they found that these cells produced various endogenous opioids, such as endorphin, enkephalin and dynorphin which activated opioid receptors at the site of inflammation. “As these analgesic effects occur at the peripheral nerves, outside the brain, it is possible to prevent undesirable side effects such as sedation, nausea and addiction,” explains Prof. Machelska. She adds: “These findings may offer new perspectives in our endeavors to develop alternative pain management options for patients.”

Opioid-containing painkillers are virtually indispensable in clinical practice and are typically used in postoperative patients and patients undergoing cancer treatment. In addition to having severe side effects, however, these drugs have also been associated with extensive misuse, particularly in the United States. Recent findings by a team of researchers from Charité – Universitätsmedizin Berlin represent a significant step towards the development of a new generation of painkillers. Published in Scientific Reports*, their findings show that tissue acidity – or tissue pH – at the source of the pain (i.e. injury) is a crucial determinant in the development of new drugs. This is because the fine-tuning of an opioid molecule's acid dissociation constant (pKa) will determine its risk profile, including its addiction potential. Opioids have powerful pain-relieving effects but can quickly lead to dependence. For some time, these drugs have been prescribed too readily, particularly in the United States, where opioid addiction is so widespread that the situation is referred to as the ‘opioid crisis’. Germany, too, is witnessing an increase in the prescription of opioid-containing drugs, which are now even used in patients with non-cancer-related chronic pain. What remains elusive to this day, is medication which offers powerful pain-relieving properties but is associated with fewer risks. A group of researchers, led by Prof. Dr. Christoph Stein, Head of Charité's Experimental Anesthesiology Unit on Campus Benjamin Franklin, has been trying to track down an alternative type of painkiller with fewer side-effects. Previous efforts resulted in the development of three new opioid substances – known as FF6, FF3 and NFEPP - which were developed in collaboration with applied mathematics colleagues from the Zuse Institute Berlin (ZIB). Using an animal model of inflammatory pain for a more in-depth study of these three substances, the researchers have been able to explore their pain-relieving effects in greater detail, while also examining typical side effects such as tiredness and constipation and studying the risk of respiratory arrest and addiction. “When compared to the standard opioid – fentanyl – results of this new class of drugs speak for themselves,” says Prof. Stein, who is also a member of the Einstein Center for Neurosciences. “The more closely the pKa value of the binding molecule matches the acidity level of the inflamed or injured tissue, the more selective is the activation of the opioid receptors at the source of pain and the lower the risk of addiction or side effects. In the case of fentanyl, the pKa value is higher than normal physiologic pH. This standard opioid also enters the brain more readily.” The researchers are exploring the option of alleviating inflammatory and postoperative pain by directly targeting the site of its origin – injured tissue. In contrast to conventional opioids, the new drugs will only activate opioid receptors (the docking stations for pain-relieving medication) under acidic conditions. This means they will only work in injured tissue; severe side effects will be prevented. “We used cultured cells to study the ways in which opioid receptors and opioid receptor-binding molecules interact at different pH levels. We did this to determine the chemical properties needed to optimize the effects of these new drugs. Some of the receptors were also genetically altered,” explains study lead Prof. Stein, and adds: “We came to the conclusion that the acid dissociation constant – or pKa value – determines a particular opioid molecule’s risk profile, i.e. its side effects, such as tiredness or respiratory arrest. Until now, nobody knew about the significance of pH and pKa values and their role in opioid safety.” A ground-breaking finding in the field of receptor research. According to the researchers’ findings, both the fine-tuning of the pKa value and the formation of specific chemical bonds to opioid receptors will be crucial factors in the development of new types of drugs. Should this new generation of painkillers become a reality, both dangerous side effects and addiction potential could become a thing of the past. “Our previous clinical studies have already shown that the selective activation of peripheral opioid receptors in injured tissue, for instance by injection of conventional opioids like morphine, can have powerful pain-relieving effects in humans. We are therefore confident that our new class of drugs, which are now available for intravenous use for the first time, will turn out to be a success,” says Prof. Stein. The first clinical trials on these new drugs are expected to start in two to three years’ time. In parallel, the team is also pursuing the study of other drugs derived from this new generation of substances. Funded via the SPARK program, this work is being conducted at the Berlin Institute of Health (BIH).

A joint press release by Charité and the MDC Research groups from Charité – Universitätsmedizin Berlin and the Max Delbrück Center for Molecular Medicine (MDC) are joining forces with other Berlin-based partners. Pooling their experience and outstanding expertise in the field of mass spectrometry, they will form a new ‘Forschungskern’ or ‘research core’. The aim of the MSTARS consortium is to further develop current technology for clinical application and for the detection and classification of treatment resistance. The Federal Ministry of Education and Research (BMBF) will provide approximately €5.7 million in funding for a minimum of three years. For many years, comprehensive genetic analysis was considered the method of choice in our attempts to better understand diseases such as cancer and provide patients with increasingly personalized treatment options. It was a successful approach which resulted in a myriad of new, targeted forms of treatment. “However, it was known from an early stage that the course of a disease is not solely determined by our genes,” explains one of the project’s four coequal coordinators, Prof. Dr. Ulrich Keilholz, Director of the Charité Comprehensive Cancer Center (CCCC). “Instead, it is often determined by the extent to which these genes are translated into proteins, how the resulting proteins interact with one another, and how the disease affects our metabolism. Mass spectrometry enables us to identify and quantify biomolecules quickly and comprehensively. We will therefore use this technology to better understand the interplay of disease-relevant cell components and, by doing so, improve precision medicine, i.e. our ability to tailor treatments to the individual patient.” The MSTARS consortium’s other three coordinators are Prof. Dr. Matthias Selbach, Group Leader of the MDC’s Proteome Dynamics Lab, Prof. Dr. Markus Ralser, Director of Charité’s Institute of Biochemistry, and Prof. Dr. Frederick Klauschen of Charité’s Institute of Pathology. The project’s research partners include numerous other experts from Charité and the MDC, as well as scientists from the Berlin Institute of Health (BIH), Humboldt-Universität zu Berlin and the Max Planck Institute for Molecular Genetics. “By establishing this new research core, we are gathering all Berlin-based expertise in the fields of mass spectrometry, patient care and data analysis, and placing it under one roof,” says Prof. Selbach. “Combining the skills and experience of the various institutions and disciplines with Charité’s extensive clinical expertise will enable us to further develop mass spectrometry-based technologies and apply them in clinical practice.” “A major aim in this regard is to make mass spectrometry-based methods even more robust and reproducible,” reflects Prof. Ralser and adds: “In order for this technology to improve patient care, we also need to be able to analyze large numbers of samples within a short time. To achieve this, we will build capacity and develop standardized procedures for all processes, from sampling through to data management.” The infrastructure which the consortium is planning to develop will be suitable for carrying out analyses on a vast array of disorders. The consortium’s research groups will start by studying treatment resistance in patients with squamous cell carcinoma of the head and neck. “The modern treatment strategies available for these patients mainly target specific genetically-determined dysfunctions present in an individual patient’s cancerous tissue,” explains Prof. Klauschen. “For reasons which remain unexplained, these treatments will work very well in some patients but show no effect in other people with the same genetic makeup. We want to study patients’ tissue samples using mass spectrometry to distinguish these groups of patients and make it easier to decide whether or not a particular treatment should be used in a specific patient.” Doing so will require the analysis of vast quantities of data. Therefore, the researchers will also be using artificial intelligence-based approaches. The MSTARS (Multimodal Clinical Mass Spectrometry to Target Treatment Resistance) project is being funded under a special BMBF funding program, which focuses on establishing research cores dedicated to mass spectrometry in systems medicine (‘Forschungskerne für Massenspektrometrie in der Systemmedizin’). MSTARS is one of a total of four such BMBF-funded consortia. Other research cores will be developed in Heidelberg, Mainz and Munich. Funding has been awarded for an initial period of three years. An interim review after two and a half years will determine whether project funding is to be extended for a further three years. The projects will be launched on 1 March 2020.

A joint press release by the DZIF and Charité The situation is extraordinary: there have only ever been four declarations of public health emergencies of international concern in the past and now there are two at the same time. Whilst the risks associated with the novel coronavirus are still unclear, people in the Democratic Republic of the Congo are still battling with an outbreak of the deadly Ebola virus which has been ongoing since 2018 and has already claimed over 2000 lives. One issue is the precise characterisation of the pathogen because the ebolaviruses, like lots of viruses, appear in various genetic forms. Only the analysis of its genetic material provides the information necessary to develop specific tests for diagnosis and decide on efficient measures for controlling the outbreak. A German Center for Infection Research (DZIF) team at Charité – Universitätsmedizin Berlin has now developed a test which accelerates the process of identifying the genetic makeup of the virus. There have been multiple Ebola outbreaks in the last decades. Since 2013, at least eight countries have been affected and 30,000 people have contracted the virus. The origin of these outbreaks is often unclear and they are caused by various ebolavirus variants. “At the moment, it often takes months to develop the right tools to fully characterise the genetic material of the ebolavirus causing an outbreak” explains Professor Jan Felix Drexler, a scientist at the German Center for Infection Research (DZIF) and Charité. “However, this knowledge is crucial for developing specific diagnostic tests, identifying transmission chains and eventually controlling the outbreak.” The scientists in Professor Drexler’s team have now developed a test which provides information about the genetic material of new ebolaviruses regardless of the species or the variant, that is, of the genetic makeup. The test is based on the commonly used polymerase chain reaction (PCR), using which the genetic material can be amplified in a manner that allows precise sequencing. The new test is compatible with various technical procedures such as high-throughput sequencing. It has been tested with four different ebolavirus species. “In cases in which different regions and countries are affected by outbreaks of this kind in particular, it is necessary to establish whether the case in question relates to the spread of a previously known variant of the virus or a new outbreak,” explains the virologist. This is exactly what the new test can now determine in one process. “Both in the current outbreak in the Democratic Republic of the Congo and in future outbreaks, we may now be able to characterise the trigger more quickly and take appropriate effective measures to end the outbreak,” says the scientist. Scientists from Charité and Marburg DZIF are involved in the current study within the framework of the DZIF working group on “Virus detection and preparedness” and have the use of a high-security laboratory which is equipped for research into highly contagious viruses. The research work was carried out in partnership with the rapidly deployable health expert group (SEEG) at the Deutsche Gesellschaft für Internationale Zusammenarbeit (GIZ) and, in addition to the DZIF, it also received funding from the EU and the German Federal Ministry for Economic Cooperation and Development (BMZ). The establishment of the method in the GIZ global partner laboratories is currently being tested.

Joint press release by Charité, MDC and the BIH Three Berlin research institutions – the Berlin Institute of Health (BIH), the Berlin Institute for Medical Systems Biology (BIMSB) of the Max Delbrück Center for Molecular Medicine (MDC), and Charité – Universitätsmedizin Berlin – are launching a joint research initiative. The goal is to use innovative single cell technologies to answer clinical research questions. In 2018, the journal Science named new technologies that can be used to analyze individual body cells its “Breakthrough of the Year.” For the first time it was possible to break down entire organs, tumors, even entire insect larvae into individual cells, measure their gene activity, and – with the help of high-performance computers and artificial intelligence – reassemble these individual cell analyses to form the entire organ or organism. This breakthrough was made possible in part by research conducted at BIMSB. “It was as if we had invented a super microscope with which we could suddenly look inside every cell in a tissue, all the cells at once, and see what was going on at the molecular level inside the cell – for example, when and why it gets sick,” explains Prof. Dr. Nikolaus Rajewsky, Scientific Director of the Berlin Institute for Medical Systems Biology (BIMSB) at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), and spokesperson for the BIH’s new focus area “Single Cell Technologies for Personalized Medicine.” At the core of the new focus area are three new, internationally appointed junior research groups. They will study various diseases at the level of individual cells in order to systematically characterize them at the molecular level and to develop new methods to better diagnose and treat these diseases. The junior research groups will be located at BIMSB, and thus in close proximity to Charité’s Berlin-Mitte campus. At BIMSB, they will have access to the latest single cell methods and systems biology expertise. Each junior research group will also work closely with a clinician at Charité, helping to develop single cell technologies for specific medical issues and clinical application. “I therefore consider this initiative to be the beginning of a ‘Cell Hospital,’ in which the basic research of the MDC/BIMSB, the clinical research of Charité, and the translational research of the BIH are brought together,” explains Prof. Rajewsky. “The idea is not only to understand the mechanisms that cause cells to become diseased, but also to discover these cells early enough to restore them to health before a disease takes such a hold that it can only be treated with great difficulty – or invasively and expensively.” Following a highly competitive recruitment process, twelve applicants for the junior group leader positions have been invited to a public symposium held in Berlin on February 6, 2020, to present their previous scientific work in the field of single cell biology and their ideas for its clinical application. These scientists come from some of the world’s leading institutions in the United States, Israel, Sweden, the United Kingdom, Switzerland and Germany. The selection committee includes BIMSB research group leaders and Department directors from Charité who have expressed interest in the new focus area. Among them are representatives from oncology, neurology, infectious diseases, cardiovascular diseases and rare diseases. Prof. Dr. Axel Radlach Pries, Dean of Charité and interim Chairman of the BIH Executive Board, explains: “The selection criteria include scientific excellence, the ability to fit into a clinical setting, and the potential to transfer research results into clinical application. We are excited about the symposium and look forward to the joint research initiative.” The recruitment symposium marks the scientific kick-off for the work of the BIH and MDC’s new focus area “Single Cell Technologies for Personalized Medicine.” Prof. Rajewsky is confident about the future: “I am sure that we will make significant progress – not for all, of course, but for some diseases. This new focus area allows a bridge to be built, and thus translation to be achieved, between basic research and the clinic. The immediate proximity of BIMSB/MDC, Charité and BIH will enable a great deal of innovation and long-term progress for patients.”

A joint press release by Charité, Munich Clinic Schwabing and the Bundeswehr Institute of Microbiology Laboratory testing by Charité – Universitätsmedizin Berlin, the Bundeswehr Institute of Microbiology and Munich Clinic Schwabing has revealed that infectious virus can be isolated from nose and throat swabs even where these have been obtained from patients with mild symptoms. The research groups have therefore come to the conclusion that even persons with mild symptoms are capable of transmitting the virus. Charité’s Institute of Virology and the Bundeswehr Institute of Microbiology have been supporting diagnostic efforts since the first case of 2019-nCoV infection was confirmed in Germany. Working independently of each other, both laboratories regularly monitor viral shedding in patients currently receiving treatment at Munich Clinic Schwabing. During the course of these investigations, the researchers found several cases in which infectious virus could be isolated from nose and throat swabs which had been obtained from patients with mild symptoms and propagated in cell culture. These patients presented with symptoms which were reminiscent of the common cold rather than severe pneumonia. Concomitant investigations by both laboratories also found evidence to suggest that the novel coronavirus replicates not only in the lungs but also in the nose, throat and gut. Their combined observations indicate that even people with mild or early symptoms of common cold (sore throat, signs of sinusitis, mild malaise without fever) can pass on the virus. The investigations were led by Prof. Dr. Christian Drosten, Director of the Institute of Virology on Campus Charité Mitte, Colonel Priv.-Doz. Dr. Roman Wölfel of the Bundeswehr Institute of Microbiology and Prof. Clemens Wendtner, Head of the Department of Infectious Diseases and Tropical Medicine at Munich Clinic Schwabing.

Joint press release by Charité and the DZIF First identified in 2012, the MERS-coronavirus is capable of causing severe and often fatal pneumonia. There are no effective treatments for MERS. Researchers from the German Center for Infection Research (DZIF) at Charité – Universitätsmedizin Berlin recently identified a cellular recycling process known as autophagy as a potential target in the fight against MERS. Autophagy-inducing substances – including certain licensed drugs – were shown to be capable of drastically reducing the rate at which the virus replicates. Results from this research have been published in Nature Communications*. The MERS pathogen is capable of causing a flu-like illness (Middle East Respiratory Syndrome) which is often associated with pneumonia. Since its appearance in 2012, approximately 2,500 cases have been reported to the WHO across a total of 27 countries. Approximately one third of infections have resulted in death. A team co-led by PD Dr. Marcel Müller of the Institute of Virology on Campus Charité Mitte recently discovered that the MERS virus can only replicate efficiently if it inhibits a cellular process known as autophagy. Based on this initial discovery, the researchers went on to identify substances which are capable of inducing autophagy and can thus be used to limit viral infection. The term autophagy refers to a type of cellular recycling process which enables cells to dispose of damaged materials and waste products, while retaining intact components for incorporation into new cellular structures. This autophagic degradation, or ‘auto-digestion’, is also capable of identifying pathogen-derived components, such as the building blocks of viruses, which are treated as waste products and eliminated. A range of viruses are known to have developed strategies to dysregulate or inhibit autophagy. PD Dr. Müller and his colleagues therefore set out to determine whether the MERS virus is capable of modulating autophagic degradation. As a first step, and using stringent biosafety conditions, the researchers infected cells with the MERS virus. Subsequent observations revealed a disruption to the cellular recycling process in cells infected with the virus. “This result clearly indicated that the MERS pathogen benefits from an attenuation of the cellular recycling process,” explains PD Dr. Müller. The researchers also succeeded in identifying a previously unknown molecular switch which regulates the process of autophagic degradation: the SKP2 protein. The researchers discovered that the MERS virus activates this molecular switch in order to slow down the cell’s recycling processes and avoid degradation. Using these new insights, the researchers treated MERS-infected cells with various SKP2 inhibitors in order to stimulate the degradation process. This strategy proved successful, the autophagy-inducing substances reducing viral replication by a factor of 28,000**. Among the substances used to elicit this effect were licensed drugs such as niclosamide, a treatment for tapeworms which had previously been identified as an SKP2 inhibitor. Importantly, niclosamide was shown to be capable of drastically reducing the replication of the MERS virus in cell culture. “Our results reveal SKP2 to be a promising starting point for the development of new substances capable of fighting the MERS virus, and potentially even other autophagy-dependent viruses,” says PD Dr. Müller. SKP2 inhibitors do not target the virus directly. For this reason, the research group leader expects their use to be associated with a reduced risk of resistance. “However, SKP2 inhibitors will need to be tested in vivo before they can be used as drugs. Furthermore, one has to properly evaluate the risks and benefits for their in vivo use, since even drugs that have already been approved can have side effects,” says the virologist. The researchers will also test whether SKP2 inhibitors could be effective against other coronaviruses such as SARS or the novel coronavirus (2019-nCoV) which is currently emerging in China.

A joint press release by Charité and the DZIF Researchers from the German Center for Infection Research (DZIF) at Charité – Universitätsmedizin Berlin have developed a new laboratory assay to detect the novel Chinese coronavirus. The assay protocol has now been published by WHO as a guideline for diagnostic detection. The new assay enables suspected cases to be tested quickly. The coronavirus, which first emerged in Wuhan, China, and can cause severe pneumonia, can now be detected in the laboratory. Developed by a group of DZIF researchers working under the leadership of Prof. Dr. Christian Drosten, Director of the Institute of Virology on Campus Charité Mitte, the world’s first diagnostic test for the coronavirus has now been made publicly available. Following its online publication by the WHO, the test protocol will now serve as a guideline for laboratories. An international consortium is currently conducting a joint evaluation study. “Now that this diagnostic test is widely available, I expect that it won’t be long before we are able to reliably diagnose suspected cases. This will also help scientists understand whether the virus is capable of spreading from human to human,” explains Prof. Drosten. He adds: “This is an important step in our fight against this new virus.”

Joint press release by Charité – Universitätsmedizin Berlin and the German Center for Infection Research (DZIF) New viruses which cause diseases often come from animals. Well-known examples of this are the Zika virus transmitted by mosquitoes, bird flu viruses, as well as the MERS virus which is associated with camels. In order to identify new viral diseases quickly and prevent possible epidemics, DZIF scientists at Charité – Universitätsmedizin Berlin are targeting their search at viruses in animals. In a current study, they have now discovered hundreds of novel viruses in insects. The results have been published in PLOS Pathogens*. “Every new virus we find could be a cause of illnesses that was previously unknown, both in humans and in livestock,” explains Prof. Dr. Christian Drosten, Director of the Institute of Virology on Campus Charité Mitte. The scientist is a specialist for virus discovery and diagnostics at the German Center for Infection Research (DZIF). For example, his team has defined the international standard approach for diagnosing MERS. He is currently focusing on rare virus diagnoses using new sequencing techniques. “The more viruses we identify and add to our database, the easier it is for us to recognise the cause of new and unusual illnesses,” says Prof. Drosten. In the current study, the research team has made use of the largest international transcriptome database on insects, a kind of catalog of gene activity, and investigated the data it contains with regard to virus genomes. Whilst scientists have previously concentrated on mosquitos and other blood-feeding insects, this study includes all groups of insects. Viruses with negative strand RNA genomes have been systematically investigated. This group of RNA viruses includes important pathogenic viruses; these cause Ebola and measles, as well as rabies and lung infections. In a total of 1.243 insect species, the researchers discovered viruses that can be classified in at least 20 new genera. “This is probably the largest sample of animals ever screened for new viruses,” says Prof. Drosten. The working group has already added the new insect viruses to its search databases. With the help of these data, it will now be possible to investigate cases of rare and unusual illnesses in humans. This includes patients who display all the symptoms of a viral infection, however no virus can be identified in the case in question. “In such cases, we use high-throughput sequencing methods to search for all the viruses present in the patient,” explains the virologist. “If the patient has a virus, we will find it, provided it is in our database or has similarities with a virus in our database.” The chances of the search being successful will increase thanks to the addition of the new insect viruses. As part of the DZIF project “Virus detection and preparedness”, the scientists at Charité will continue to focus on anticipating and detecting future viral threats.

A team of researchers led by Charité – Universitätsmedizin Berlin has succeeded in deciphering a basic physical principle involved in the progression of brain tumors. Soft tumors, such as glioblastomas, infiltrate surrounding tissues and spread quickly. Solid tumors, in contrast, consist of a firm mass of tissue and maintain clearly defined boundaries as they expand. Whether the growing tumor displaces neighboring tissues, keeps clearly delineated boundaries or displays infiltrative behavior, its growth pattern is determined by its viscous properties. A study of the underlying mechanisms has been published in the journal Proceedings of the National Academy of Sciences*. Brain tumors are particularly dangerous when they display an infiltrative pattern of growth. They then lack discernible margins and readily spread out into healthy tissue. This is the reason why, in contrast to encapsulated tumors, glioblastomas are difficult to treat. State-of-the-art procedures using the latest surgical techniques, radiotherapy or chemotherapy usually fail to completely remove glioblastoma often leading to the tumor’s recurrence. But, how can a soft tumor which is embedded in more rigid brain tissue manage to grow at all; and why does this type of tumor grow so quickly and spread so aggressively? The principles of solid mechanics would suggest that this is impossible. Working alongside colleagues from Leipzig University’s Department of Neuroradiology, Prof. Dr. Ingolf Sack and his team of researchers from Charité’s Department of Radiology have been studying the mechanical properties and infiltration behavior of brain tumors. Solid, encapsulated tumors show much higher mechanical rigidity, which enables them to maintain a solid boundary as they expand into the surrounding tissue. Glioblastomas behave in an unusual way in that they expand into an environment which is more rigid than the tumor tissue itself. In order to be able to describe this unusual infiltration behavior, the researchers had to change their perspective: “We no longer regard the brain as merely a solid body, but as a highly viscous – i.e. very thick – fluid. This allows us to understand the physical mechanisms involved,” says study lead Prof. Sack. “Over longer time scales, the brain responds in a way that is similar to honey,” explains Prof. Dr. Josef A. Käs of Leipzig University’s Faculty of Physics and Earth Sciences. He adds: “Whether the expanding tumor maintains a clear boundary or grows by infiltration is determined by its viscosity. If its viscosity is low, like that of water, its boundaries will become unstable. The near-fluid tumor virtually fingers into the surrounding honey. If tumor viscosity is high, meaning the tumor has a markedly thicker consistency which is more akin to tofu, its boundaries will be smooth and clearly delineated.” The underlying principle is well known from physics of fluid matter and describes the fact that interfaces between fluids of differing viscosities can be unstable. Using tissue-mimicking phantoms such as heparin gel and tofu, the researchers were able to show how the abnormal fluid characteristics of soft brain tumors enable them to penetrate the tissues surrounding them. The researchers used high-resolution brain elastography, an MRI-based imaging technique which was developed at Charité for the purpose of visualizing tumor consistency. This enabled the researchers to use their new insights to explore the characteristics of brain tumors. Aggressively invasive glioblastomas were found to have a higher water content than the surrounding brain tissue. Conversely, benign meningiomas were found to contain less water than the surrounding brain tissue. The two tumor types did not differ with regard to their stiffness properties, both being softer than the surrounding tissue. This led the researchers to conclude that tumor fluidity (i.e. the tumor’s viscosity and flow-properties) can provide an indication of the tumor’s infiltration potential and, hence, its aggressiveness. Summing up the significance of the research, Prof. Sack says: “This new way of staging brain tumor aggressiveness opens up a world of opportunities for the field of diagnostic radiology. It allows brain and tumor viscosity to be determined using elastography – without the need for contrast enhancement, radiation or invasive surgery.” Further clinical studies involving this relatively new imaging technology will be needed to develop a diagnostic technique capable of classifying brain tumors.

Cancer development is associated with the gradual accumulation of DNA defects over time. Thus, cancer is considered an age-related disease. But why do children develop cancer? An international team of researchers, led by Charité – Universitätsmedizin Berlin and the Memorial Sloan Kettering Cancer Center in New York, now reveal that mysterious rings of DNA known as extrachromosomal circular DNA can contribute to cancer development in children. Producing the first detailed map of circular DNA, the scientists have shed new unanticipated insights on long standing questions in the field of cancer genetics. The work has been published in Nature Genetics*. Every year, nearly half a million people in Germany develop cancer. Approximately 2,100 cancer patients are children under the age of 18. The fact that the majority of cancers develop in old adults is due to the mechanisms contributing to cancer development. A range of exogenous factors, including tobacco smoke and radiation, can cause damage to cellular DNA. If this type of DNA damage is left to accumulate over many years, affected cells may lose control over cell division and growth. This results in cancer development. Children, however, are not old enough to be affected by this mechanism of cancer development. What, then, is the reason for childhood cancers? A team of researchers, led by Dr. Anton Henssen of Charité’s Department of Pediatrics, Division of Oncology and Hematology and the Experimental and Clinical Research Center (ECRC,) an institution jointly operated by Charité and the Max Delbrück Center for Molecular Medicine (MDC), are a large step closer to finding an answer. Working alongside a team of scientists led by Dr. Richard Koche from the Memorial Sloan Kettering Cancer Center and other international partners, the groups of researchers were able to show that rings of DNA can cause disruption of our cells’ genetic information, which can contribute to cancer development. Scientists have known about these ring-shaped sections of DNA for decades. Found inside our cells, they do not form part of our normal genetic information, which is stored in the form of chromosomes. It is for this reason that they are referred to as extrachromosomal circular DNA. But even nowadays, scientists know relatively little about their function, mainly because they have lacked technologies for a more detailed analysis of circular DNA. In their now published study, the researchers combined state-of-the-art sequencing techniques with pioneering bioinformatics algorithms to perform the first-ever detailed mapping of circular DNA in neuroblastoma, a deadly childhood tumor . Based on their findings, the researchers were able to draw important conclusions regarding the development of this type of cancer. Working with colleagues from the Barcelona Supercomputing Center, the researchers analyzed neuroblastoma tissue samples from a total of 93 children. Their analysis revealed that the prevalence and diversity of circular DNA is far greater than previously anticipated. According to the researchers’ findings, each tissue sample contained on average 5,000 circular DNA copies. DNA sequencing also revealed the process by which specific DNA sections separate from a chromosome to form circular DNA before reintegrating into the chromosome at a different location. “This can potentially cause cancer if it results in the original sequence of genetic information being disrupted,” explains the Emmy Noether Independent Junior Research Group’s leader, Dr. Henssen, who is also a researcher at the German Cancer Consortium (DKTK) in Berlin and a Berlin Institute of Health (BIH) Clinician Scientist. Stressing the significance of the researchers’ findings, Dr. Henssen says: “The detailed processes involved had not previously been elucidated in this manner and provide insight into how even young cells, like those found in children, can transform into cancer cells.” “We were also able to show that certain types of circular DNA may accelerate neuroblastoma growth,” explains Dr. Koche and adds: “Testing for their presence may therefore make it easier to predict the course of the disease. Additionally, studying this process in the relatively quiet genomes of these pediatric tumors may help illuminate similar mechanisms which were previously missed in more complex adult cancers. Given the recent interest in circular DNA in a variety of normal and disease contexts, the current study may have implications for a broad range of tumor types and associated clinical outcomes.” The research groups plan to conduct a follow-up study to verify the diagnostic validity of circular DNA. “We also want to conduct more detailed research into the origins of circular DNA in order to better understand why it is that children develop cancer,” says Dr. Henssen.

A joint press release by Charité and the Max Planck Institute for Human Development Members of a polar research expedition have provided researchers from Charité – Universitätsmedizin Berlin and the Max Planck Institute for Human Development with an opportunity to study the effects of social isolation and extreme environmental conditions on the human brain. The researchers found changes to the dentate gyrus, an area of the hippocampus responsible for spatial thinking and memory. Results from their study have been published in The New England Journal of Medicine*. Setting off on an Antarctic expedition to Neumayer-Station III, a German Antarctic research station run by the Alfred Wegener Institute, Helmholtz Centre for Polar and Marine Research (AWI), means having to face temperatures as low as -50 degrees Celsius (-58 degrees Fahrenheit) and almost complete darkness during the winter months. Life at the research station offers little in the way of privacy or personal space. Contact with the outside world is minimal, and cutting one’s stay short is not an option – at least not during the long winter months. Emergency evacuation and deliveries of food and equipment are only possible during the relatively short summer. “This scenario offers us the opportunity to study the ways in which exposure to extreme conditions affect the human brain,” says study lead Dr. Alexander Stahn of Charité’s Institute of Physiology and Assistant Professor in the Perelman School of Medicine at the University of Pennsylvania. Working alongside Prof. Dr. Simone Kühn (Group Leader of the Lise Meitner Group for Environmental Neuroscience at the Max Planck Institute for Human Development), and supported by the AWI, Dr. Stahn set out to determine whether or not an Antarctic expedition produces changes to the structure and function of the human brain. Five men and four women volunteered to participate in the study. They spent a total of 14 months at the Antarctic research station, nine of which were spent in isolation from the outside world. Before, during and after their mission, the participants completed a set of computer-based cognitive tests. These included evaluations of concentration, memory, cognitive reaction time and spatial thinking. Regular blood tests were carried out to measure levels of a specific growth factor known as brain-derived neurotrophic factor (BDNF), a protein responsible for promoting the growth of nerve cells and synapses in the brain. The researchers used magnetic resonance imaging to determine brain structure in each of the participants before and after their mission. They did so in order to record changes in brain volume, paying particular attention to the hippocampus, a structure located deep inside the brain. “For this, we used a high-resolution methodology which makes it possible to take precise measurements of individual areas of the hippocampus,” says Prof. Kühn. A group of nine control participants underwent identical tests. Measurements taken after the end of the exhibition revealed that the dentate gyrus, an area of the hippocampus with an important role in spatial thinking and memory formation, was smaller in members of the expedition team than in controls. These changes were also associated with a decrease in BDNF levels. After only three months in the Antarctic, levels of the growth factor had decreased to levels below those recorded prior to the start of the expedition and had not returned to normal one-and-a-half months after the expedition. Cognition tests showed effects on both spatial abilities and the so-called selective attention, which is necessary to ignore irrelevant information. Repeated testing is normally associated with improvements in test results. This learning effect, however, was reduced in participants whose dentate gyrus had decreased in volume, the reduction proportional to the extent of the volume lost. “Given the small number of participants, the results of our study should be viewed with caution,” explains Dr. Stahn, adding: “They do, however, provide important information, namely – and this is supported by initial findings in mice – that extreme environmental conditions can have an adverse effect on the brain and, in particular, the production of new nerve cells in the hippocampal dentate gyrus.” As a next step, the researchers plan to study whether or not physical exercise might be able to counteract the observed changes in the brain.

Following the signing of a broader cooperation agreement, Charité – Universitätsmedizin Berlin and King’s are now launching six joint research projects. Within the framework of this new partnership, the two institutions will provide start-up funding for six binational projects in key fields including immuno-oncology, cardiology, neurology, immunology, medical sociology and genetics. The ultimate aim of the collaboration is to foster synergies between the two institutions and promote the development of further research endeavors, thus laying the foundation for fruitful long-term international collaboration. The six initial projects address topical questions within the fields of cancer immunology and forensic science as well as exploring innovative imaging methods and public health challenges. Start-up funding will facilitate joint research endeavors, workshops, conferences and travel. To qualify for funding, applicants were required to demonstrate that projects showed long-term perspective and an international focus. In the context of an impending Brexit and against the backdrop of uncertainties in the European research landscape, the Charité’s Dean, Prof. Dr. Axel Radlach Pries expressed his delight at the launch of these first joint research projects: “In this day and age, forward-looking international cooperation is the key to furthering research and innovation. Additionally, such partnerships show that political uncertainties can be overcome by collaborating across national borders and thus achieving best possible outcomes for all involved. I wish all participants of this pioneering research partnership every success for the future.” Professor Sir Robert Lechler, King’s Senior Vice President/Provost (Health), added: “We are pleased to see such a positive response to the first Charité – King’s Joint Research Seed Fund Call. It covers a wide-range of disciplines that showcase the research strengths of both institutions in the medical sciences. We look forward to this contributing towards research with global impact.” Projects will be completed by summer 2020, after which activity reports will be evaluated and further pursuits encouraged, thus fostering sustained cross-channel collaboration.

Joint Press Release of Charité, the BIH and the Wellcome Trust Charité – Universitätsmedizin Berlin and the Berlin Institute of Health (BIH) are the first institutions in Germany to receive funding to create a translational partnership with the UK-based Wellcome Trust. Via its translational partnerships, the Wellcome Trust supports institutions in finding new ways to translate biomedical discoveries into novel treatments, technologies and medical devices. Its partner institutions in Berlin will receive over €1.1 million in project funding. The Wellcome Trust, a politically and financially independent foundation, is thus expanding its translational partnership network, which already includes a number of university partners. The Governing Mayor of Berlin and Senator for Higher Education and Research, Michael Müller, said: “I am delighted that the Wellcome Trust has established a presence in Berlin and will now become an active partner for our health capital. The fact that the BIH and Charité are among the first institutions in continental Europe to be funded under this scheme underscores their achievements and prominent position in the translational research field. The foundation’s engagement in Berlin is furthermore an important signal in terms of international collaboration, something that we hold very highly here in Berlin.” The overarching aim of the translational partnership between the Wellcome Trust and Charité/BIH is to effect a change in research culture, thus maximizing the possibilities for translational medicine to benefit patients and society at large. The project team at Charité/BIH will use the funding to raise the quality of biomedical research, improve the understanding of regulatory needs and establish incentives for translational research. Project leaders are Prof. Dr. Ulrich Dirnagl, Director of the BIH QUEST Center, and Prof. Dr. Hans-Dieter Volk, Head of the Institute of Medical Immunology at Charité and Director of the BIH Center for Regenerative Therapies (BCRT). Stephen Caddick, Director of Innovations at the Wellcome Trust, said: “Science is international and needs collaboration and cooperation to succeed. Our translational partnerships seek to tackle some of the barriers discovery researchers face when translating their work by providing support at an institutional level – including financial support, mentorship, and regulatory advice. We’re delighted to be working in partnership with the BIH and Charité.” The translational partners from Berlin already have a proven track record in moving forward translational projects. For example, researchers at the BIH Center for Regenerative Therapies leveraged research findings to develop genetically engineered immune cells, called Treg cells, which they then used to improve the long-term acceptance of transplanted organs. A successful phase 1 clinical trial study showed promising results, which are now being developed further clinically through the use of new technologies like CRISPR-Cas9. Prof. Dr. Heyo K. Kroemer, Chairman of the Executive Board of Charité and BIH Executive Board Member, also expressed his delight about the partnership: “The Wellcome Trust is one of the world’s leading foundations focused on medical research and has so far supported research institutions like the University of Oxford and Cambridge University. That the BIH and Charité now belong to the foundation’s translational partnership network reflects the groundbreaking role that our translational research plays in paving the way for innovative personalized healthcare. This new partnership once again affirms that the Federal Government’s decision to integrate the BIH into Charité was the right one. In addition, the partnership is a great honour for our city, bestowing international recognition and visibility whilst simultaneously highlighting Berlin’s role as a biomedical research hub with a strong translational focus.” As Dean of Charité and interim Chairman of the BIH Executive Board, Prof. Dr. Axel Radlach Pries recently attended Wellcome’s Translational Partnerships’ Annual Meeting in London. “The BIH’s core mission is to advance translational medicine. As such, the pioneering work behind our motto ‘Turning Research into Health’ was clearly well received by the Wellcome Trust. In the context of this partnership, the BIH aims to help create a ‘translational ecosystem’ by systematically supporting the entire translational chain from laboratory findings to clinical application. Together, the BIH and Charité will serve as key partners in international efforts to develop new and improved medical therapies and diagnostic procedures for patients.” "Crucial hurdles to translation often lie in the quality of biomedical research itself. QUEST aims to increase the value and benefits of medical research. As a result, QUEST addresses the exact questions that the Wellcome Trust is posing in its sustained drive to promote translation”, said Prof. Dirnagl. “The translational partnership with the Wellcome Trust will enable us to further develop and expand our strategies for promoting translation.” Prof. Volk added: “The BCRT has a wealth of experience in introducing new diagnostics and therapies, including the very latest cell-based approaches. As a result, we have acquired a vast amount of expertise on regulatory issues. We now wish to transfer this knowledge to colleagues working in the field of translational medicine, adapting our findings as they evolve and thus addressing specific project requirements. By collaborating closely with the QUEST Center, we hope to develop a comprehensive translational ecosystem that will allow robust research findings to be swiftly transferred into innovative healthcare solutions.”

For ten years, researchers from Charité – Universitätsmedizin Berlin have been studying how kidney function changes with age. Their work as part of the Berlin Initiative Study (BIS) has produced two equations which enable physicians to better estimate kidney function in elderly patients. More precise estimates of kidney function can ensure patients do not receive drugs at too high a dose. The researchers’ findings also revealed that lowering blood pressure is associated with an increased risk of death in certain elderly adults. It is a long-established fact that kidney function decreases with age. But what level of kidney function is normal in elderly adults and how many of them have impaired kidney function? Also, how quickly does kidney function decline? The answers to these questions are of particular significance to people who need to take medications because a decline in the rate at which the kidneys eliminate a particular drug from the body may result in overdose – with potentially serious consequences. For this reason, physicians will obtain an estimate of kidney function prior to setting treatment doses for certain drugs. The problem they had previously faced was that the only equations available to estimate kidney function had been developed based on the data of younger people. In 2009, a team of researchers led by Prof. Dr. Elke Schäffner, Deputy Director of Charité's Institute of Public Health, launched the Berlin Initiative Study to improve our understanding of kidney function in elderly adults. The aim of the research was to study more than 2,000 individuals aged 70 years or older from the Berlin and Brandenburg areas. Participants were followed up for a period of several years, undergoing detailed examinations at regular intervals. “Given that participants had an average age of 80 and presented with age-related comorbidities including, in many cases, frailty, this was no simple task,” emphasizes Prof. Schäffner. Participants underwent five separate examinations, scheduled at two-year intervals. During these examinations, researchers asked the participants about their habits, illnesses and medications. They also measured their blood pressure and kidney function and analyzed both blood and urine samples. As it turns out, the effort was worth it: the researchers produced a veritable treasure trove of data on the health and habits of elderly adults – as vast as it is unique. One in five participants reported consuming alcohol daily. Half of all participants were either smokers or ex-smokers. One in four participants were overweight and one in four had cancer and/or diabetes. Furthermore, nearly 80 percent of participants were taking blood pressure-lowering drugs. This group of patients became the focus of an investigation into the effects of blood pressure on overall mortality. An analysis of the researchers’ data showed that it is not always beneficial for older adults to keep their blood pressure below 140/90 mmHg. The reality is, in fact, quite the opposite: lower blood pressure is associated with an increased risk of death in adults over the age of 80, and in adults who have previously had a heart attack or stroke. The researchers also collected new data on kidney function as represented by the ‘glomerular filtration rate’. Their findings revealed that approximately half of all participants had renal impairment. The researchers also found that the equations previously used to estimate a person’s glomerular filtration rate overestimated kidney function in elderly patients. “What this means is that inaccurate estimates might result in physicians setting treatment doses which are too high for patients,” explains Prof. Schäffner, who is both a nephrologist and an epidemiologist. To remedy this situation, Prof. Schäffner worked alongside her team to develop a new method for estimating kidney function. First developed in 2012 and consisting of two formulas (known as the BIS1 and BIS2 equations), this method produces more accurate estimates of kidney function in adults aged 70 years and over. “Today, physicians can use these equations free of charge via an online GFR calculator. There are also a number of laboratory networks which have adopted this new method as part of their portfolio of tests,” says Prof. Schäffner. Expressing her delight at the wealth of data produced by the study, she adds: “The Berlin Initiative Study has helped us to improve our understanding of health in older people and pay more attention to this age group.” Prof. Schäffner and her team are in the process of conducting further statistical analyses. They are hoping to find out how age-related kidney decline develops over time and what factors have an influence on this development.

Stem cells are responsible for the regeneration of the intestinal wall. But what happens when the stem cells responsible for regeneration are damaged by an infection? Researchers from Charité – Universitätsmedizin Berlin and the Max Planck Institute for Infection Biology set out to address this question. They were able to identify the precise mechanism involved in restoring the body’s ability to regenerate the intestinal wall. This knowledge may be able to help researchers develop new treatment options for patients with intestinal disorders. Results from this study have been published in the journal Nature Communications*. Our gut represents an interface between the body’s own tissues and its environment. As such, it is exposed to a myriad of factors. Many of these are beneficial to our health or even essential for our survival. Others, however, such as pathogens and toxic food components, can damage the lining of our intestinal walls, causing injury and inflammation. Faced with this situation, the body can activate its ‘tissue regeneration program’, which prompts stem cells residing in the base of invaginations of the intestinal wall (crypts) to proliferate. Newly formed ‘daughter cells’ then move to replace damaged cells within the tissue’s surface layer, thereby restoring the tissue's normal barrier function. However, some foreign materials do not merely attack cells within the surface layer of the intestinal wall, they will also destroy stem cells deep within the intestinal crypts. Using an animal model, a team of researchers led by Dr. Michael Sigal of Charité’s Medical Department, Division of Hepatology and Gastroenterology (Campus Charité Mitte and Campus Virchow-Klinikum), has been exploring how the intestinal wall can recover from such damage and restore its normal barrier function. “We were able to show that muscle cells located directly below the damaged cell layer play a crucial role in this regard,” explains Dr. Sigal. The researchers proved that, as soon as the stem cells stop functioning, these muscle cells release the protein R-spondin 3. This signaling molecule prompts some of the remaining healthy cells to take on the function of stem cells. They start to produce daughter cells, which then restore damaged tissue sections. Experiments which involved ‘knocking out’ the gene responsible for the release of R-spondin 3 showed that this mechanism of regeneration is essential to survival after severe intestinal injury. Explaining the study’s findings, Dr. Sigal, who is the Leader of an Emmy Noether Independent Junior Research Group and a BIH Charité Clinician Scientist, says: “Our study also shows that the body has a contingency plan for when the gut's normal tissue regeneration program is impaired.” He adds: “When the body is unable to implement this contingency plan, however, a severe gut infection may prove fatal. Here, our observations show parallels to what we see in patients with inflammatory bowel disorder: many of these patients will recover quickly, others will develop a chronic form of the disease or develop severe complications.” The researchers hope to use their new insights into the body's capacity for regeneration to develop new treatment options for both acute and chronic inflammatory bowel disorders. “By finding ways to activate the gut's regenerative capacity, we may one day be able to positively influence the course of intestinal disorders,” says Dr. Sigal.

A joint press release by Charité and the BIH According to clinical trial results published by an international team of researchers co-led by Charité – Universitätsmedizin Berlin and the Berlin Institute of Health (BIH), a new triple combination therapy has been shown to be highly effective in the treatment of patients with cystic fibrosis. In patients with the most common causative genetic defect (F508del), the new treatment resulted in unprecedented improvements in both lung function and quality of life. As the treatment is not symptomatic but targeted at the underlying defect, its early use in children may be able to prevent the onset of lung disease. The research has been published in the New England Journal of Medicine*. At the beginning of the 20th century, traditional midwife wisdom held that “a child whose brow tastes salty when kissed will soon die”. The characteristic salty taste was caused by Germany’s most common lethal hereditary disease, cystic fibrosis. The disease, caused by abnormalities in the way salt and fluid is transported across epithelial membranes, is characterized by excessively viscous mucus secretions. In addition to causing airway obstruction, these thick secretions also cause chronic lung infection and inflammation, as well as a progressive decline in lung function. The disease also impairs the function of other organs, such as the pancreas, bowel and liver, as well as the male reproductive organs and sweat glands in the skin. Approximately one in 2,500 to 3,000 newborn infants born in the Western world are affected by the disease. It is caused by a defect in the CFTR gene, which produces abnormalities in the function of a specific ion channel found in epithelial cells. So far, researchers have discovered more than 2,000 individual CFTR gene defects capable of causing cystic fibrosis. The most common defect, known as the F508del mutation, is found in approximately 90 percent of patients with cystic fibrosis. “Cystic fibrosis was once a purely pediatric disease, as most patients died before they reached adulthood,” explains the study’s joint first author, BIH and Einstein Professor Dr. Marcus Mall, who is also the Director of the Department of Pediatrics, Division of Pneumonology, Immunology and Intensive Medicine and of Charité’s Christiane Herzog Cystic Fibrosis Center. He adds: “Thankfully, things have changed, and most patients will now live into adulthood. However, life expectancy remains significantly reduced and, for many patients, the disease burden is extremely high.” Previous treatments had been primarily symptomatic in nature: special physiotherapy and inhaled therapies help patients to clear and cough up thick secretions from their lungs; antibiotics help to control infections; medications replace missing digestive enzymes; and a high fat diet helps to combat malnutrition. Researchers across the globe have also been striving to develop treatment strategies which address the underlying cause of the disease. Attempts to use gene therapy to deliver non-defective CFTR genes into the cells of patients have so far proved unsuccessful. A different approach, however, appears to have delivered rather promising results. The approach involves ‘CFTR modulators’, drugs capable of correcting the abnormal function of the CFTR channel. “Correcting this abnormality proved particularly difficult in patients with the F508del mutation, as this mutation results in several different molecular defects, which could not be corrected using a single drug,” explains Prof. Mall. The combined use of three separate drugs (elexacaftor, tezacaftor and ivacaftor), has now been shown to be effective in influencing the various molecular defects involved. A total of 403 patients with at least one (of a possible two copies) of the F508del mutation took part in the study and were recruited from more than 100 study centers in North America, Europe and Australia. Use of the triple combination therapy resulted in a substantial and sustained improvement in patients’ health when compared with placebo. Based on the analysis of sweat salt concentration, the authors estimated that, in treated patients, CFTR channel function reached approximately 50% of the level found in healthy individuals. In addition to being shown to be safe, the triple combination therapy was also shown to be generally well tolerated by patients. Side effects resulting in treatment withdrawal were recorded in just one percent of treated patients. Explaining the significance of the results, Prof. Mall says: “Study results suggest that this new triple combination therapy will be suitable for use in up to 90% of patients with cystic fibrosis. Among experts, this is being heralded as a breakthrough in the treatment of a previously fatal disease.” He adds: “The development a preventive treatment for cystic fibrosis, ideally one suitable for use from infancy, would represent a major opportunity to significantly delay – or even entirely prevent – the onset of cystic fibrosis lung disease, effectively turning a previously fatal disease into a treatable one. However, this will still leave approximately ten percent of patients for whom there is no similarly effective causal therapy. Our future research will therefore focus on finding an effective treatment option for this group of patients.” The U.S. Food and Drug Administration (FDA) has approved the new triple combination therapy for patients 12 years and older with at least one F508del mutation in the CFTR gene. The approval was granted in a fast-track procedure following an expedited review. The application for a Europe-wide marketing authorization has been submitted.

A joint press release by Charité and the Medical University of Innsbruck Teams of researchers from Charité – Universitätsmedizin Berlin and the Medical University of Innsbruck have developed a new therapeutic concept for the treatment of temporal lobe epilepsy. It represents a gene therapy capable of suppressing seizures at their site of origin on demand. Having been shown to be effective in an animal model, the new method will now be optimized for clinical use. Results from this research have been published in EMBO Molecular Medicine*. Epilepsy affects approximately 5 million people in Europe. The disorder is characterized by the recurrent and synchronized firing of groups of nerve cells. The propagation of these electrical discharges interrupts normal brain function and produces an epileptic seizure. The most common form of epilepsy is known as temporal lobe epilepsy (TLE), which is characterized by seizures originating in the temporal lobes. Long-term consequences of TLE can include memory problems as well as impaired learning and emotional control. Additionally, TLE patients’ quality of life is severely affected by restrictions on their ability to work, drive a car or do sports. This is further compounded by the fact that the drugs used to treat TLE patients are often unable to adequately control the disorder yet are still associated with severe side effects. For this particular group of patients, surgical removal of the temporal lobe frequently remains the only treatment alternative. However, this treatment is associated with adverse cognitive outcomes and does not guarantee that patients will remain free from seizures. Working alongside Prof. Dr. Christoph Schwarzer (Medical University of Innsbruck's Department of Pharmacology), Prof. Dr. Regine Heilbronn (Director of the Institute of Virology on Charité's Campus Benjamin Franklin) developed a new therapeutic concept for drug-resistant TLE. The new treatment method is based on targeted gene therapy. This technique involves the selective delivery of a specific gene to nerve cells within the area of the brain from which the epileptic seizures originate. The gene provides the cells with the information needed to synthesize dynorphins. These are naturally produced peptides which modulate neural activity. Once the gene has been delivered into the nerve cells, it remains there permanently. The cells then start to produce and store dynorphins. Explaining the new technique's mechanism of action, Prof. Schwarzer says: “High-frequency stimulation of the nerve cells, such as that seen at the beginning of a seizure, results in the release of stored dynorphins. Dynorphin dampens signal transduction and, as a result, the epileptic seizure doesn’t spread.” The neurobiologist and epilepsy expert goes on to add: “As the cells will only release this substance when needed, this type of gene therapy is referred to as ‘release-on-demand’.” Using an animal model, the researchers were able to show that this gene therapy is capable of suppressing epileptic seizures for several months. Reduction of seizures also meant relief from their adverse effects on memory and learning. Moreover, no side effects have been observed so far. This is most probably due to the site-specific release of dynorphin and its short duration of action. Thanks to the substance's on-demand delivery, there was also no evidence of drug tolerance. The researchers then went on to test their new treatment concept using tissue samples obtained from epilepsy patients. They did so with great success, as dynorphin was shown to significantly reduce the severity and frequency of synchronized nerve cell activity in human epileptic tissue. “The results from our study are encouraging, prompting us to hope that this new therapeutic concept could also be successful in humans,” says Prof. Heilbronn. “As a transport vehicle for delivering the dynorphin gene, we are using a virus known as ‘adeno-associated virus’. This has been approved for use in humans and is considered to be safe.” Prof. Heilbronn and Prof. Schwarz hope to make this new gene therapy available for clinical use as rapidly as possible. “We are currently working on the viral vector which ferries the gene to its destination, in order to optimize it for use in humans,” explains Prof. Heilbronn. “Our aim is to have this gene therapy ready for its first ever use in a clinical trial in just a few years.” If the treatment is shown to be effective, this one-off treatment would offer a real alternative to patients on whom TLE drugs fail.

The Berlin Museum of Medical History at Charité (BMM) has today launched the ‘Art of Healing’ exhibition. Prints and paintings by Indigenous Australian artists will be juxtaposed with historic specimens from the museum’s permanent display. The contemporary works of art depict healing practices and medicines from the artists’ own Indigenous communities and cultures. Through their depictions of a rich Indigenous medicinal flora, the artists celebrate a long tradition of healing which predates Western medicine by tens of thousands of years. Contemporary Aboriginal and Torres Strait art also has a role in teaching medical history and serves as a means of transferring knowledge to future generations. The exhibits invite visitors to open their minds and senses, allowing themselves to move beyond cultural borders. Commenting on the current art intervention, Prof. Dr. Thomas Schnalke, Director of the BMM, said: “Our permanent exhibition shows the history of research dedicated to exploring the human body. The main exhibition hall contains approximately 750 specimens, which depict the ways in which pathologists viewed, recorded and interpreted abnormal organs around the turn of the century in 1900. We will now contrast this wholly Western perspective of the human body and its form with ‘the Art of Healing’, an exhibition purposely designed as an art intervention. The exhibits by contemporary Indigenous artists will enable visitors to view medicine from an entirely different perspective.” Developed by the Melbourne Medical History Museum, the exhibition was first shown there in 2018/2019. Stressing the significance of the exhibition, H. E. Ms. Lynette Wood, the Australian Ambassador to Germany, said: “I am delighted that the ‘Art of Healing’ exhibition will be on display at the Berlin Museum of Medical History at Charité from October 2019 to February 2020. This cooperation of two outstanding institutes in Germany and Australia – Charité and University of Melbourne – honours the art, history and achievements of the Indigenous peoples of Australia, and further deepens the German-Australian relationship in the fields of art, academia and research.” The art intervention ‘The Art of Healing: Australian Indigenous Bush Medicine’ will be at the Berlin Museum of Medical History at Charité, Campus Charité Mitte, Charitéplatz 1, 10117 Berlin, from 25 October 2019 to 2 February 2020. Campus address: Virchowweg 17.