Innovation / 08.02.2021
Eckert & Ziegler Wins Order for Hot Cell Construction from Dutch Research Center
Eckert & Ziegler has been awarded a contract to build hot cells with a value of several million euros. The order was placed by the Nuclear Research and Consultancy Group (NRG) in Petten (NL), a global market leader in producing medical isotopes.
The contract includes the planning and construction of hot cells for the GMP-compliant processing of alpha and beta emitters in NRG's so-called FIELD-LAB at the Petten (NL) site. The FIELD-LAB is intended to provide a practical environment for companies and research institutes to develop radiopharmaceuticals for the personalized treatment of cancer and other diseases.
"The order underlines our high level of expertise in special plant engineering for radioactive materials. We are pleased to contribute to this exciting project with our expertise in the fields of radiopharmacy, technology and process development," explains Felix Husmann, Managing Director of the Eckert & Ziegler subsidiary Isotope Technologies Dresden GmbH (ITD), which specializes in plant engineering. "In view of the high global demand for radiopharmaceuticals, special plant engineering is becoming increasingly important. With our many years of experience, we are ideally positioned as a competent partner for the pharmaceutical industry.”
"What convinced us about ITD were the perfect package of their many years of experience, their price and their customer-oriented approach to solutions”, stated Vinod Ramnandanlal, Commercial Director of NRG. “With ITD, we have found a strong partner with whom we can jointly build up the technical infrastructure of our FIELD-LAB and thus accelerate the development of radiopharmaceuticals to fight cancer.”
About Eckert & Ziegler.
Eckert & Ziegler Strahlen- und Medizintechnik AG with more than 800 employees, is one of the world's largest providers of isotope-related components for nuclear medicine and radiation therapy. The company offers services for radiopharmaceuticals at various locations, from early development to commercialization. Eckert & Ziegler shares (ISIN DE0005659700) are listed in the TecDAX index of Deutsche Börse.
Contributing to saving lives.
About Isotope Technologies Dresden
Isotope Technologies Dresden GmbH (ITD) is a subsidiary of Eckert & Ziegler AG and one of the leading international specialists for the development, design and manufacture of hot cells for production, material testing, research & development and other applications in the radiopharmaceutical and industrial sectors. ITD has many years of experience in the development, manufacture and installation of customer-specific special equipment.
About Nuclear Research and Consultancy Group (NRG)
NRG is an internationally operating nuclear service provider. The company produces isotopes, conducts nuclear technological research, is a consultant on the safety and reliability of nuclear installations and provides services related to radiation protection.
FIELD-LAB is an initiative of the Advancing Nuclear Medicine consortium and is a unique breeding ground for the development of new nuclear medicine, which are expected to take an increasing role in the personalized treatment of life-threatening diseases like cancer.
Research / 02.02.2021
Four new groups use single-cell methods to advance medicine
A year ago, BIH, MDC and Charité launched the joint research focus "Single Cell Approaches for Personalised Medicine". Its aim is to use innovative single cell technologies to answer clinical questions. This aspiration will be put into practice by four new junior research groups, which have now started.
They were declared the “2018 Breakthrough of the Year”: new single cell technologies that let researchers analyze the genetic activity of individual cells was chosen as that year’s top scientific achievement by the eminent journal Science. “These revolutionary technologies can play a major role in personalized medicine,” says Professor Christopher Baum, Chair of the BIH Board of Directors and Chief Translational Research Officer of Charité – Universitätsmedizin Berlin. “We have therefore decided to promote the translation of single-cell analysis. We want to expedite the transfer of research findings into clinical practice and vice versa, using clinical observations to explore new avenues of single-cell research.” To this end, the Berlin Institute of Health (BIH), the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) and Charité – Universitätsmedizin Berlin have jointly established the focus area “Single-Cell Approaches to Personalized Medicine.”
State-of-the-art technologies for clinical use
At the core of the new focus area are four new junior research groups, whose leaders were selected in a competitive international recruitment process. Dr. Leif Ludwig, who comes to Berlin from the Broad Institute in Cambridge, Massachusetts, will study with his group how the development and function of stem cells is linked to the DNA of their “cellular power plants,” the mitochondria. Dr. Simon Haas comes from the German Cancer Research Center in Heidelberg and will use cancer stem cell analysis to investigate the origin of leukemia diseases in a targeted way. Dr. Stefanie Grosswendt from Berlin’s Max Planck Institute for Molecular Genetics wants to find out how individual cells know what task they have to perform in the overall network. Dr. Ashley Sanders is Canadian and comes from the European Molecular Biology Laboratory in Heidelberg and will research how new mutations arise in individual cells and drive different characteristics within an organ or tumor.
The junior research groups will be located at the MDC’s Berlin Institute for Medical Systems Biology (BIMSB) in Mitte. Here, they will have access to the latest single-cell methods and can collaborate with excellent systems biologists. BIMSB’s Scientific Director, Professor Nikolaus Rajewsky, has himself played a major role in the development of single-cell technologies. “It was as if we had invented a super microscope with which we could suddenly look inside every cell in a tissue, all the cells at once, and see what was going on at the molecular level inside the cell – for example, when and why it gets sick,” he explains. Rajewsky and Professor Angelika Eggert, Director of the Charité’s Department of Pediatrics, Division of Oncology and Hematology, are the spokespersons for the BIH’s new focus area.
Collaborating with clinicians
BIMSB is located in Berlin’s Mitte district, and thus in close proximity to Campus Charité Mitte (CCM). This will prove to be a big plus for their translational work because each junior research group will also work closely with a clinician at Charité, helping to develop single-cell technologies for real-world medical issues and clinical applications. Ashley Sanders will collaborate with Britta Siegmund, the Director of Charité’s Medical Department, Division of Gastroenterology, Infectiology and Rheumatology. Angelika Eggert will be the clinical partner of Stefanie Grosswendt. Simon Haas and Leif Ludwig will team up with the directors of Charité’s Medical Department, Division of Hematology, Oncology and Tumor Immunology, Lars Bullinger at Campus Virchow-Klinikum (CVK) and Ulrich Keller at Campus Benjamin Franklin (CBF).
“I believe that cancer research in particular will benefit from the new single-cell technologies,” says Eggert. “That’s because tumors are by no means made up wholly of the same kind of cells , but are often a very heterogeneous mixture of distinctly differentiated cancer cells, connective tissue cells, blood vessel cells and immune cells. The more precisely you know the cellular composition of a tumor, the more specifically you can target your strategies to combat it.”
The beginning of a “Cell Hospital”
“I am very pleased and also a little proud that we were able to bring these amazing young people to Berlin,” says Rajewsky. At the same time, they could hardly pass up such a unique opportunity. While the researchers can gain an in-depth understanding of the molecular details, the partnering physicians assess the clinical relevance of the findings and provide the researchers with insights into pathologies that single-cell technologies could potentially elucidate.
“I therefore consider this initiative to be the beginning of a ‘Cell Hospital,’ in which the basic research of the MDC/BIMSB, the clinical research of Charité and the translational research of the BIH are brought together,” explains Rajewsky. “The idea is not only to understand the mechanisms that cause cells to become diseased, but also to discover these cells early enough to restore them to health. I am sure that we will make significant progress for at least some diseases.”
Press release of BIH and Charité together with the MDC
Research / 29.01.2021
Singles or pairs in cancer cells
An important receptor on the surface of cancer and immune cells prefers to remain noncommittal; sometimes it is present as a single, sometimes as a pair. This was first shown by an MDC team in the journal PNAS, and will decisively advance the development of new medications.
It all sounds similar to a dance event – but are singles or couples dancing here? This was the question Ali Isbilir and Dr. Paolo Annibale at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) were trying to answer. However, their investigation did not involve a ballroom, but the cell membrane. The question behind their investigation: does a particular protein receptor on the surface of cancer and immune cells appear alone or connect in pairs?
The receptor is called “CXCR4” – the subject of heated debate among experts in recent years due to its mysterious relationship status. Does it appear in singles or pairs on the cell membrane? And what makes the difference? The research team of the Receptor Signaling Lab at the MDC, has now solved the puzzle of its relationship status for the first time. Their findings were recently published in the journal “Proceedings of the National Academy of Sciences” (PNAS).
CXCR4 is an important receptor on immune and cancer cells
“When CXCR4 is found in large numbers on cancer cells, it also ensures that they can migrate, thereby laying the foundation for metastases,” says lead author Isbilir. Metastases are known to be difficult to treat; some patients die as a result of these secondary tumors.
CXCR4 is also involved in inflammations. The center of inflammation releases messenger substances from the chemokine class. In lymph nodes, chemokines ensure that immune cells form many CXCR4 receptors on their membrane. With the help of these receptors, immune cells can locate the center of inflammation and migrate to it. The name CXCR, which stands for “chemokine receptor,” also refers to this ability. “Such receptors are the most important target structures in pharmaceutical research,” emphasizes Professor Martin Lohse, the last author of the study. “Approximately one-third of all drugs address this class of receptors.”
Whether such receptors are present as pairs or singles is therefore not only central to basic research, but also to the pharmaceutical industry. Using new methods of optical microscopy, the team has now been able to answer this question for the first time. Apparently, CXCR4 wants to remain noncommittal – it occurs temporarily in pairs (as a transient dimer), but also alone (as a monomer). The team found that the relationship status depends largely on how many CXCR4 receptors are located on a cell. If the cell surface is densely occupied, more pairs are formed. If only a few receptors are present, they more often appear singly. At the same time, the researchers could show that certain drugs acting as CXCR4 blockers can suppress pair formation. “It is assumed that CXCR4 pairs negatively affect one’s health. We can use our new microscopic methods to test whether this is really the case,” explains Lohse.
Fluorescent pairs and singles
The scientists combined two recent optical microscopy methods: Using single-molecule microscopy, they were then able to determine the relationship status of individual CXCR4 receptors on the surface of living cells. Fluorescence fluctuation spectroscopy also made it possible to measure the relationship status in cells that had a large number of receptors. The special feature here: to do this, the researchers had to develop a method to efficiently mark all receptors. They also had to develop a highly sensitive microscopy strategy with which they could see individual molecules and their oligomerization. The team presents the new methods in a report in the journal “Nature Protocols”.
“The exciting thing is that we can now use these fluorescence methods to study living cancer cells. We can find out whether CXCR4 is present in pairs or alone,” says Annibale, who is co-head of the Receptor Signaling Lab and also last author of the study in “Nature Protocols”. “And then we can apply CXCR4 blockers to singles and pairs and test which are more effective against tumors. This will hopefully lead to more specific cancer drugs with fewer side effects.”
Pathologists today are also examining the properties of patients’ cancer cells in detail. This allows cancer therapies to be designed in the most personalized and effective way possible. Annibale hopes that the approach could be now used for screening the effects of different drugs on the function of this and similar receptors. This could be helpful in devising new therapies for breast, or lung cancer, for example.
Text: Susanne Donner
Research / 29.01.2021
Naked mole-rats speak in dialect
Some converse in Creole, while others speak Scots, but it’s not only humans who can be identified by the diversity of language they speak. Naked mole-rats have their own dialects, too. Shared dialect also strengthens cohesion within a colony, a team led by MDC researcher Gary Lewin reports in the current "Science" cover story.
In the wild, naked mole-rats live exclusively in underground burrows and tunnels in semi-arid regions of Eastern Africa. The rodents obtain all the water they need through their food such as the underground tubers of plants. Credit: Felix Petermann, MDC
Some converse in Creole, while others speak Scots, but it’s not only humans who can be identified by the diversity of language they speak. Naked mole-rats have their own dialects, too. Shared dialect also strengthens cohesion within a colony, a team led by MDC researcher Gary Lewin reports in the current "Science" cover story.
The computer program, which uses AI, didn’t only identify the animals on the basis of their individual voices: “It also detected similarities in the types of sounds made within a single colony,” says Lewin. The program was therefore also able to identify which colony a specific individual came from. “That meant that each colony probably had its own distinct dialect,” says Barker. But at that point, the research team did not yet know whether the animals were aware of that, and whether they could recognize their own dialect and distinguish it from others.
A preference for kith and kin
In order to find out both those things, Barker performed several experiments. In the first, she repeatedly placed one naked mole-rat in two chambers, connected via a tube. In one chamber the chirping of another naked mole-rat could be heard, while the other chamber was silent. “We observed that the animals always immediately headed for the chamber where the chirps could be heard,” says Barker. If the sounds were made by an individual from the test subject’s own colony, it would give an immediate vocal response, but if they were made by an individual from a foreign colony, the mole-rat would remain silent. “That enabled us to infer that naked mole-rats can recognize their own dialect and will selectively respond to that.”
To ensure that the test subjects were responding to the dialect and not to the voice of an individual known to them, the researchers deliberately created artificial sounds. These contained characteristics of each dialect but did not resemble the voice of a specific individual. “The naked mole-rats produced vocal response to the chirps developed by the computer,” reports Barker. And the experiment worked even when the chamber where the familiar and trusted dialect could be heard was given the scent of a foreign colony. “That demonstrated that the naked mole-rats were responding specifically to dialect rather than scent, and that they have a positive reaction to hearing their own dialect,” says Lewin.
Foster pups learn the dialect of their new colony
In further experiments, the researchers placed three orphaned naked mole-rat pups in foreign colonies where the queen – the only female in naked mole-rat colonies that reproduces – had also recently had a litter. “That ensured that the new arrivals would not be attacked,” explains Barker. “Six months later, our computer program showed that the foster pups had acquired the dialect of their new home.”
It was rather more by chance that the team discovered another interesting fact: a naked mole-rat queen isn’t only responsible for reproduction in her colony, she also plays a decisive role in controlling and preserving dialect integrity. “During the course of the study, one of our colonies lost two queens within relatively quick succession,” says Lewin. “In the anarchy that ensued, we observed that the vocalizations of the other naked mole-rats in the colony began to vary much more widely than usual. Dialect cohesiveness was thus greatly reduced and didn’t return until a few months later, with the ascendance of another high-ranking female as the new queen.”
Insight into the basic workings of human culture
“Human beings and naked mole-rats seem to have much more in common that anyone might have previously thought,” concludes Lewin. “Naked mole-rats have a linguistic culture that developed long before human beings even existed. The next step is to find out what mechanisms in the animals’ brains support this culture, because that could give us important insight into how human culture evolved.”
Text: Anke Brodmerkel
Audio examples. Credit: Alison Barker, Lewin Lab, MDC
Innovation, Patient care / 12.01.2021
Eckert & Ziegler: Seed Implantation for Prostate Cancer Receives Reimbursement for Outpatient Care
Seed implantation for prostate cancer is now to be reimbursed as an outpatient treatment by public health insurances in Germany. This was decided by the Federal Joint Committee (G-BA) with effect from January 8, 2021.
Seed implantation or so called LDR brachytherapy is an organ-preserving, minimally invasive radiation procedure. In this procedure, millimeter-sized, low-level radioactive titanium tubes are inserted into the prostate while protecting the surrounding tissue. Compared to other treatment options, such as removal of the prostate or external radiation therapy, brachytherapy has a different side effect profile that is often more beneficial for the patient.
"We are pleased that the treatment costs of seed brachytherapy for prostate cancer are now to be covered by the public health insurance funds, both on an inpatient and outpatient basis," explains Dr. Harald Hasselmann, member of the Executive Board of Eckert & Ziegler AG and responsible for the Medical segment. "In its summary assessment, the G-BA recognizes the benefit of the method as sufficiently proven and its medical necessity as given."
"As a result of the consideration of benefit and medical necessity, brachytherapy for localized prostate cancer can achieve a PSA-based recurrence-free survival comparable to other curative therapies (radical prostatectomy, percutaneous radiotherapy). The side effect profile of LDR brachytherapy shows advantages in terms of preservation of continence and sexual function as well as bowel function," summarizes the G-BA in its overall assessment of interstitial brachytherapy for localized prostate cancer with a low risk profile.
There are approximately 473,000 new cases of prostate cancer in Europe each year (Globocan, 2020). In Germany, inpatient seed brachytherapy has been included in the reimbursement catalog of health insurance companies since 2004. Eckert & Ziegler BEBIG is the European market leader for seeds and produces them at its Berlin site.
About Eckert & Ziegler.
Eckert & Ziegler Strahlen- und Medizintechnik AG with more than 800 employees, is one of the world's largest providers of isotope-related components for radiation therapy and nuclear medicine. Eckert & Ziegler shares (ISIN DE0005659700) are listed in the TecDAX index of Deutsche Börse.
Research / 12.01.2021
Enhanced speed, contrast, and information: New contrast mechanism improves xenon MRI
Xenon magnetic resonance imaging offers deep insights into the human body and opens up new possibilities in the diagnosis and treatment of diseases. Physicists from the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) in Berlin have now achieved a considerable improvement of the method of detection involving the noble gas xenon. Applying a number of new technical tricks and testing two molecules, the scientists managed, within seconds, to gain more image information from single-shot data acquisition than was previously possible. Moreover, the new contrast mechanism requires less contrast agent and no gadolinium, the subject of continued debate with regard to potential intolerance. The method is around 850 times more sensitive than comparable contrast agents in conventional MRI involving water molecules. The results of the study have now been published in the journal “Chemical Science”.
The ability to detect pathological processes in the body that would otherwise remain hidden using conventional imaging techniques – this is the potential promised by xenon magnetic resonance imaging. In contrast to conventional MRI, this method involves detecting the non-toxic noble gas xenon rather than water molecules. Thanks to the special magnetization of xenon, it has an extremely high signal strength in MRI. In addition, xenon imaging also has analytical potential because molecules that interact with xenon can be used as drug carriers that can now be localized and characterized using MRI.
Physicists at the FMP have been working for years to further perfect xenon MRI so that it can be used, for example, in the diagnosis and treatment of cancer. Following the discovery of several molecules that are able to bind the noble gas xenon very well to deliver high-contrast images from inside the body, Dr. Leif Schröder’s team has now achieved another success.
“We have made accessible another contrast mechanism that is capable of generating significantly more image information than the previous method in a shorter space of time,” explained Leif Schröder. “The so-called relaxivity is much higher, which means that we need much less contrast agent than required by conventional methods to generate image contrast, which is extremely beneficial, particularly for medical applications.”
T2 contrast needs only short contact time
The work now published in “Chemical Science” focused on the T2 contrast – one of the two contrast parameters in magnetic resonance imaging alongside T1 – and how it can be influenced by the two molecules cryptophane-A monoacid (CrA-ma) and cucurbituril (CB6). Although these two metal-free molecules are considered highly potent candidates for xenon MRI, this question had not been investigated previously.
Leif Schröder and his colleague Martin Kunth were able to demonstrate that even short contact times between xenon and the molecule resulted in a signal change. A single shot involving elaborate, continuous observation of the signal suffices to be able to display the T2 contrast for an entire series of images. Previously, at least two measurements were required for a single image – one with an “on” signal and the other with an “off” signal – and it took at least 30 or seconds for an image to be encoded. The new contrast mechanism manages this in around 7 seconds from just a single shot.
“It results in extreme time savings compared to the old method,” remarked Martin Kunth. Another advantage of the new mechanism is that no additional reference images or controversial metal complexes are needed to create the T2 contrast. In addition, more than 1,000 images with progressive contrast can now be reconstructed from a single continuous signal. The conventional method was only able to generate a maximum of 30 images, each of which had to be taken separately, involving far greater effort. “Essentially, it is a very simple measurement; we need just one data set to obtain an information-rich series of images with a much better spatial resolution,” emphasized the physicist.
Data with a high informative value
The simple measurement is coupled with complex data processing, which is also innovative. The software, programmed by the FMP researchers, is able to compute more than just relative signal comparisons – where is it lighter, and where darker. In fact, it is able for the first time to calculate absolute numbers for certain physical parameters. The numbers describe the exact exchange rate between xenon and the molecules, enabling conclusions to be drawn on aspects such as the stability of a molecule as a drug carrier.
“Drug transporters must possess a certain degree of stability to ensure that they do not release the drug too early or too late. We are now able to measure this property, as well as the activation energy needed for entering the drug carrier,” stated Martin Kunth, describing one of the many new potential applications.
“In a nutshell, our new method enables us not only to improve clinical imaging, but also to provide answers to pharmacological or chemical-analytical questions,” added Leif Schröder. “As such, we have taken xenon MRI a crucial step forward, which will now benefit all researchers and clinics that work with it.”
Kunth M., Schröder L.; Binding Site Exchange Kinetics revealed through Efficient Spin-Spin Dephasing of Hyperpolarized 129Xe, Chemical Science 2021, 12, 158-169, DOI: 10.1039/D0SC04835F
Text press release: Beatrice Hamberger, Translation: Teresa Gehrs
Research, Patient care / 11.01.2021
A potent weapon against lymphomas
MDC researchers have developed a new approach to CAR T-cell therapy. The team has shown in Nature Communications that the procedure is very effective, especially when it comes to fighting follicular lymphomas and chronic lymphocytic leukemia, the most common type of blood cancer in adults.
The body’s defense system generally does not recognize cancer cells as dangerous. To correct this sometimes fatal error, researchers are investigating a clever new idea, one that involves taking a handful of immune cells from cancer patients and “upgrading” them in the laboratory so that they recognize certain surface proteins in the malignant cells. The researchers then multiply the immune cells and inject them back into the patients’ blood – setting them off on a journey through the body to detect and attack all cancer cells in a targeted way.
In fact, the first treatments based on this idea have already been approved: So-called CAR T cells have been used in Europe since 2018, particularly in patients with B-cell lymphomas for whom conventional cancer therapies have not worked.
T cells are like the immune system’s police force. The abbreviation CAR stands for “chimeric antigen receptor“ – meaning that the cellular police force is equipped with a new, laboratory-designed special antenna that targets a surface protein on the cancer cells. Thanks to this antenna, a small number of T cells can round up a large number of cancer cells and destroy them. Ideally, the CAR T cells patrol the body for weeks, months or even years and thus prevent tumor relapse.
A kind of signpost for B cells
Until now, the antenna on the CAR T cells was primarily directed against the protein CD19, which B cells – a type of immune cells – carry on their surface. Yet this form of therapy is by no means effective in all patients. A team led by Dr. Uta Höpken, head of the Microenvironmental Regulation in Autoimmunity and Cancer Lab at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), has now developed a new twist on this therapy that sensitizes the T cells in the laboratory to a different identifying feature: the B-cell homing protein CXCR5.
“CXCR5 was first described at the MDC more than 20 years ago, and I have been studying this protein myself for almost as long,” says Höpken. “I am therefore very pleased that we have now succeeded in using CXCR5 to effectively combat non-Hodgkin's lymphomas, such as follicular and mantle cell lymphoma as well as chronic lymphocytic leukemias, in the laboratory.” This protein is a receptor that helps mature B cells move from the bone marrow – where they are produced – to immune system organs such as the lymph nodes and spleen. “Without the receptor, the B cells would not find their way to their target site, the B-cell follicles of these lymphoid organs,” Höpken explains.
A well-suited target
“All mature B cells, including malignant ones, carry this receptor on their surface. So it seemed to us to be well suited to detect B-cell tumors – thereby enabling CAR-T cells directed against CXCR5 to attack the cancer,” says Janina Pfeilschifter, a PhD student in Höpken’s team. She and Dr. Mario Bunse from the same research group are the lead authors of the paper, which appeared in the journal Nature Communications. “In our study, we have shown through experiments with human cancer cells and two mouse models that this immunotherapy is most likely safe and very effective,” says Pfeilschifter.
The new approach may be particularly well suited for patients with a follicular lymphoma or chronic lymphocytic leukemia (CLL). “Both types of cancer involve not only B cells but also follicular T helper cells, which also carry CXCR5 on their surface,” Bunse explains. The special antenna for the identifying feature, the CXCR5-CAR, was generated by Dr. Julia Bluhm during her time as a PhD student in the MDC’s Translational Tumorimmunology Lab, which is headed by physician Dr. Armin Rehm. He and Höpken are the corresponding authors of the study.
First successes in the petri dish
Pfeilschifter and Bunse first showed that various human cells, for example, from blood vessels, the gut and the brain, do not carry the CXCR5 receptor on their surface and are therefore not attacked in the petri dish by T cells equipped with CXCR5-CAR. “This is important to prevent unexpected organ damage from occurring during therapy,” Pfeilschifter explains. In contrast, experiments with human tumor cell lines showed that malignant B cells from very different forms of B-non-Hodgkin’s lymphoma all display the receptor.
Professor Jörg Westermann, from the Division of Hematology, Oncology and Tumor Immunology in the Medical Department of Charité – Universitätsmedizin Berlin at the Campus Virchow Clinic, also provided the team with tumor cells from patients with CLL or B-non-Hodgkin’s lymphomas. “There, too, we were able to detect CXCR5 on all B-lymphoma cells and follicular T helper cells,” Pfeilschifter says. When she and Bunse placed the tumor cells in the petri dish together with the CXCR5-targeted CAR T cells, almost all of the malignant B and T helper cells disappeared from the tissue sample after 48 hours.
Mice with leukemia were cured
The researchers also tested the new procedure on two mouse models. “The CAR T cells are infused into the blood of cancer patients,” Höpken says. “So animal research is needed to show that the cells home to the niches where the cancer resides, multiply there and then do their job effectively.”
One model consisted of animals with a severely suppressed immune system, which could therefore be treated with human CAR T cells without causing rejection reactions. “We also developed a pure mouse model for CLL specifically for the current study,” Bunse reports. “We administered mouse CAR T cells against CXCR5 to these animals by infusion and were able to eliminate mature B cells and T helper cells, including malignant ones, from the B-cell follicles of the lymphoid organs.”
The researchers discovered no serious side effects in the mice. “We know from experience with cancer patients that CAR T-cell therapy increases the risk of infection for a few months,” Rehm says. But in practice this side effect is almost always easily managed.
A clinical trial is in the works
”No laboratory can tackle such a study on its own,” Höpken emphasizes. “It has only come about thanks to a successful collaboration between many colleagues at the MDC and Charité.” For her, the study is the first step toward creating a “living drug” – similar to other cellular immunotherapies being developed at MDC. “We are already cooperating with two cancer specialists at Charité and are currently working with them to prepare a phase 1/2 clinical trial,” adds Höpken’s colleague Rehm. Both hope that the first patients will begin to benefit from their new CAR-T cell therapy in the near future.
Text: Anke Brodmerkel
The German José Carreras Leukemia Foundation has funded the research with around 240,000 euros over a period of three years. The non-profit organization supports forward-looking research projects and infrastructure projects that investigate the causes of leukemia and improve treatment, as well as social projects.
Mario Bunse, Janina Pfeilschifter et al. (2021): “CXCR5 CAR-T cells simultaneously target B cell non-Hodgkin’s lymphoma and tumor-supportive follicular T helper cells”. Nature Communications, DOI: 10.1038/s41467-020-20488-3.
Innovation / 05.01.2021
Single Mouse Trials: mimicking clinical phase II trials in PDX models with manageable costs and efforts
The long and successful collaboration of EPO with the Charité University Hospital in Berlin recently led to the following publication:
Combination of copanlisib with cetuximab improves tumor response in cetuximab-resistant patient-derived xenografts of head and neck cancer
The article has been published in the peer-reviewed journal Oncotarget (Oncotarget, 2020, Vol. 11, (No. 41), pp: 3688-3697).
Head and neck squamous cell carcinoma (HNSCC) represents the 6th most common type of cancer and despite recent advances remains an area of high unmet medical need. Around 66% of HNSCCs harbor genomic alterations in one of the major components of the phosphoinositide 3-kinase (PI3K) signaling pathway, making PI3K an attractive target.
EPO has established a thoroughly characterized panel of more than 70 HNSCC patient-derived xenograft (PDX) models (HPV +/-). To explore the activity of the PI3K inhibitor copanlisib in monotherapy and in combination with the EGFR inhibitor cetuximab, 33 PDX models were selected out of this panel for a mouse clinical trial together with Bayer AG.
How YOUR projects could benefit from it
We successfully applied the one mouse, one tumor, one treatment trial design on our HNSCC PDX panel to establish a sound preclinical rational for the evaluation of copanlisib in combination with cetuximab in a clinical setting. This demonstrates that a large number of heterogeneous tumors can be evaluated and a clinical phase II trial can be mimicked in PDX models with manageable costs and efforts.
Mouse clinical trials in oncology drug development
Around 85% of preclinical agents entering oncology clinical trials fail to demonstrate sufficient safety or efficacy to gain regulatory approval. This high failure rate highlights the continued limitations of the predictive value of existing preclinical models and clearly shows an urgent need for experimental systems that better replicate the diversity of human tumor biology in a preclinical setting. While PDX models faithfully recapitulate human tumor biology and predict patient drug response, studies with small numbers of models have limited value in predicting potential clinical-trial response at the population level. Mouse clinical trials (MCTs) are population-based efficacy studies mimicking human trials. For these, the single mouse study design is a feasible and very cost-effective approach to reliably screen a large numbers of models with diverse genetic characteristics.
Important considerations for your study
Similar to clinical trials, rational design of MCTs requires statistical power calculation and sample size determination, thus the number of mouse models as well as the number of mice per model needs to be carefully considered. In general, the study design depends on factors such as the study aims, the efficacy of the applied drugs and the available resources. For example, when there is only a limited number of suitable PDXs, e.g., PDXs carrying a particular mutation or PDXs of a specific subtype, the number of mice per PDX could be increased to boost statistical power. Our scientific and bioinformatics team will actively support you to tailor a study design specifically for your needs based on detailed statistical and bioinformatics analyses.
There is a broad variety of possible applications for single mouse trials. These include exploration of new drug combinations as demonstrated by our new publication, comprehensive analysis of one tumor entity, identification of biomarkers for predicting treatment responses, screening of a large number of compounds in diverse tumor populations and many more. Please reach out to learn more!
Source: EPO Gmbh Newsletter December 2020: Single Mouse Trialsepo-berlin.com
Research, Patient care / 30.12.2020
Integration of BIH into Charité and the privileged partnership with the MDC
Joint press release of the Berlin Institute of Health and Charité – Universitätsmedizin Berlin
On January 1, 2021, the Berlin Institute of Health (BIH) will become the translational research unit of Charité – Universitätsmedizin Berlin and will then form – alongside the hospital and the medical faculty – Charité’s third pillar. The Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) will become the Privileged Partner of the BIH. The three institutions are completing the final stage of implementing the administrative agreement between the federal government and the State of Berlin that was signed by German Research Minister Anja Karliczek and Governing Mayor of Berlin and Senator for Science and Research Michael Müller in July 2019. Through this novel science policy initiative, the federal government will be structurally involved for the first time in an institution of a university medical center and will have a seat on Charité’s Supervisory Board.
German Research Minister Anja Karliczek explains: “The integration of the BIH into Charité will finally become reality at the turn of the year. We are placing great hope in this new structure, which closely links together medical research and clinical practice. I would like to thank all those involved for their commitment and dedication to implementing the integration over the past months. We are all very excited about the research activities. I wish the BIH, Charité and the Max Delbrück Center much success with their joint cooperation. I am convinced that this alliance will become a national and international beacon for translational biomedical research.”
Governing Mayor of Berlin and Senator for Science and Research Michael Müller says: “The integration of the BIH into Charité will greatly benefit medical research and the healthcare hub of Berlin, but above all patients all across Germany. The path was not always easy, but it was always right to pursue this goal. I would therefore like to warmly thank everyone who in the past months has helped bring this process to a successful conclusion. The fact that the federal government is so strongly committed to a state institution on a permanent basis and that we are all working in unison is not something that can be taken for granted and is a sign of confidence in the outstanding work that is being done at Charité, the BIH and the MDC.”
Professor Christopher Baum will in the future represent the BIH in Charité’s Board of Directors as Board Member responsible for the translational research unit. He welcomes the integration for he is convinced that translational medicine depends on close interaction between research and clinical care. “We belong together, but at the same time we will maintain our special identity and purpose. We are working together for the benefit of patients who urgently need new medical approaches. Both perspectives – that of today’s clinical care practices and that of tomorrow’s medicines – stimulate our scientific work.”
Professor Heyo K. Kroemer,Chief Executive Officer of Charité, welcomes the BIH as the third pillar for translational research within Charité: “I look forward to working with the BIH to further advance the translation of research findings into clinical care for our patients and to fruitfully use the synergies between Charité and the BIH. Yet the integration is not only important for us, but has the potential to serve as a blueprint for future federal-state cooperation in supporting research. Special thanks are especially due to Axel Pries, who over the past years has not only been deeply committed to this project, but has also played a key role in driving it forward.”
Professor Axel Radlach Pries, Dean of Charité, served for two years, until early October 2020, as interim Chief Executive Officer of the BIH. He looks with satisfaction on what has been achieved and with much anticipation to the next phase: “Integrating the BIH into Charité and establishing the Privileged Partnership with the MDC has required very extensive coordination between our three institutions. The implementation of the administrative agreement can now be concluded as planned and without any notable problems. Parallel to this process, the BIH has established new structures, made dynamic scientific progress and attracted outstanding researchers to Berlin. I therefore have no doubt that going forward the BIH will be successful as the Charité’s third pillar.”
Professor Thomas Sommer, interim Scientific Director of the MDC, says: “I very much look forward to the close collaboration. As a bridge between basic research and clinical practice, the BIH is the ideal partner for us in Berlin. Our scientists provide innovative capabilities in vascular biomedicine and single cell analysis and help advance technology facilities. The MDC, the BIH and Charité want to further develop the idea of a translational research commons focused on improving the well-being of patients. Our close links will give the healthcare hub of Berlin a boost.”
Turning research into health
The mission of the BIH, which was founded in 2013, is to transfer basic research findings to the patient’s bedside and, vice versa, to use clinical observations to develop new research ideas. In the past this has already required close collaboration between the BIH, Charité and the MDC. For example, Charité and the BIH jointly run the Clinical Study Center (CSC) in order to significantly improve the quality of all clinical studies and together with other partners have launched the BIH Charité Clinician Scientist Program to train a new generation of scientists with translational training. The technology transfer unit BIH Innovations is also a joint undertaking by the two institutions. During the coronavirus pandemic, BIH researchers have teamed up with Charité scientists and physicians to make valuable discoveries in the fight against the SARS-CoV-2 virus and the COVID-19 disease. Their findings have been published in leading scientific journals.
“The trusting collaboration between Charité and the BIH, as well as the MDC, is not only tried and tested, but also works excellently,” says Professor Kroemer. “The successful application of our three institutions to be a location of the National Center for Tumor Diseases in Berlin is an expression of this. Now it’s a matter of optimizing the framework conditions even further to create the best environment for translational research.”
Promoting translation nationwide
With its integration into Charité, the BIH has also received a mandate from the federal government to support promising translational projects throughout Germany. “We are delighted to take on this mandate,” says Christopher Baum. “And here, in particular, I see us playing a role in rare and complex diseases, for which we want to specifically expand the possibilities of university medicine.” Baum also wants to further develop translation into an exact science whose results can not only be measured quantitatively and objectively but also reproduced. “That will be necessary in order to identify those projects that are most promising and take the best possible next steps in each case,” he explains. Here the BIH Quest Center has already done crucial groundwork to raise the quality of biomedical research.
Single cells, blood vessels and regenerative medicine
The BIH has established three focus areas in collaboration with Charité and the MDC, selecting areas that link up excellent research approaches with clinical expertise. The focus area “Single Cell Technologies for Personalized Medicine” aims to use innovative single cell technologies to answer clinical research questions, while the focus area “Translational Vascular Biomedicine” seeks to gain a better understanding of how malfunctions in the smallest of blood vessels are responsible for many common diseases. Through the full takeover of the BCRT, the BIH Center for Regenerative Therapies, from 2021 and the cooperation with the German Stem Cell Network (GSCN), the BIH will conduct research in particular in the field of stem cell research and advanced therapy medicinal products (ATMPs) and translate its findings into practice.
Multiple locations for the BIH
The integration of the BIH into Charité will increase the number of scientific teams belonging to the BIH from 43 at present to 58; by the end of 2021 this number will be 71. The BIH will then have around 400 employees, who will be spread across multiple locations: Starting in March, the scientific teams working on vascular biomedicine will move into the Käthe Beutler Building in Berlin-Buch, in the immediate vicinity of the Privileged Partner, the MDC. In this building, named after a Jewish pediatrician and researcher, BIH and MDC teams will work together under one roof. In the Outpatient, Translation and Innovation Center (Ambulanz-, Translations- und Innovationszentrum – ATIZ) in Berlin-Mitte, which celebrated its topping-out ceremony in July 2020 and is scheduled for completion in early 2022, teams involved in digital medicine, such as the BIH Digital Health Center, and other research groups will work together with experts from Charité. ATIZ will also house the joint Clinical Study Center. The single cells focus area will be based at the MDC’s Berlin Institute for Medical Systems Biology (BIMSB), which is also located in Berlin-Mitte. The scientific teams working in the field of regenerative medicine will primarily carry out research at the Charité Campus Virchow Clinic in Berlin-Wedding, on the premises of the BCRT. The BIH Digital Health Accelerator will move into new offices at Zirkus in Berlin-Mitte at the beginning of 2021.
Research / 21.12.2020
The Achilles’ heel of cancer stem cells
Colon cancer stem cells have one weak spot: the enzyme Mll1. An MDC team led by Walter Birchmeier has now shown in Nature Communications that blocking this protein prevents the development of new tumors in the body.
Since colonoscopies were introduced in Germany for early cancer detection, the number of diagnoses of advanced cancer every year has decreased, as precancerous lesions can now be detected and immediately removed as part of the examination. As a result, the death rate from colon cancer has also gone down – by 26 percent in women and 21 percent in men. Nevertheless, it remains the fourth deadliest cancer in the Western world – just behind lung, prostate and breast cancer. This is because the slow-growing tumors only become noticeable in the advanced stages of the disease and are therefore often diagnosed too late. Survival rate for advanced colorectal cancer is just five percent.
“Treatment options are very limited – not least because the cancer can return even after successful chemotherapy,” explains Johanna Grinat, the study’s lead author and a doctoral student in the Signal Transduction in Development and Cancer Lab. “The recurrent cancer is often more aggressive than the original tumor, which is thought to be caused by cancer stem cells. So we took a closer look at these cells.”
Molecular switch found in cancer stem cells
The researchers led by Professor Walter Birchmeier identified Mll1, a protein that regulates stem cell genes in mice and in human colon cancer cells. In mice, the team was able to genetically trigger the formation of intestinal tumors. However, if the mice lacked the gene for Mll1, no tumors were able to be induced. And this seems to be the case in humans as well: Human colon cancer cell cultures that the team enriched with cancer stem cells lost some of their stem cell properties and behaved less aggressively when Mll1 was blocked. Together with Professor Eduard Batlle and bioinformaticians at the IRB in Barcelona, the MDC group used clinical data to show that colon cancer patients whose tumors have a large amount of this protein have a worse prognosis than patients with tumors that contain little Mll1.
Mll1 is an enzyme that sits on the DNA and controls the expression of certain genes “epigenetically,” as the researchers say. “It primarily does this in cancer stem cells, where the Wnt signaling pathway is strongly activated,” Grinat explains. “This means that, by deactivating it, we can specifically treat cancer stem cells.”
The Wnt signaling pathway regulates the self-renewal and division of stem cells. If mutations occur that trigger a more active Wnt signaling cascade, the affected stem cells become more resistant than healthy stem cells. They then multiply uncontrollably and form tumors. Although chemotherapy slows down the cell division, it can also increase the selection pressure on cancer stem cells: “They become resistant to the treatment and form new tumors that, due to the mutation, grow more rapidly and are even more aggressive,” says Dr. Julian Heuberger. This is why it is so important, he explains, to understand the regulatory mechanisms of cancer stem cells in particular. The postdoctoral researcher is also lead author and head of the study and now works in the Division of Hepatology and Gastroenterology in Charité’s Medical Department. “With Mll1,” he adds, “we have found a molecular switch that primarily controls the self-renewal and division of cancer stem cells in colon cancer”
Hope and more effective therapies
Genetically “knocking out” a gene, as the scientists did with mice, is not possible in humans. In mice, the formation of cancer stem cells can be followed over time and there are always enough stem cells available for experiments. However, MII1 could be blocked with a chemical drug. Small molecules have already been developed for this research, for example, the inhibitors MI-2 and MM-401, which bind to essential Mll1 complexes and thereby inactivate its function. “Understanding the way these molecules work will enable us to develop and test these and even more clinically effective Mll1 inhibitors,” says Birchmeier, who is the study’s last author.
Healthy stem cells in the intestine are apparently not blocked in the process. “We were able to use another system in mice, salivary gland cancer cells, to show that Mll1 only affects cancer cells and not healthy stem cells,” says Birchmeier. This also provides hope for the treatment of other types of cancer, as animal models have shown that head and neck tumors have the same Achilles’ heel. “On the basis of our mouse studies, clinical trials are currently being conducted at the University Hospital of Düsseldorf to evaluate the use of Mll1 inhibitors in the treatment of head and neck tumors.“
If they are successful, patients with colon cancer could be treated in the future with both chemotherapy and Mll1 inhibitors, i.e., therapeutics that specifically impede cancer stem cells. This increases the chances of a successful treatment – even with advanced colon cancer.
Text: Catarina Pietschmann
Research, Innovation, Patient care, Education / 21.12.2020
Calling all young STEM talent
The 57th edition of the “Jugend forscht” competition will soon kick off under the theme “Lass Zukunft da.” The MDC is once again co-sponsoring the search for tomorrow’s scientists – this year to be held fully virtual. The young researchers apparently don’t mind the new format: almost 9,000 children and young people have signed up for the competition so far.
During extraordinary times like this pandemic, it is particularly important to promote young talent in the fields of science, technology, engineering and mathematics (STEM) through special initiatives. The Germany-wide young researcher competition “Jugend forscht” is therefore going virtual this year, with the regional round starting in February.
For the first time, Buch campus is one of the three locations in Berlin. The competition’s sponsors include the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Campus Berlin-Buch GmbH and – as an associate sponsor – the Experimental and Clinical Research Center (ECRC) of the MDC and Charité – Universitätsmedizin Berlin.
“Let there be a future”
Despite facing difficult circumstances at school and in their free time, almost 9,000 children and young people have signed up and submitted a project idea. This year, they will present their research projects under the theme “Lass Zukunft da” (Let there be a future) at over 120 competitions across Germany.
A total of 64 projects by schoolchildren and students between the ages of 10 and 21 will compete in the regional round hosted by the Buch campus. The sponsoring institutions are in charge of organizing a program for the regional rounds – from the introductory event to the presentations and their evaluation by the jury to the award ceremony.
“As a science and biotech campus, we’re excited about being able to support the ‘Jugend forscht’ competition,” says Dr. Ulrich Scheller, managing director of Campus Berlin-Buch GmbH. “Promoting young talent in the STEM fields is one of our key aims, which we also pursue through other activities such as the Life Science Learning Lab (Gläsernes Labor) for schoolchildren.”
About the competition
“Jugend forscht” is Germany’s biggest and best-known competition for the next generation of researchers. It is a joint initiative of the federal government, the magazine Stern, the business and scientific communities, and schools. The aim is to support talented achievers in the areas of science, technology, engineering and mathematics (STEM). Young researchers compete each year in seven subject areas. Gifted children up to the age of 14 can take part in the junior segment “Schüler experimentieren,” while “Jugend forscht” is open to young people from the age of 15 onwards. The non-profit association Stiftung Jugend forscht e.V. organizes the competition. (https://www.jugend-forscht.de/information-in-english.html)
Innovation / 17.12.2020
Glycotope announces licensing agreement with ONK Therapeutics for humanized GlycoBody targeting TA-MUC1
GlycoBody to be integrated into ONK pre-clinical program ONKT103, for solid tumors.
Glycotope GmbH, an oncology/immuno-oncology platform company built on world-leading glycobiology expertise, today announces that is has signed an agreement to license a humanized, tumor-specific antibody (GlycoBody) targeting an aberrantly glycosylated tumor associated form of MUC1 (TA-MUC1) to ONK Therapeutics Ltd. (ONK), an innovative natural killer (NK) cell therapy company.
The GlycoBody will be integrated into ONKs pre-clinical program ONKT103, for solid tumors. ONK’s unique platform approach combines the expression of a chimeric antigen receptor (CAR) and a high affinity, membrane-bound TNF related apoptosis inducing ligand variant (TRAILv).
Multiple solid tumor types express the mucin MUC1, including non-small cell lung cancer, breast cancer and ovarian cancer. MUC1 is also expressed on healthy tissues and previous attempts to target this antigen have proved problematic. By utilizing Glycotope’s antibody, ONK can tailor its CAR to target the glycosylation pattern distinct to tumor associated MUC1 (TA-MUC1) with specific recognition of the carbohydrate antigens Tn and T on MUC1. The expression of these antigens is restricted to cancer cells and by targeting them ONK hopes to increase tumor-specificity and reduce the potential for on-target off-tumor toxicity.
Henner Kollenberg, Managing Director of Glycotope GmbH commented “This is an exciting development. Our technology platform has identified the glycosylation pattern that could enable ONK to unlock the potential of TA-MUC1 as a solid tumor target with their unique dual-targeted NK cell therapy approach. This represents further validation of our platform’s ability to enable the development of highly-specific immunotherapies across a broad range of cancer indications.”
Managing Director Phone: +49 30 9489 2600
Chris Gardner, Chris Welsh
Consilium Strategic Communications
Phone: +44 (0) 20 3709 5700
Glycotope is a biotechnology company utilizing a proprietary technology platform to develop highly tumor-specific monoclonal antibodies called GlycoBodies. GlycoBodies bind to targets (GlycoTargets) tumor-specific carbohydrate structure dependent, enabling the development of highly-specific immunotherapies across a broad range of cancer indications. Glycotope has to date discovered in excess of 150 GlycoTargets with GlycoBodies against eight of these targets currently under development.
Each GlycoBody can be developed in an array of modalities with different modes of action such as Antibody-drug conjugates, CAR/cell therapies or bispecifics, providing a unique offering in the (immuno) oncology space. Currently six clinical and pre-clinical programs based on the GlycoBody technology are under development by Glycotope or its licensing partners. Visit www.glycotope.com.
About ONK Therapeutics – www.onktherapeutics.com
ONK Therapeutics Ltd is an innovative cell therapy company dedicated to developing the next generation of ‘off-the-shelf’, dual-targeted NK cell therapies targeting solid and hematological cancers.
Its core proprietary platform is based on a dual-targeted NK cell expressing both a chimeric antigen receptor (CAR) targeting a known tumor antigen and a TNF-related apoptosis-inducing ligand variant (TRAILv) targeting the death receptor pathway (i.e. DR4 or DR5). This unique approach has the potential to enhance efficacy by addressing both intrinsic (e.g. CAR engagement of a tumor-specific antigen) and extrinsic (e.g. signaling through the death receptor pathway) apoptotic pathways and to reduce the susceptibility to possible target antigen escape through the engagement of tumor antigen-independent TRAILv.
ONK Therapeutics is headquartered in the med-tech hub of Galway, Ireland, with a wholly-owned US subsidiary, ONK Therapeutics, Inc. based at JLabs @ San Diego. Shareholders include Acorn Bioventures, ALSHC (principally Seamus Mulligan), and Enterprise Ireland.
economic development / 14.12.2020
Alrise announces acquisition of its ImSus® drug delivery technology by Ferring International Center S.A.
The drug delivery specialist Alrise Biosystems GmbH has entered into an Asset Purchase and Exclusive License Agreement with Ferring International Center S.A. for the development and commercialisation of products manufactured with Alrise’s ImSus® platform technology.
Alrise and Ferring have been working together since 2017 on the development of an injectable, controlled-release formulation of a peptide therapeutic. Based on the successful partnership Ferring has now exercised its option to enter into a definite agreement to further leverage and get exclusive access to Alrise’s process knowhow and intellectual property rights. The parties have committed not to disclose the contractual terms and conditions as well as details of the on-going product development.
“We are pleased that we were able to continue and strengthen our successful collaboration with Ferring”, stated Dr. Heiko Seemann, Alrise’s Managing Director. “This agreement paves the way to making the first product utilising our ImSus® technology platform available to patients.”
“On this occasion we would like to express our special thanks to our investors IBB Ventures and Creathor Venture for their long-standing trust and support”, Dr. Volker Rindler, Alrise’s Managing Director, added. “Our thanks also go to our consultants from tytonis b.v. and Bay Pharma GmbH for their help in various business development matters.”
Alrise Biosystems GmbH is a drug delivery company located in the Biotech Park Berlin-Buch and is managed by Dr. Heiko Seemann und Dr. Volker Rindler. Through application of its ImSus® technology platform Alrise develops drug-loaded micro particle formulations, which are used for injectable, controlled-release depot products. The company has been financed primarily through venture capital investments from the VC companies Creathor Venture and IBB Ventures
Quelle: Press release of Alrise Biosystems GmbHwww.alrise.de
Research / 11.12.2020
Muscle cell secrets
A muscle fiber consists of just one cell, but many nuclei. A team at the MDC led by Professor Carmen Birchmeier has now shown just how varied these nuclei are. The study, which has been published in Nature Communications, can help us better understand muscle diseases such as Duchenne muscular dystrophy.
Usually, each cell has exactly one nucleus. But the cells of our skeletal muscles are different: These long, fibrous cells have a comparatively large cytoplasm that contains hundreds of nuclei. But up to now, we have known very little about the extent to which the nuclei of a single muscle fiber differ from each other in terms of their gene activity, and what effect this has on the function of the muscle.
A team led by Professor Carmen Birchmeier, head of the research group on Developmental Biology / Signal Transduction at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), has now unlocked some of the secrets contained in these muscle cell nuclei. As the researchers report in the journal Nature Communications, the team investigated the gene expression of cell nuclei using a still quite novel technique called single-nucleus RNA sequencing – and in the process, they came across an unexpectedly high variety of genetic activity.
Muscle fibers resemble entire tissues
“Due to the heterogeneity of its nuclei, a single muscle cell can act almost like a tissue, which consists of a variety of very different cell types,” explains Dr. Minchul Kim, a postdoctoral researcher in Birchmeier’s team and one of the two lead authors of the study. “This enables the cell to fulfill its numerous tasks, like communicating with neurons or producing certain muscle proteins.”
Kim undertook the majority of the experimental work in the study, and his data was also evaluated at the MDC. The bioinformatics analyses were performed by Dr. Altuna Akalin, head of the Bioinformatics and Omics Data Science Platform at the MDC’s Berlin Institute of Medical Systems Biology (BIMSB), and Dr. Vedran Franke, a postdoctoral fellow in Akalin’s team and the study’s co-lead author. “It was only thanks to the constant dialogue between the experiment-based and theory-based teams that we were we able to arrive at our results, which offer important insight for research into muscle diseases,” emphasizes Birchmeier. “New techniques in molecular biology such as single cell sequencing create large amounts of data. It is essential that computational labs are part of the process early on as analysis is as important as data generation,” adds Akalin.
Injured muscles contain activated growth-promoting genes
The researchers began by studying the gene expression of several thousand nuclei from ordinary muscle fibers of mice, as well as nuclei from muscle fibers that were regenerating after an injury. The team genetically labeled the nuclei and isolated them from the cells. “We wanted to find out whether a difference in gene activity could be observed between the resting and the growing muscle,” says Birchmeier.
And they did indeed find such differences. For example, the researchers observed that the regenerating muscle contained more active genes responsible for triggering muscle growth. “What really astonished us, however, was the fact that, in both muscle fiber types, we found a huge variety of different types of nuclei, each with different patterns of gene activity,” explains Birchmeier.
Stumbling across unknown nuclei types
Before the study, it was already known that different genes are active in nuclei located in the vicinity of a site of neuronal innervation than in the other nuclei. “However, we have now discovered many new types of specialized nuclei, all of which have very specific gene expression patterns,” says Kim. Some of these nuclei are located in clusters close to other cells adjacent to the muscle fiber: for example, cells of the tendon or perimysium – a connective tissue sheath that surrounds a bundle of muscle fibers.
“Other specialized nuclei seem to control local metabolism or protein synthesis and are distributed throughout the muscle fiber,” Kim explains. However, it is not yet clear what exactly the active genes in the nuclei do: “We have come across hundreds of genes in previously unknown small groups of nuclei in the muscle fiber that appear to be activated,” reports Birchmeier.
Muscle dystrophy seemingly causes many nuclei types to be lost
In a next step, the team studied the muscle fiber nuclei of mice with Duchenne muscular dystrophy. This disease is the most common form of hereditary muscular dystrophy (muscle wasting) in humans. It is caused by a mutation on the X chromosome, which is why it mainly affects boys. Patients with this disease lack the protein dystrophin, which stabilizes the muscle fibers. This results in the cells gradually dying off.
“In this mouse model, we observed the loss of many types of cell nuclei in the muscle fibers,” reports Birchmeier. Other types were no longer organized into clusters, as the team had previously observed, but scattered throughout the cell. “I couldn’t believe this when I first saw it,” she recounts. “I asked my team to repeat the single-nucleus sequencing immediately before we investigated the finding any further.” But the results remained the same.
The mouse nuclei resemble those of human patients
“We also found some disease-specific nuclear subtypes,” reports Birchmeier. Some of these are nuclei that only transcribe genes to a small extent and are in the process of dying off. Others are nuclei that contain genes that actively repair damaged myofibers. “Interestingly, we also observed this increase in gene activity in muscle biopsies of patients with muscle diseases provided by Professor Simone Spuler’s Myology Lab at the MDC,” says Birchmeier. “It seems this is how the muscle tries to counteract the disease-related damage.”
“With our study, we are presenting a powerful method for investigating pathological mechanisms in the muscle and for testing the success of new therapeutic approaches,” concludes Birchmeier. As muscular malfunction is also observed in a variety of other diseases, such as diabetes and age- or cancer-related muscle atrophy, the approach can be used to better research these changes too. “We are already planning further studies with other disease models,” Kim confirms.
Text: Anke Brodmerkel
Research / 09.12.2020
Mina Gouti awarded ERC Consolidator Grant
The European Research Council (ERC) awarded Dr. Mina Gouti a €2.8 million Consolidator Grant to further develop miniature neuromuscular organoids for studying neuromuscular development and diseases. It was the second honor in as many weeks; she was also named an EMBO Young Investigator for her work.
The motor neurons controlling arms, legs and other skeletal muscles come from distinct sections of the spinal cord. Organoids – miniature, organ-like structures grown in the lab – representing each segment aim to reveal regional differences in degenerative diseases and identify potential treatments for spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS).
“With this grant, we have a great opportunity now to realize our ideas, take our organoid model to the next level, and prove that the model is useful for identifying novel therapies,” says Gouti, who leads the Stem Cell Modeling of Development and Disease Lab at the Max Delbrück Center for Molecular Medicine (MDC).
ERC Consolidator Grants are awarded to “outstanding researchers of any nationality and age, with at least seven and up to twelve years of experience after PhD, and a scientific track record showing great promise and an excellent research proposal.” Research must be conducted in a public or private research organization in a European Union Member State or associated country.
Gouti and her colleagues recently developed very advanced neuromuscular organoids that contain all critical cell types involved in the formation of functional neuromuscular junctions. The result is the organoid’s motor neurons instruct its mini-muscles to contract like in the human body. Those organoids, reported in Cell Stem Cell in early 2020, resemble the lower part of the spinal cord communicating with leg muscles.
Now, with the ERC support, her lab will work on “Generation of Position Specific (GPS) organoids” – developing organoids that represent the middle and upper sections of the spinal column. Having position-specific organoids is important because motor neurons that control different muscle groups are located in distinct regions of the spinal cord. In SMA and ALS, motor neurons innervating limbs, located in the upper and lower sections of the spinal cord, are usually affected first, while motor neurons from the middle section are affected later. The organoids will enable the researchers to explore in detail what influences these differences, and the sequence of events leading to disease before the onset of symptoms.
“Studying these diseases has so far been extremely difficult due to the limited availability of reliable human in vitro models that take into account the position of the motor neurons and the interaction with the skeletal muscles,” Gouti says.
The grant also specifically funds a high-content imaging system, which is a confocal microscope that can analyze multiple organoids in one go. The system will help the team screen how organoids generated from SMA patient cells react to different drugs. The researchers can help validate newly established treatments, investigate the best time to begin treatment to prevent motor neuron death, and potentially identify novel therapies.
Since the organoids are generated from human induced pluripotent stem cells, they provide an excellent opportunity to screen drugs in the target tissue. “I hope the organoid model can be a bridge between preclinical and clinical trials,” Gouti says. “It’s as close to a human as you can get.”
The whole system
The next phase of research will also include fusing cerebral organoids with neuromuscular organoids and seeing if they will form functional connections. “The neuromuscular organoids we have developed stay alive in the lab for more than 18 months, but they stop contracting after some months,” Gouti says. “We think this might be because there is no input from the brain.”
Fusing brain-like organoids with neuromuscular organoids would enable the researchers to study the full neuromuscular circuit in the lab, starting with signals from the brain going to the spinal cord and then the muscle.
Last week, the European Molecular Biology Organization (EMBO ) also named Gouti one of 30 EMBO Young Investigators in 2020. More than 200 researchers applied. “These 30 scientists have demonstrated scientific excellence and are among the next generation of leading life scientists,” says EMBO Director Maria Leptin. “Their participation in the EMBO Young Investigator Programme will help them in this critical phase of their careers.”
EMBO Young Investigators are outstanding life scientists who have established their first laboratories in the past four years. They join a network of 73 current and 384 past Young Investigators. EMBO offers the researchers access to a range of benefits, including an award of €15,000 and the opportunity to apply for additional grants of up to €10,000 per year, as well as networking and training opportunities.
“I am looking forward to connecting with researchers and mentors in the EMBO network,” Gouti says. “It’s a great opportunity, not just for me, but for members of my lab who can now also participate in EMBO activities. We are all very excited.”
Text: Laura Petersen
Research / 08.12.2020
Feeling out fine differences in touch sensitivity
We have known about a skin touch sensor for more than 160 years. MDC scientists now publish in Nature Neuroscience some of the first proof of its involvement in detecting tiny vibrations that help us to distinguish between a rough or a smooth surface.
A large protein produced in a unique structure in the fingertips, called the Meissner corpuscle, plays a major role in touch sensitivity, new research finds. Identified in the 1850s by Georg Meissner, the Meissner corpuscle is an oval-shaped capsule found in the fingertips and lips, filled with cells intertwined with a nerve ending that sends a “touch” signal to the brain.
“For a century and half, people have looked at the Meissner corpuscle and said ‘this is a beautiful structure, but we don’t really know what it’s there for,’” says Professor Gary Lewin, who heads the Molecular Physiology of Somatic Sensation Lab at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association. In a new publication in the journal Nature Neuroscience, he and his team show that a protein made by the Meissner corpuscle is required to maintain normal touch perception.
The Usher connection
Based on previous research into the interplay between hearing and touch sensory systems, Lewin and his colleagues suspected that the protein USH2A may be involved in touch. Mutations in the gene, that codes for the USH2A protein, are common in Usher syndrome an inherited human disease, which includes hearing loss, tunnel vision and some loss of touch sensitivity.
To investigate, the researchers worked with 13 Spanish patients with Usher syndrome who have specific mutations affecting the USH2A protein. They wanted to find out what was the smallest vibration the patients could perceive on their little finger. The researchers also tested their perceptions of temperature changes and small pin pricks. They conducted the same tests on healthy volunteers, mostly colleagues from the MDC, to compare results.
The patients with Usher syndrome could sense temperature changes and mild pain similar to the healthy controls, but had significantly reduced sensitivity to very small vibrations. Vibrations needed to be, on average, four times stronger before Usher patients could feel them.
“We are very sensitive to touch,” Lewin says. “If you have a very good sense of touch, you can detect with your finger, the difference between a very fine silk and an even finer silk. But the Usher patients would not be able to tell the difference.”
While the human studies showed the USH2A protein is important for touch, it did not explain how or why. So, the researchers turned to mice. First, Fred Schwaller, the lead author on the study, turned to the Neural Circuits and Behaviour Lab led by Professor James Poulet, who helped him train healthy mice and mice missing the USH2A protein to indicate when they felt very small vibrations on their forepaw. Just like the Usher patients, mice without USH2A proteins needed a larger stimulus before feeling the vibration, but detected temperature changes and mild pain normally, suggesting the mechanism has been highly conserved through evolution.
“It’s amazing to see the match between the patients and animal model. We were not expecting it to be so clear like that,” says Dr. Valérie Bégay, a scientist in Lewin’s lab who was involved in the study as well.
Looking closer with the help of fluorescent biomarkers, Schwaller found the protein is produced by the cells in the Meissner corpuscle, and not in nerve cells like they had expected. “To our surprise we could not detect the USH2A protein in sensory neurons, it wasn’t there,” Lewin says. This clearly demonstrated the Meissner corpuscle is essential for fine touch perception by producing the USH2A protein.
More to learn
The USH2A protein is quite large compared to other molecules in the body, and sits in the extracellular matrix of the corpuscle cells. Since touch sensitivity decreases when the protein is missing, Lewin theorizes that it serves as a physical connector, helping transmit touch vibrations from the outside of the fingertip to the nerve ending inside the corpuscle. His team is actively investigating the theory and he is interested to see what other elements the protein interacts with. “It is likely not working alone,” he says.
The insight might help with research into related hearing and vision loss in Usher patients. While it is unlikely the protein works the same way in those systems, it might provide some hints about how mutations in the USH2A gene affect those senses.
The researchers were especially appreciative of their colleagues at MDC who volunteered for the study, providing essential control data. More than 100 people over the past several years have participated. “You need good controls to increase confidence in your data, but it can be very difficult to get enough volunteers who are willing to concentrate closely for an hour or an hour and a half,” says Bégay. “The support from our MDC colleagues has been invaluable.”
Text: Laura Petersen
Research, Patient care / 30.11.2020
New PhD programs kick off at the MDC
PhD candidates now have the opportunity to apply for two new training programs. The EU is supporting the program for talented early-stage researchers at the MDC and other European research institutions to the tune of €4 million per network.
Whether it’s turning up the heat on cancer cells or scrutinizing a small signaling molecule that can trigger mental illnesses, two new Marie Skłodowska-Curie Innovative Training Networks (ITNs) are gearing up to train outstanding PhD students in multimodal cancer therapies and neuronal development. Application for one of the scholarships is already open.
In addition to the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), ten other members of the consortium such as universities, university hospitals and non-university research institutions as well as several non-academic partner organizations are involved in both programs. The proposals for “Hyperboost” and “Serotonin and Beyond” were revised several times before they were successful in a highly competitive call under the EU’s Horizon 2020 research and innovation framework program.
Developing effective cancer therapies
Elevating the body’s temperature can enhance the effectiveness of radiation therapies. Chemotherapy used in combination with hyperthermia – the heating of tumor tissue to temperatures of 40–44°C – contributes to tumor shrinkage and helps cancer patients live longer.
The aim of the program “Hyperboost” is the interdisciplinary training of specialists who combine expertise in physics, bioinfomatics and biology with experience in clinical and preclinical studies. This is only achievable by taking an integrative and holistic approach. The participating 14 PhD students will jointly contribute to the development of highly effective personalized cancer therapies.
While the junior researchers at the other consortium members will investigate the molecular mechanisms of hyperthermia at the cellular level, the PhD candidate at the MDC will develop a special magnetic resonance imaging (MRI) technique. “High-frequency radiation generates heat,” explains Professor Thoralf Niendorf. “In this way, we can increase elevated temperatures in specific areas in the body and monitor it via MRI scanners for diagnostic and therapeutic purposes.”
Niendorf, who leads the Experimental Ultrahigh-Field MR Lab at the MDC, conducts research into temperature-dependent processes in living tissue and will now supervise the new addition to the MDC. The aspiring doctoral student will plan, build, and ultimately test the technology in clinical studies over a three-year period. The team collaborates closely with the Department of Radiation Oncology and Radiotherapy at Charité – Universitätsmedizin Berlin. The coordinator of the network, which will start in December 2020, is the University of Amsterdam in the Netherlands. The application process is already running but not yet completed. The Niendorf lab will help with further information.
A new approach to psychiatric drugs
Many drugs used to treat mental disorders target serotonin – a substance in the brain that helps nerve cells communicate with each other and influences many physiological processes. “But in some patients with mental disorders common drugs have no effect,” says Dr. Natalia Alenina from the MDC, who will be supervising two “Serotonin and Beyond” PhD fellows in Professor Michael Bader’s research lab.
In addition to functioning as a signaling molecule, serotonin also plays a role in embryonic and early childhood brain development. “Yet drugs often neutralize disturbances in serotonin neurotransmission – rather than targeting the developmental processes in the brain that are altered by serotonin,” Bader says, who heads the Molecular Biology of Peptide Hormones Lab at the MDC. He suspects this is why such drugs are ineffective in some patients.
The two PhD students in Bader’s team will now investigate fundamental genetic and environmental factors that influence serotonin levels during brain development. They are studying such factors in the brains of mice and rats, which either carry themselves genetic alterations in proteins responsible for serotonin synthesis or metabolism, or experienced disturbances in maternal serotonin supply during development.
The colleagues in the consortium investigate how serotonin-mediated developmental processes affect cognition and behavior and can lead to mental disorders. In this way, all 15 participating PhD students are jointly contributing to finding new targets for therapies. The training program and the MDC application process starts in January 2021, further information about the procedure will be provided by the Bader lab. The network is coordinated by the Stichting Katholieke Universiteit in Nijmegen, the Netherlands.
About the ITNs
The funding by the European Union covers salaries as well as additional funding of research costs, travel, coordination and management of all activities that take place within the network.
During their three-year fellowship, PhD candidates of all consortium members receive first-class supervision by experienced experts and attractive opportunities for further education, professional exchange and networking. They can work for several months at another consortium member or one of the participating partner organizations in order to gain intersectoral experience, e.g., in preclinical research, clinical practice or an industry setting and to establish contacts with future employers.
Text: Christina Anders
Research / 27.11.2020
A tricky kidney puzzle
By analyzing the gene expression of single cells, algorithms are able to not only reconstruct their original location in the tissue, but also to determine details about their function. Teams led by Kai Schmidt-Ott and Nikolaus Rajewsky have published their findings in JASN, using the kidney as an example.
To find out exactly what happens when in a particular cell, scientists look at its transcriptome – the totality of all genes that are expressed and transcribed into RNA at a specific point in time. Today, single-cell RNA sequencing allows the expression profiles of many thousands of cells to be analyzed simultaneously. But this method requires the cells to first be detached from their cell aggregate, which causes information on the cell’s original location in the tissue to be lost.
Nevertheless, gene expression enables this information to be reconstructed bioinformatically. “We wanted to know whether, in addition to providing a reconstruction of the cells’ spatial arrangement, algorithms could also be used to gain functional information from single-cell sequencing – for example, about the environmental conditions of kidney cells,” says Dr. Christian Hinze from Charité – Universitätsmedizin Berlin and the Molecular and Translational Kidney Research Lab at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC). He is the first author of the study, which has now been published in the Journal of the American Society of Nephrology (JASN).
A heterogeneous organ
Spatially speaking, the kidneys of mammals are very heterogeneous. The two bean-shaped organs consist of a renal cortex and an outer and inner renal medulla. The inner renal medulla is where highly concentrated urine forms after undergoing various filtering processes, and is then excreted via the ureter and bladder. “Over 15 different cell types are found in a mouse kidney, for example – and some are present in all three kidney regions,” says Hinze. Think it sounds like an impossible puzzle? Actually, it’s not. Because the microenvironment in which a cell lives is also reflected in its gene expression.
Back in 2019, the team led by Professor Nikolaus Rajewsky, Scientific Director of the MDC’s Berlin Institute for Medical Systems Biology (BIMSB) and one of the current study’s last authors, developed the program NovoSpaRc, which allows the spatial arrangement of cells within an organ to be reconstructed based on gene expression. In initial studies, the researchers found that cells that are arranged close to each other also resemble one another in terms of the activity of certain genes. “This is because they have to function in the same environment,” explains Hinze. “In the inner renal medulla, for example, conditions are much more severe than in the renal cortex. This is because the osmolality of the environment – i.e., the concentration of dissolved substances in the cell’s surroundings – increases drastically from the outside to the inside of the organ.”
An algorithm solves the 3D puzzle
For their current study, the researchers concentrated primarily on a specific cell type in the kidney known as principal cells. These cells play an important role in the reabsorption of blood salts and water and are distributed throughout the entire organ. Thanks to the particular gene expression of this cell type, they were able to extract these cells from the single-cell data of mouse kidneys. They then subjected the cells to the NovoSpaRc algorithm, which organized the expression data by comparing more than 800 selected genes for similarities. “NovoSpaRc works like someone doing a jigsaw puzzle,” explains bioinformatician Dr. Nikos Karaiskos from the Rajewsky Lab. “It tries to bring the different parts, which are the cells, together in such a way that the end result makes sense.” Karaiskos is also co-developer of NovoSpaRc and leading the DFG -funded “Unbiased Single-Cell Spatial Transcriptomics” project.
And the algorithm succeeded in completing the puzzle. “The gene expression analysis confirmed that osmolality in the tissue greatly increases along the axis from the renal cortex to the inner medulla,” says Hinze. “At higher salt concentrations, the cell switches on certain protective genes so that it can survive in this environment.” The researchers verified their results by carrying out comparative tests on tissue from genetically modified mice, in which the normal salt gradient had been disrupted.
An atlas of gene expression in the kidney
So, to what extent does spatial single-cell analysis actually advance kidney research? “We are now able to more accurately predict the spatial gene expression in the kidney, and thus also to make deductions about functions or malfunctions in certain regions of the kidney,” explains Professor Kai Schmidt-Ott, a nephrologist at the MDC and Charité and co-last author of the study. “We were already able to take a first step and create a high-resolution spatial atlas of the gene expression of healthy mouse kidneys, which we are now making available online to the scientific community.”
Previous data analyses are limited to healthy and genetically modified kidneys from animal models. Now, the researchers want to turn their attention to sick kidneys. “We believe that the new methods can also give us a better understanding of the regional molecular processes in kidney disease,” says Schmidt-Ott.
Reconstructed in seconds
Combining single-cell RNA sequencing with bioinformatic tissue reconstruction has a number of benefits. For one, several experiments are usually necessary to study different regions of an organ. “Now, we can simply cut up the entire kidney, sequence it, and determine all sorts of information from the transcriptomes – which saves a lot of time and money on research,” Hinze emphasizes. It can be used to investigate practically everything that is reflected in the gene expression of a cell – complete with spatial resolution. This includes the oxygen or nutrient supply of the tissue, or, as is the case here, the osmolality. What is particularly exciting, however, is that existing archived data sets can be used to answer new research questions – even if samples of the corresponding cells have long since ceased to exist.
And one last benefit: It takes practically no time for the expression data puzzle to be completed. “In one minute, the algorithm scans the data of a couple of thousand cells,” says Karaiskos. “And for a full reconstruction of the small mouse kidney, it only needed a few seconds.”
Text: Catarina Pietschmann
Picture: Section through a mouse kidney: The messenger RNA of a gene is stained brown. The more intense the staining, the stronger the gene expression. This illustrates the spatially heterogeneous expression of genes in the kidney. © AG Schmidt-Ott, MDC
Research / 19.11.2020
CLCN6 identified as disease gene for a severe form of lysosomal neurodegenerative disease
A mutation in the CLCN6 gene is associated with a novel, particularly severe neurodegenerative disorder.
Scientists from the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) and the Max Delbrück Center für Molekulare Medizin (MDC), together with an international team of researchers, have now analyzed the effect of a point mutation that was found in three unrelated affected children. ClC-6 is one of nine members of the CLCN gene family of chloride channels and chloride/proton exchangers and, apart from ClC-3, was the only one that could not yet be associated with any human disease. The results have just been published in the American Journal of Human Genetics.
The term "lysosomal storage disease" summarizes a number of genetically determined metabolic diseases that are due to incorrect or insufficient function of lysosomes. These cellular organelles are important both as “cellular waste disposal” and for the regulation of cellular metabolism. If lysosomal function is compromised, substances that normally would be degraded may accumulate in the affected cells. This may impair their function and may eventually lead to cell death. In the central nervous system, which is often affected because adult neurons are unable to regenerate, this can lead to neurodegeneration.
Researchers from the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) and the Max-Delbrück-Centrum für Molekulare Medizin (MDC), in close collaboration with colleagues from Rome, Hamburg and the USA, have now found and characterized the gene defect underlying a novel severe form of neurodegenerative disease: A mutation in the CLCN6 gene in three unrelated children from Italy, Germany and the USA, leads to severe developmental delay, intellectual disability, hypotonia severely affecting muscle tone, respiratory insufficiency, visual impairment, and early-onset brain atrophy.
Ion transporter ClC-6 is a member of the chloride channel family
Human geneticists, including the study’s co-leader Marco Tartaglia from Rome and Kerstin Kutsche from Hamburg, independently discovered the same point mutation in their young patients and asked Prof. Thomas Jentsch and his team to examine possible effects of the mutation on the transport properties of ClC-6 and its cellular functions. Jentsch, the discoverer of the CLC chloride channel family, had already found or characterized different disease-causing mutations in almost all nine CLC genes. These are associated with a broad spectrum of different pathologies. Only the genes encoding the ion transporters ClC-3 and ClC-6 had not yet been found to be mutated in human disease. "About fifteen years ago, we had generated a ClC-6 knockout mouse and found that it displayed mild neuronal lysosomal storage. However, our search for patients with similar loss function mutations in ClC-6 was unsuccessful," explains Prof. Jentsch. "Now we have identified a different type of ClC-6 mutation in a much more severe human disease.”
The presence of exactly the same mutation in three independent patients displaying the same disease pattern already indicated a causal role of the mutation. But only the functional analysis in cell culture brought final certainty and led to the classification as lysosomal disease. "Our cell cultures experiments clearly show that increased ion transport by the mutated ClC-6 affects lysosomes and thereby prove the deleterious effect of the mutation. Based on these results, and taking into account our previous mouse model, we assume that the novel disease can be classified as lysosomal storage disease," explains Thomas Jentsch. However, definitive proof of this classification would require post-mortem examination of brain slices from patients or a novel mouse model carrying the same mutation.
More chloride uptake leads to abnormally large, lysosome-like vesicles
Unlike the chloride channels ClC-1, -2, -3 and -K, the chloride/proton exchangers ClC-3, -4, -5, -6, and -7 are not located on the plasma membrane but in intracellular membranes, mainly on endosomes and lysosomes. In previous studies, Jentsch and coworkers identified mutations of ClC-7 as the cause of a form of lysosomal storage disease associated with osteopetrosis, and mutations of ClC-4 lead to intellectual deficits. While ClC-7 is found on lysosomes, ClC-6 is predominantly located on late endosomes, kind of lysosome precursors.
The Berlin team found that the patients’ mutation, in contrast to the loss of ClC-6 in their previous knock-out mouse model, caused a hyperactive ClC-6: The transport of chloride and protons was highly increased and was no longer modulated by pH. Normally acidic pH, as gradually achieved in the transition from endosomes to lysosomes, inhibits the transporter. This regulation is missing in the disease-causing mutant. The increased, unregulated ion transport - a pathological gain of function - resulted in drastically enlarged, lysosome-like vesicles in cells that were made to produce the mutated ClC-6. According to Jentsch, this pathological gain of function can explain the children's disease. "Vesicles carrying the mutated ClC-6 in their membrane are pathologically enlarged by an increased uptake of chloride, which is later followed by water. This uptake is driven by the ClC-6-mediated exchange for protons which are abundantly present in the acidic interior of vesicles. This severely impairs the function of lysosomes and, in the long run, probably leads to lysosomal storage in neurons, cells that are unable to proliferate. The tissue distribution of ClC-6, which is found almost exclusively in neurons, contributes to the predominantly neurological disease ".
"The present work highlights the importance of ion transport for the endosomal-lysosomal pathway," says Jentsch. "We see a broad spectrum of genetic diseases that are caused by mutations in vesicular CLCs or in different intracellular channels.” Very different organs can be affected: For example, mutations in the endosomal ClC-5 lead to kidney stones and protein loss into the urine, as Jentsch’s team showed a long time ago.
Jentsch is confident that also the ClC-3 exchanger will soon be linked to a genetic disease - a KO mouse previously published by the group shows dramatic neurodegeneration. Together with the current finding, this would link all nine CLCN genes to human genetic disease. "The gap is closing", says Jentsch, "and we can see very clearly how important basic research - we had cloned the first CLC from an electric fish - is for the diagnosis and understanding of human disease".
Picture: Image of two cells overproducing the ClC-6 transporter (red) carrying the disease-causing mutation. This leads to the appearance of large vesicles that are positive for the lysosomal marker protein LAMP-1 (shown in green). Vesicles with high levels of both proteins appear yellow. | Picture: Carlo Barbini
Research / 18.11.2020
Cell cycle surprises
The process of cells multiplying is one of the most well-understood processes in life. When MDC biologists joined forces with a physicist and mathematician, they gained new and unexpected insights about the cell cycle, now published in “Molecular Systems Biology”.
The cell cycle, the process through which cells multiply, has evolved to be as simple as possible by minimizing potential for errors. An interdisciplinary team of researchers from the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) report this in the journal Molecular Systems Biology.
Cells multiply by going through a four-step cycle: expanding in size, copying their genetic information, preparing to divide, and then finally dividing into two cells. Textbooks typically display this by a simple circle, but for no particular scientific reason. For the first time, a study shows that this depiction is justified, as cells do display a circular pattern of gene expression while going through the cell cycle. It also shows that this is not a coincidence; this pattern significantly reduces how many mistakes can occur in the process – an evolutionary achievement.
“The cell cycle is one of the most studied processes in biology,” says Professor Nikolaus Rajewsky, Scientific Director of MDC’s Berlin Institute for Medical Systems Biology (BIMSB), who spearheaded the project. “The power of ultra-deep, single-cell sequencing combined with computational approaches has allowed us to look at the cell cycle in greater detail and make new unexpected discoveries.”
Big, big data
The findings come thanks to Rajewsky and molecular biologists in his Systems Biology of Gene Regulatory Elements Lab at BIMSB in the city center, teaming up with a physicist and a mathematician in the Mathematical Cell Physiology Lab at Buch campus.
Rajewsky and his colleagues sequenced messenger RNA (mRNA) for thousands of individual cells throughout the entire cell cycle. Levels of mRNA indicate which genes are active and what the cell is doing. Paper co-author Sara Formichetti led these “ultra-deep sequencing” efforts and gained more detailed information about gene activity in each cell than previously possible. Usually, there is a trade off in sequencing studies – either scientists can sequence a lot of cells, or they can get a lot of information per cell. Formichetti optimized to get the best of both worlds, building a detailed dataset that covered the whole cycle.
Formichetti and Rajewsky began to computationally sort the cells along the cell cycle time, but Formichetti’s guest visit in the Rajewsky lab ended and so Rajewsky reached out to Professor Martin Falcke, who heads the Mathematical Cell Physiology Lab, and first paper author Daniel Schwabe, a Ph.D. candidate in his lab.
Geometry for biology
The team wanted to see if the data cloud would form a geometric shape reflecting the cell cycle process. They expected something like a messy knot of string, which would correspond to many genes being turned on and off multiple times throughout the cycle.
At first, they didn’t see any pattern or shape. So, they began to rotate the data cloud to view it from different angles. Imagine holding a mug or cup, turning it around in your hands to view it from all sides, lifting it up to see the bottom and then peering down at it from the top. The researchers did essentially the same thing and discovered that from a particular angle, the data forms a hollow cylinder, and, like when looking at the mug straight down, a circle that corresponds to the cell cycle – the simplest shape possible.
“There was no evidence that would indicate the cell cycle would be this simple,” Schwabe says. “What this tells us is that each gene involved in the cell cycle is turned on and off only once throughout the cycle.”
Since turning genes on and off only once helps reduce potential for errors, it suggests the cell cycle has evolved to be as simple and efficient as possible. Furthermore, in the immortalized cell lines they studied, the researchers found that the cell cycle is basically independent of other biological processes active in the cell, which makes it even more robust against errors.
“The level of optimization and isolation we observe is remarkable,” Rajewsky says. “On the one hand, we completely capture the biology of the cell cycle in a two-dimensional circular motion while at the same time processes such as epigenetics and changes in the environment push the cells along a perpendicular axis. Taken together, these two influences cause a spiraling motion along a hollow cylinder.”
“On the fly”
The researchers made another unexpected discovery. The cell cycle is known to have check points, at which cells make sure all necessary steps are complete before moving onto the next phase of the cycle. They expected that gene activation, during which the gene is transcribed into mRNA, slows down before check points, providing well-defined moments for determining whether or not to proceed. But the data here show a continuous, relatively even rate of gene expression activity, with no defined breaks.
“I was surprised,” Falcke says. “You would expect the cell to stop when it checks that everything on its to do list has been completed, but that is not the case. This occurs on the fly, while the engine keeps running.”
The revelations may not stop there. The team is able to use their approach to precisely remove cell cycle effects from data sets, leaving only the irregularities, something of great interest to researchers in similar fields. For example, it could help clarify what goes wrong in the cycle that enables unchecked cell division and tumor growth. Rajewsky and Falcke plan to continue using it to explore the origin of cell variability, which is what drives or enables clonal cells to have very different gene expression levels, as well as other questions.
Text: Laura Petersen
Research / 10.11.2020
Christian Hackenberger receives breakthrough award in life sciences at the Berlin Science Week
Christian Hackenberger is honored at the Falling Walls conference with a “breakthrough of the year”-award in the life sciences. Ten scientific "breakthroughs of the year" were announced on Monday in various disciplines. With this award the jury recognizes Christian Hackenberger's research on protein-based biopharmaceuticals.
Today, the treatment of cancer with chemotherapy has many negative side effects, and treatments against viral infections have shortcomings. The research group of Christian Hackenberger found a way to improve the treatment of both. They have pioneered the development of protein-based therapeutics, based on the modification and cellular delivery of antibodies to target cancer and viral infections. This includes the engineering of an inhibitor against human and avian influenza and safer next-gen antibody-drug conjugates. These efforts led to the foundation of the highly successful start-up Tubulis.
Jury Chair Marja Makarow : “Christian Hackenberger’s breakthrough is a technology that enables drug molecules to be attached to antibodies, which find the broken linkers within the patient’s cancer cells, and release the necessary drug only where it should work – without harming normal tissue in its course. The jury concluded that the core idea of this science is fascinating, the theoretical approach great and the potential concerning cancer therapy and virus infection prevention is huge.”
The Falling Walls Foundation announced the Falling Walls Science Breakthroughs of the Year 2020. In ten categories, ranging from life sciences to science in the arts, outstanding research projects are honoured on 9 November, the day the Berlin Wall came down peacefully in 1989. The ten breakthroughs were identified by a distinguished global jury chaired by Helga Nowotny, president emeritus of the European Research Council.
The juries chose the science breakthroughs of the year from 940 research projects that were nominated by academic institutions from 111 countries on all continents.https://www.leibniz-fmp.de
Innovation / 10.11.2020
Nine-Month Figures Eckert & Ziegler: Growth in Radiopharmaceuticals Compensates for Corona Losses
Eckert & Ziegler Strahlen- und Medizintechnik AG (ISIN DE0005659700, TecDAX), a specialist for isotope applications in medicine, science and industry, again achieved a very strong result of EUR 17.7 million in the first nine months of 2020. Compared to the same period of the previous year, consolidated net income decreased only slightly by EUR 1.1 million or 6% despite Corona. Revenues amounted to EUR 126.9 million, thus 5% below prior year's level. The shortfall in net income is mainly due to a weaker result in the Isotope Products segment, while the Medical segment showed a significant increase.
Due to Corona, the Isotope Products segment could not maintain the high revenues level of the previous year and, at EUR 66.8 million, generated revenues of EUR 11.6 million or about 15% lower than in the first nine months of 2019. Revenues were particularly affected by lucrative components for industrial measurement technology, the Brazilian business and disposal services. Slight growth was only recorded for components for medical equipment and in raw materials trading.
In contrast, the Medical segment recorded another growth spurt, increasing its revenues by 5.4 million EUR or 10% to 60.1 million EUR, mainly due to rising revenues from pharmaceutical radioisotopes. On the level of the main product groups, however, the picture was mixed. While laboratory equipment and brachytherapy sources, including iodine implants, suffered considerably from reduced orders from hospitals due to corona, revenues from pharmaceutical radioisotopes grew by more than 6 million EUR or almost 30% to about 30 million EUR.
In view of the second global wave of restrictions that began in September, the Executive Board has left its full-year net profit estimate of € 21 million for 2020 unchanged for the time being. This translates into earning per share of € 1 using the current calculation method and € 4 per share using the old method (before the share split). The Executive Board has left the revenue forecast unchanged at € 170 million.
The complete financial statements can be viewed here:
About Eckert & Ziegler.
Eckert & Ziegler Strahlen- und Medizintechnik AG with more than 800 employees, is one of the world's largest providers of isotope-related components for radiation therapy and nuclear medicine. Eckert & Ziegler shares (ISIN DE0005659700) are listed in the TecDAX index of Deutsche Börse.
Research / 09.11.2020
Falling Walls announces Science Breakthroughs of the Year 2020
“Revolutionary new medicines” – “concepts for a more inclusive society”– “energy transmission without loss” – these are three of the ten Falling Walls Science Breakthroughs of the Year 2020.
The Falling Walls Foundation announces the Falling Walls Science Breakthroughs of the Year 2020. In ten categories, ranging from life sciences to science in the arts, outstanding research projects will be honoured on 9 November, the day the Berlin Wall came down peacefully in 1989. The ten breakthroughs were identified by a distinguished global jury chaired by Helga Nowotny, president emeritus of the European Research Council. The juries chose the science breakthroughs of the year from 940 research projects that were nominated by academic institutions from 111 countries on all continents. The breakthroughs will be presented and honoured in a freely accessible livestream on 9 November 13.00 Berlin Time (CET) on the Falling Walls website (www.falling-walls.com).
These breakthroughs mark significant progress in a wide range of fields. For human health the use of modified proteins as Troyan horses to treat cancer and viral infections marks a breakthrough as much as microrobots that move like jellyfish in the human body replacing risky surgery. Other breakthroughs qualify refugees for leadership positions or involve hundreds of thousands of volunteers to solve complex innovation challenges. One breakthrough achieves superconductivity at close-to room temperatures. Another set of breakthroughs addresses global challenges as our perception of nature or the human ability to act in solidarity on a global scale.
Please find a detailed description of the Falling Walls Science Breakthroughs of the Year 2020 at the end of this document.
Jürgen Mlynek, Chairman of the Falling Walls Foundation: „We were overwhelmed by the global response to our open call for research breakthroughs and by the quality of the work. The pandemic put tremendous stress on the research community, as much as it underscored the global need for research progress.“
From the 940 nominations, 650 finalists were chosen. They provided a short video along with their research publications – published in a growing library on the digital platform of Falling Walls. Ten juries reviewed all finalists in ten categories to identify ten winners per category. The winners were publicly presented in ten live Falling Walls Winners Sessions. Finally, the jury picked the best of the best to become Falling Walls Science Breakthrough of the Year.
„The juries were impressed by the global spread of excellence and we truly enjoyed to see ever more researchers to overcome the boundaries of narrow disciplines,“ says Helga Nowotny, chair of the juries.
„Let us work together to turn this crisis into an opportunity for more innovation, better international collaboration and more effective science communication. This is what the Falling Walls Conference stands for. “, says Anja Karliczek, German Minister for Education and Research and supporter of the Falling Walls Foundation.
Falling Walls Conference
The Falling Walls Conference took place for the first time on 9 November 2009 on the occasion of the 20th anniversary of the peaceful fall of the Berlin Wall. As 9 November marks the first Nazi pogrom in 1938, too, the aim of the Falling Walls Foundation is to celebrate freedom and to commemorate persecution by sharing knowledge. In 2020 the Falling Walls Conference and the Berlin Science Week, which was established to provide a platform for academic institutions worldwide, take place in a digital format which is freely accessible to everybody. Over 200 individual events with over 500 speakers take place from 1 – 10 November 2020. The programme is available and completely free accessible on the website www.falling-walls.com. The programme is made possible by contributions from a wide array of public sources, foundations and corporations.
The Falling Walls Science Breakthroughs of the Year 2020
Descriptions and jury statements on the Falling Walls Science Breakthroughs of the Year
Physical Sciences: Mikhail Eremets
Breaking the Wall to Room-Temperature Superconductivity
Max-Planck-Institute for Chemistry, Mainz
Jury Chair Daniel Zajfman, Israel Science Foundation
Towards Room-Temperature Superconductivity. Superconductivity, applied to everyday life, would solve numerous problems in the fields of energy and data transmission. For a long time, superconductivity was only achievable at ultra-cold temperatures that could only be created inside a laboratory. Mikhail Eremets, the Belarusian-born physicist, has pioneered experiments that allow superconductivity at temperatures of a common household freezer by using unusual materials such as metallic hydrogen.
Jury Chair Daniel Zajfman: “The breakthrough made by Mikhail Eremets and colleagues is the discovery of room-temperature superconductors, which will allow an electric current to flow without any resistance”.
Science in the Arts: Alexandra Daisy Ginsberg
Breaking the Wall to Machine Auguries
Studio Alexandra Daisy Ginsberg, London
Jury Chair: Horst Bredekamp, Humboldt University Berlin
Machine Auguries. Humankind has forced those species that did not extinct to change its behaviour. Birds for example change the time and tone of their songs. The London-based artist Alexandra Daisy Ginsberg created new bird voices to help us understand our negative impact on nature. In dialogue with scientists and experts, she uses emerging technologies such as Generative Adversarial Networks (GANs) to create deep fakes that challenge our perception of nature.
Jury Chair Horst Bredekamp: “Alexandra Daisy Ginsberg is a young, but worldwide lauded London based artist who works at the cross-section between nature and technology, actively developing it further. Using machine learning to recreate a lost version of a Dawn Chorus, she highlights the loss of bird populations. As in her earlier projects, she combines biology with artificial intelligence in a both deeply critical and poetic sense.“
Life Sciences: Christian Hackenberger
Breaking the Wall to Next Generation Biopharmaceuticals
Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Berlin
Jury Chair: Marja Makarow, Biocentre Finland
Protein-based Biopharmaceuticals. Today, cancer treatment by chemotherapy has many negative side effects and treatments against viral infections have shortcomings. Christian Hackenberger found a way to improve the treatment of both. He has pioneered the development of protein-based therapeutics, based on the modification and cellular delivery of antibodies to target cancer and viral infections. This includes the engineering of an inhibitor against human and avian influenza and safer next-gen antibody-drug conjugates. These efforts led to the foundation of the highly successful start-up Tubulis.
Jury Chair Marja Makarow: “Christian Hackenberger’s breakthrough is a technology that enables drug molecules to be attached to antibodies, which find the broken linkers within the patient’s cancer cells, and release the necessary drug only where it should work – without harming normal tissue in its course. The jury concluded that the core idea of this science is fascinating, the theoretical approach great and the potential concerning cancer therapy and virus infection prevention is huge.”
Social Sciences and Humanities: Margaret Levi
Breaking the Wall to an Expanded Community of Fate
Centre for Advanced Study in the Behavioural Sciences, Stanford University
Jury Chair: Shalini Randeria, Institute for Human Sciences (IWM), Vienna
A Moral Political Economy – A Community of Fate on a Planetary Scale. Global challenges such as climate change and pandemics call for a new political economy. The work of Margaret Levi explores how the concept “community of fate”, that is common to small groups like families, can be implemented on a global scale to address global challenges. By studying the culture of unions and our collective behaviour during the Covid-19 pandemic, she proposes tangible approaches towards a global community of fate.
Jury Chair Shalini Randeria: “Margaret Levi’s brilliant project develops a framework to understand how innovative institutions could help individuals to recognize how their destinies are inextricably entangled with distant strangers. She shows us how to create a new political economy model, that promotes planetary well-being without losing sight of economic productivity and innovation. The jury is highly impressed by Levi’s project, which tears down the narrow walls of national solidarity and sovereignty, whilst advocating for a bold conception of Justice”.
Digital Education: Chrystina Russell
Breaking the Wall of Refugee Education
Southern New Hampshire University
Jury Chair: Deborah Quazzo, GSV Ventures, San Francisco
Remote Academic Degrees for Refugees. Tens of millions of people worldwide are refugees with little to no access to education. The Global Education Movement directed by Chrystina Russell created outstanding results in providing degree-level education to refugees. 95 percent of her students graduate and close to 90 percent are employed within six months after graduation. The Global Education Movement unlocks the potential of a new generation of leaders that can take on intractable problems – from poverty and famine to conflict and disease – that once were significant barriers to their success.
Jury Chair Deborah Quazzo: “Chrystina Russell and her Global Education Movement initiative have been awarded for being the organization offering the highest impact with the highest learning efficacy, at the largest opportunity of scale. GEM focuses on millions of displaced people, who are prevented from adequate access to education.”
Science and Innovation Management: Jacob Friis Sherson
Breaking the Wall of Hybrid Intelligence
Jury Chair: Michael Kaschke, Karlsruhe Institute of Technology
The ScienceAtHome Project. The approach by Jacob Sherson to involve hundreds of thousands of people to collaborate with him in addressing complex research challenges marks a breakthrough in Science and Innovation Management. His big idea is to turn a quantum computing issue into a popular video game that – in conjunction with AI – provides insights to researchers from natural, social and cognitive sciences.
Jury member Kumsal Bayazit: “Jacob Sherson and his team bring together hundreds of thousands of citizen science volunteers. ScienceAtHome’s interdisciplinary and collaborative approach combines human and artificial intelligence in an online laboratory, harvesting the power of large-scale human problem-solving. The jury found Jacob’s approach to be a genuine breakthrough for the unique way in which it captures the rich diversity of people – with diverse backgrounds, levels of expertise and perspectives – to solve a problem.”
Engineering and Technology: Metin Sitti
Breaking the Wall to Wireless Medical Robots Inside Our Body
Max Planck Institute for Intelligent Systems
Jury Chair: Joël Mesot, ETH Zurich
Medical Microrobots. Conventional surgeries are associated with risks. The observations Metin Sitti made in nature, studying worms and jellyfish, inspired a range of versatile microrobots that can navigate and function safely inside the human body. This breakthrough revolutionizes the way we can deliver drugs, pump fluids, perform biopsies or clear clogged vessels.
Jury Chair Joël Mesot: “Metin Sitti’s research points the way to a revolution in medicine. His micrometer-sized soft robots, which have proven to be multi-talented, could be used for both diagnosis and therapy. The idea that such microrobots will enable therapies within human’s blood vessels with pinpoint accuracy, or perform biopsies, is a step closer to non-invasive treatment and robot-supported medicine. The jury congratulates Sitti for his genuine research approach and engineering solutions”.
The winners in the categories “Emerging Talents”, “Science Start-ups” and “Science Engagement” will be announced during the Falling Walls Grand Finale on 9 November, 13.00 Berlin (CET) time / 7.00 New York time / 21.00 Tokyo time.
Research / 25.09.2020
An in-depth atlas of the heart
Researchers from three continents have produced a first extensive draft of a cell atlas of the human heart to understand how this vital organ functions and to shed light on what goes wrong in cardiovascular disease. As the team reports in Nature, it reveals a huge cellular and molecular diversity.
Each day, the human heart beats around 100,000 times. It keeps blood flowing in one direction through the four different chambers, varying speed with rest, exercise or stress. This is extremely complex and needs the cells in each part of the heart to coordinate with each other for every heartbeat. Researchers have, until now, known amazingly little about how the organ manages to pull off this daunting feat, which ensures that the body is supplied with oxygen and nutrients and carbon dioxide and waste products are carried away from other vital organs and tissues.
In order to change this, Professor Norbert Hübner, head of the Genetics and Genomics of Cardiovascular Diseases Lab at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), teamed up with Dr Sarah Teichmann from Wellcome Sanger Institute in Cambridge, UK; Professors Jonathan Seidman and Christine Seidman, both from Harvard Medical School in Boston; and Dr Michela Noseda from Imperial College London. Together they launched the Human Heart Cell Atlas, a project dedicated to probing and understanding the human heart, cell by cell. The Human Heart Cell Atlas is part of the international Human Cell Atlas and has received a grant of nearly four million US dollars from the Chan Zuckerberg Initiative as well as 2.5 million euros from the German Center for Cardiovascular Research (DZHK ) and the British Heart Foundation (BHF).
Insights from around half a million cells and cell nuclei
The teams involved in this project, comprised of 33 scientists from 19 institutions in Germany, the United Kingdom, the United States, Canada, China and Japan, analysed around half a million individual cells and cell nuclei of the human heart. Now, they are releasing their first extensive draft of the human heart cell atlas in the journal Nature. It shows the huge diversity of cells and reveals previously unknown subtypes of heart muscle cells and supporting cardiac cells as well as certain types of protective immune cells in the heart and an intricate network of blood vessel cells. It also predicts how the cells communicate to keep the heart working.
“This is the first time anyone has looked at the single cells of the human heart at this scale, which has only become possible with large-scale single cell sequencing,” says Professor Norbert Hübner, senior author from the MDC, Charité – Universitätsmedizin Berlin, the Berlin Institute of Health (BIH ) and the DZHK. “This study shows the power of single cell genomics and international collaboration. Knowledge of the full range of cardiac cells and their gene activity is fundamental to understanding how the heart functions and to unravel how it responds to stress and disease.”
Professor Christine Seidman, a senior author from Brigham and Women’s Hospital, Harvard Medical School and Howard Hughes Medical Institute, says: “Millions of people are undergoing treatments for cardiovascular diseases. Understanding the healthy heart will help us understand interactions between cell types and cell states that can allow lifelong function and how these differ in diseases. Ultimately these fundamental insights may suggest specific targets that can lead to individualized therapies in the future, creating personalized medicines for heart disease and improving the effectiveness of treatments for each patient.” Cardiovascular disease is the leading cause of death worldwide, killing an estimated 17.9 million people each year, with heart attacks and strokes causing the majority of these.
A heterogenous organ
For their work, the researchers used seven female and seven male hearts from brain-dead donors between 40 and 75 years of age from Europe and the United States whose hearts were healthy but not suitable for transplantation for various reasons. In order to characterize the heart cells as precisely as possible, the scientists examined which genes are switched on in the individual cells and cell nuclei from six different regions of the heart. These regions included the left and right atria and ventricles; the lower tip of the heart, called the apex; and the ventricular septum, the partition that separates the two ventricles. After all, the heart is a rather heterogeneous organ. For example, the differences in blood pressure between the left and right ventricles are quite large.
Using single cell sequencing methods, which the scientists adapted beforehand to the particular properties of heart tissue, and with the aid of machine learning and imaging techniques, the team discovered that there were major differences in the cells in these areas of the heart. Each area had specific sets of cells, highlighting different developmental origins and potentially different responses to treatments.
All known cell types in the heart also contain numerous subtypes. There is, for instance, not one heart muscle cell, but many different cardiomyocytes with, in some cases, different functions. The gene expression profiles indicate that of some of them are equipped to handle a much higher metabolic rate than others. The researchers don’t yet know why this is so. They also found very different patterns of gene expression in the fibroblasts that form the heart’s connective tissue.
Too much scaffolding
After a heart attack, or myocardial infarction, the fibroblasts attempt to replace damaged cardiac tissue with new scaffolding to provide support to withstand the forces associated with a normal heartbeat. Sometimes, they overbuild this scaffolding, or extracellular matrix (ECM). This excess scar tissue is often responsible for arrythmias and heart failure.
“We saw various subtypes of fibroblasts. Some produce extracellular matrix via different processes. Some remodel this scaffolding. And some communicate with immune cells that are physically next to them. This could also influence how much scarring occurs,” says MDC researcher Dr Henrike Maatz, a member of Hübner’s lab and one of the four first authors of the paper. “With the Human Heart Cell Atlas, we created a basis to really understand fibrotic processes: Why are they different in the ventricles and atria? How can we control them?”
Another unexpected finding was that the ventricles of the female hearts had higher numbers of muscle cells and fewer connective tissue cells than those of the male hearts – even though they are typically smaller. This finding may be a clue to why women are less vulnerable than men to cardiovascular diseases. “It’s intriguing but it’s based on just seven hearts of each gender. We’ll have to see whether this result holds up to further investigation,” says Maatz.
Zooming in to investigate small areas
As part of this study, the researchers also investigated the blood vessels running through the heart in unprecedented detail. The atlas showed how the cells in these veins and arteries are adapted to the different pressures and locations, and could help understand what goes wrong in the blood vessels during coronary heart disease.
Dr Michela Noseda, a senior author from the National Heart and Lung Institute, Imperial College London, says: “Our international effort provides an invaluable set of information to the scientific community by illuminating the cellular and molecular details of cardiac cells that work together to pump blood around the body. We mapped the cardiac cells that can be potentially infected by SARS-CoV-2 and found that specialized cells of the small blood vessels are also virus targets. Our data sets are a goldmine of information for understanding the subtleties of heart disease.”
For a long time scientists only had a bird’s eye view of the heart, which was like looking at a map from above. With the help of single-cell sequencing technology, researchers can now, for the first time, zoom in to investigate small areas.
Dr Sarah Teichmann, a senior author from the Wellcome Sanger Institute and co-chair of the Human Cell Atlas Organising Committee, says: “This great collaborative effort is part of the global Human Cell Atlas initiative to create a ‘Google map’ of the human body. Openly available to researchers worldwide, the Heart Cell Atlas is a fantastic resource, which will lead to new understanding of heart health and disease, new treatments and potentially even finding ways of regenerating damaged heart tissue.”
This study was supported by the British Heart Foundation (BHF), European Research Council, the Federal Ministry of Education and Research of Germany, the German Center for Cardiovascular Research (DZHK), the Leducq Fondation, the German Research Foundation (DFG ), the Chinese Scholarship Council (CSC), the Alexander von Humboldt Foundation, the European Molecular Biology Organization (EMBO ), the Canadian Institutes for Health Research (CIHR), the Heart and Stroke Foundation (HSF), Alberta Innovates (AI), the Chan Zuckerberg Initiative (CZI), the Wellcome Sanger Institute, Wellcome, the US National Institutes of Health (NIH) and the Howard Hughes Medical Institute.
- All data from this study can be explored online.
- WHO statistics on cardiovascular disease
- How the heart works (website of the British Heart Foundation)
- Press release: “Straight to the heart”
- Press release: “Unlocking the secrets of heart cells”
Monika Litviňuková, Carlos Talavera-López, Henrike Maatz, Daniel Reichart et al. (2020): “Cells of the adult human heart”. Nature, DOI: 10.1038/s41586-020-2797-4.
Professor Norbert Hübner
Head of the Genetics and Genomics of Cardiovascular Diseases Group
Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
Dr Henrike Maatz
Postdoc in the Genetics and Genomics of Cardiovascular Diseases Group
Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
The Max Delbrück Center for Molecular Medicine
The Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) was founded in Berlin in 1992. It is named for the German-American physicist Max Delbrück, who was awarded the 1969 Nobel Prize in Physiology and Medicine. The MDC’s mission is to study molecular mechanisms in order to understand the origins of disease and thus be able to diagnose, prevent, and fight it better and more effectively. In these efforts the MDC cooperates with Charité – Universitätsmedizin Berlin and the Berlin Institute of Health (BIH) as well as with national partners such as the German Center for Cardiovascular Research (DZHK) and numerous international research institutions. More than 1,600 staff and guests from nearly 60 countries work at the MDC, just under 1,300 of them in scientific research. The MDC is funded by the German Federal Ministry of Education and Research (90 percent) and the State of Berlin (10 percent), and is a member of the Helmholtz Association of German Research Centers. www.mdc-berlin.de
The Wellcome Sanger Institute
The Wellcome Sanger Institute is a world leading genomics research centre. We undertake large-scale research that forms the foundations of knowledge in biology and medicine. We are open and collaborative; our data, results, tools and technologies are shared across the globe to advance science. Our ambition is vast – we take on projects that are not possible anywhere else. We use the power of genome sequencing to understand and harness the information in DNA. Funded by Wellcome, we have the freedom and support to push the boundaries of genomics. Our findings are used to improve health and to understand life on Earth. Find out more at www.sanger.ac.uk
Wellcome exists to improve health by helping great ideas to thrive. We support researchers, we take on big health challenges, we campaign for better science, and we help everyone get involved with science and health research. We are a politically and financially independent foundation. www.wellcome.ac.uk
The Imperial College London
Imperial College London is one of the world's leading universities. The College's 17,000 students and 8,000 staff are expanding the frontiers of knowledge in science, medicine, engineering and business, and translating their discoveries into benefits for our society.
Imperial is the UK’s most international university, according to Times Higher Education, with academic ties to more than 150 countries. Reuters named the College as the UK's most innovative university because of its exceptional entrepreneurial culture and ties to industry. www.imperial.ac.uk
The Harvard Medical School
Harvard Medical School has more than 11,000 faculty working in the 11 basic and social science departments comprising the Blavatnik Institute and at the 15 Harvard-affiliated teaching hospitals and research institutes: Beth Israel Deaconess Medical Center, Boston Children’s Hospital, Brigham and Women’s Hospital, Cambridge Health Alliance, Dana-Farber Cancer Institute, Harvard Pilgrim Health Care Institute, Hebrew SeniorLife, Joslin Diabetes Center, Judge Baker Children’s Center, Massachusetts Eye and Ear/Schepens Eye Research Institute, Massachusetts General Hospital, McLean Hospital, Mount Auburn Hospital, Spaulding Rehabilitation Network and VA Boston Healthcare System. www.hms.harvard.eduwww.mdc-berlin.de
Innovation / 21.09.2020
DCprime and Glycotope Sign Licensing Agreement to Advance Program Combining Cancer Vaccination and Therapeutic Antibody Platforms
21.09.2020 / DCprime, the front-runner in the field of relapse vaccines, and Glycotope GmbH, a clinical-stage oncology/immuno-oncology company built on world-leading glycobiology expertise, today announced an expansion of their existing partnership through a new research collaboration and licensing agreement.
Originally initiated in July 2018, the partnership combines DCprime’s proprietary DCOne® relapse vaccine platform and Glycotope’s highly specific anti-tumor antibody platform with the aim of developing novel immunotherapeutic approaches in oncology. Under the expanded agreement a therapeutic antibody program has been selected from Glycotope’s portfolio which will be further evaluated in preclinical studies to potentially treat a broad range of solid tumors.
“Today’s agreement further exemplifies our commitment to develop novel cancer immunotherapies based on partnerships, in addition to pioneering the relapse vaccine paradigm. Our relationship with Glycotope has matured and brought forward a very promising program, potentially leading to a highly differentiated novel combination therapy towards solid tumors,” commented Erik Manting, CEO of DCprime.
“We are delighted to expand our collaboration with DCprime and to see one of our antibody programs move forward in a novel combination therapy approach with a cancer vaccine based on the DCOne® platform,” said Henner Kollenberg, Managing Director of Glycotope GmbH. “Glycotope has developed a growing pipeline of high-value cancer therapies and today’s announcement further highlights the promising product opportunities for monotherapeutic or combinational approaches offered by our portfolio.”
DCprime is the front-runner in the field of relapse vaccines, a new class of oncology vaccines administered after or in conjunction with standard of care therapy to delay or prevent disease recurrence. Our lead product is a whole-cell-based vaccine addressing blood cancers with a high risk of relapse. We are pursuing similar vaccination approaches for solid tumors. We believe relapse vaccines will improve survival by putting the patient’s immune system back in control. For more information, please visit: https://dcprime.com.
Glycotope, founded in 2000 in Berlin, focuses on the development of antibodies with an increased tumor-specificity by binding to proteins carrying tumor-specific carbohydrate structures. These “GlycoBodies” are developed in different highly potent formats such as ADCs, bispecifics or in combination with cell and gene therapy approaches in-house or by license partners. The Company’s further pipeline includes biopharmaceuticals for various oncological indications. Visit https://www.glycotope.com.
Research / 08.09.2020
Towards a cell-based interceptive medicine in Europe
Hundreds of researchers, clinicians, industry leaders and policy makers from all around Europe are united by a vision of how to revolutionize healthcare. In a perspective in Nature and the LifeTime Strategic Research Agenda they now present a roadmap of how to leverage the latest scientific breakthroughs and technologies over the next decade, to track, understand and treat human cells throughout an individual’s lifetime.
The LifeTime initiative, co-coordinated by the Max Delbrück Center of Molecular Medicine in the Helmholtz Association (MDC) in Berlin and the Institut Curie in Paris, has developed a strategy to advance personalized treatment for five major disease classes: cancer, neurological, infectious, chronic inflammatory and cardiovascular diseases. The aim is a new age of personalized, cell-based interceptive medicine for Europe with the potential of improved health outcomes and more cost-effective treatment, resulting in profoundly changing a person’s healthcare experience.
Earlier detection and more effective treatment of diseases
To form a functioning, healthy body, our cells follow developmental paths during which they acquire specific roles in tissues and organs. But when they deviate from their healthy course, they accumulate changes leading to disease which remain undetected until symptoms appear. At this point, medical treatment is often invasive, expensive and inefficient. However, now we have the technologies to capture the molecular makeup of individual cells and to detect the emergence of disease or therapy resistance much earlier.
Using breakthrough single-cell and imaging technologies in combination with artificial intelligence and personalized disease models will allow us to not only predict disease onset earlier, but also to select the most effective therapies for individual patients. Targeting disease-causing cells to intercept disorders before irreparable damage occurs will substantially improve the outlook for many patients and has the potential of saving billions of Euros of disease-related costs in Europe.
A detailed roadmap for implementing LifeTime
The perspective article “The LifeTime initiative and the future of cell-based interceptive medicine in Europe” and the LifeTime Strategic Research Agenda (SRA) explain how these technologies should be rapidly co-developed, transitioned into clinical settings and applied to the five major disease areas. Close interactions between European infrastructures, research institutions, hospitals and industry will be essential to generate, share and analyze LifeTime’s big medical data across European borders. The initiative’s vision advocates ethically responsible research to benefit citizens all across Europe.
According to Professor Nikolaus Rajewsky, scientific director of the Berlin Institute for Medical System Biology at the Max Delbrück Center for Molecular Medicine and coordinator of the LifeTime Initiative, the LifeTime approach is the way into the future: "LifeTime has brought together scientists across fields – from biologists, to clinicians, data scientists, engineers, mathematicians, and physicists – to enable a much improved understanding of molecular mechanisms driving health and disease. Cell-based medicine will allow doctors to diagnose diseases earlier and intercept disorders before irreparable damage has occurred. LifeTime has a unique value proposition that promises to improve the European patient’s health.”
Dr. Geneviève Almouzni, director of research at CNRS, honorary director of the research center from Institut Curie in Paris and co-coordinator of the LifeTime Initiative believes that the future with LifeTime offers major social and economic impact: “By implementing interceptive, cell-based medicine we will be able to considerably improve treatment across many diseases. Patients all over the world will be able to lead longer, healthier lives. The economic impact could be tremendous with billions of Euros saved from productivity gains simply for cancer, and significantly shortened ICU stays for Covid-19. We hope EU leaders will realize we have to invest in the necessary research now."
- The LifeTime Initiative
- Focus area ”Single cell technologie for personalized medicine” at the MDC and BIH
- Single cell analysis at the MDC
- Rajewsky, Nikolaus et al. (2020): “The LifeTime initiative and the future of cell-based interceptive medicine in Europe”. Nature, DOI: 10.1038/s41586-020-2715-9.
- LifeTime Strategic Research Agenda
- Torres-Padilla, Maria Elena et al. (2020): “Thinking ‘ethical’ when designing a new biomedical research consortium”. EMBO J, DOI: 10.15252/embj.2020105725
Prof. Dr. Nikolaus Rajewsky
Co-coordinator of the LifeTime Initiative
Director of the Berlin Institute of Medical Systems Biology (BIMSB)
Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
+49 (0)30 9406-2999 (office)
Communication manager for the LifeTime Initiative
Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
+49 176 6563 9465
The LifeTime Initiative is a growing community of more than 100 leading European research institutions and hospitals, together with international advisers and over 80 supporting companies. LifeTime includes the preeminent European laboratories developing multi-omic strategies, scientific infrastructures, bioimaging and computational technologies, as well as world-renowned laboratories in the area of personalized disease models, bioethicists and a core group of leading clinician scientists. Many of the involved institutions include or are linked to translational/clinical research facilities and hospitals, ensuring that LifeTime discoveries can be rapidly translated into clinical practice.
Research / 03.09.2020
ERC funding for pioneering research
Two MDC scientists – Kathrin de Rosa and Ilaria Piazza – have earned ERC Starting Grants to fuel their pioneering research. They are seeking answers to questions that may one day change the way we approach vaccines and think about how small molecules influence gene expression and disease.
Dr. Kathrin de la Rosa and Dr. Ilaria Piazza, who are both junior group leaders at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), have each won European Research Council (ERC) Starting Grants. The prestigious grants provide about €1.5 million over five years to early-career scientists and scholars to build their own teams and conduct “high risk, high reward” research. The researchers must have completed their Ph.D. within the last two to seven years and have a scientific track record showing great promise. This year, 436 European scientists from diverse research fields will receive the funding.
“The ERC Starting Grants tend to fund projects that would perhaps fail in other contexts, because the ideas are, to simply put it, too crazy,” says Piazza, who heads the Allosteric Proteomics Lab. De la Rosa, who heads the Immune Mechanisms and Human Antibodies Lab, agrees: “It enables us to address more risky hypotheses.”
Small interactions, big impact?
Piazza investigates the interactions between proteins and small molecules, which can be either natural metabolites, or manmade drugs. “We know quite a lot about how proteins interact with each other, or interact with nuclei acids like DNA or RNA, but exploring how they interact with metabolites or drugs on a global scale, that is new,” Piazza says.
She has developed an innovative approach to analyze these interactions: a combination of protease, a protein that chops up or “cleaves” proteins, and mass spectrometry, a machine that detects and reads all the different segments of proteins, called peptides. Piazza compares peptide chains of a protein exposed to a small molecule versus not exposed. If the chains are different, it indicates the protein was cut differently because it was bound to the small molecule.
The power of the approach is she can study thousands of proteins at the same time, to see which ones bind to a particular small molecule of interest. The “crazy” part of her hypothesis is that the interactions between proteins and small molecules that occur inside the cell nucleus can directly affect gene expression. She suspects these interactions – which reflect the influences of the outside world, versus predetermined genetics – hold the key to explaining why diseases develop.
“Why is it that twins, which have the same genetic code, can have different personalities and diseases?” Piazza asks. “How we live and the environment we live in affect how DNA is translated into proteins, and I believe the interactions between proteins and small molecules plays a huge role that is totally unexplored.”
It might be that the effect is much smaller than she suspects, but receiving the ERC Starting Grant is validation the idea is worth pursing, Piazza says. The grant of about €1.7 million for her project proteoRAGE will enable her to hire additional team members for her lab, which started earlier this year. “I need brave people who aren’t afraid to think out of the box,” she says.
Exploiting nature’s successful tricks
Kathrin de la Rosa, who started her immunology research lab at MDC in 2018, could hardly believe she had won the grant. “But when congratulations came from others who helped me through the submission process, then I could celebrate,” she says. She was awarded about €1.5 million for her project AutoEngineering.
It is focused on tweaking the body’s own B cells in the laboratory so that they produce antibodies that are even more powerful than their natural counterparts. But de la Rosa will not use genetic scissors such as CRISPR-Cas9 to alter their DNA. “If these scissors cut in the wrong place, there can be unintended side effects. The cells can even turn cancerous,” she says. Instead, de la Rosa wants to harness the natural ability of B cells.
B cells are a type of white blood cell. They produce highly specialized antibodies that recognize and bind to intruders in the body. In this way, they attract defensive cells that destroy pathogens such as viruses, bacteria and parasites. When B cells encounter such pathogens, they get activated – they multiply and their DNA strands break especially often at sites where antibodies are encoded. This randomly modifies the antibodies, creating versions with a better fit. In rare cases during malaria infection, antibodies “steal” a segment of another gene: A whole new pathogen receptor is inserted that leads to broadly reactive antibodies. “Pathogens have a harder time escaping from these antibodies, even when the intruder mutates and changes its surface,” de la Rosa says.
De la Rosa wants to uncover the process of natural “segment stealing” step by step, which she and colleagues observed for the first time in 2016. Her lab will seek to understand the underlying mechanisms to induce the process in the petri dish. “First, we have to find efficient ways of exploiting this cell’s own mechanism, test whether it is safer than CRISPR-Cas9 and then use it to create new types of antibodies,” she says. “Just imagine if we could copy the most successful tricks from nature and thereby help the immune system keep pathogens such as HIV in check!” For her and her team it is very exciting to work on something that could one day be a completely new approach to vaccines. “It’s going to be an interesting journey,” de la Rosa says.
Text: Laura Petersen
Research, Patient care / 03.09.2020
In pursuit of the origin and role of ecDNA
How does cancer develop and how does it progress? Dr. Anton Henssen from the Experimental and Clinical Research Center (ECRC) wants to find out more about circular DNA in order to use its cancer cell-specific characteristics for therapy, diagnosis or clinical prognosis. He has now been awarded an ERC Starting Grant.
The research community is increasingly turning its attention to the role of extrachromosomal DNA in cancer development. According to the latest research, cancer cells appear to have the ability to produce small, ring-shaped sections of extrachromosomal DNA known as ecDNA, which they can then reintegrate into existing chromosomal DNA. If the original order of DNA segments is disrupted, this can lead to the dysregulation of cell growth and cancer.
“We have already shown that this phenomenon occurs more frequently than previously thought in primary neuroblastoma, a type of cancer found primarily in children,” confirms Dr. Anton Henssen, scientist at the Experimental and Clinical Reseach Center (ECRC ), a facility jointly operated by the Charité – Universitätsmedizin Berlin and the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC). Henssen also works as a physician at Charité’s Department of Pediatrics, Division of Oncology and Hematology. He adds: “This observation suggests that the circularization of DNA is an important driver behind the remodeling of cancer cell DNA”.
The intention of CancerCirculome
The launch of the CancerCirculome project will see the pediatric oncologist and Emmy Noether Independent Junior Research Group leader work alongside his research team to unravel the principles governing DNA modifications in pediatric cancers. Over the next five years, the researchers will focus on the mechanisms and effects of DNA circularization and the reintegration of DNA fragments into chromosomes. “The details of how ecDNA is made and how it replicates remain unknown. To get closer to identifying the origin of these tiny ring-shaped fragments, we will reconstruct the exact DNA sequences they contain,” explains Henssen. He adds: “To do this we will identify the molecular factors responsible for the generation and replication of ecDNA at the single-cell level.”
The team hope to discover previously unknown mechanisms which cause cells to lose control over cell growth and proliferation. “These mechanisms could be used as new diagnostic and treatment targets – not just in pediatric cancers, but as a fundamental principle governing all cancers,” says Henssen, who is also a BIH Charité Clinician Scientist and a researcher at the German Cancer Consortium (DKTK). Using single-cell CRISPR-based methods (which enable researchers to alter and disrupt ecDNA in a targeted manner), the researchers will attempt to demonstrate the biological effects of DNA circularization and reintegration. The researchers plan to target and manipulate the genetic information contained in ecDNA fragments inside human cells in order to evaluate their effects on cancer cell fitness and function. The researchers also plan to study the behavior, presence and genomic integration of these fragments at the single-cell level during cancer treatment. The aim is to uncover the oncogenic role of ecDNA and determine the mechanisms responsible for the reintegration of ecDNA into chromosomes.
The researchers hope to translate this knowledge into clinical benefits for patients. “We hope to use our understanding of the underlying principles to define novel diagnostic and predictive markers which could then be used for the personalized diagnosis, risk assessment and treatment of cancers,” concludes Henssen. The researchers’ long-term aim is to contribute to and inform our understanding of different cancers, and to support clinical trials involving personalized treatments for children with difficult-to-treat cancers.
Research / 27.08.2020
A team at the MDC has answered a question that has puzzled scientists for some 40 years. In the journal Cell, the group explains how cells are able to switch on completely different signaling pathways using only one signaling molecule: the nucleotide cAMP. To achieve this, the molecule is virtually imprisoned in nanometer-sized spaces.
There are up to a hundred different receptors on the surface of each cell in the human body. The cell uses these receptors to receive extracellular signals, which it then transmits to its interior. Such signals arrive at the cell in various forms, including as sensory perceptions, neurotransmitters like dopamine, or hormones like insulin.
One of the most important signaling molecules the cell uses to transmit such stimuli to its interior, which then triggers the corresponding signaling pathways, is a small molecule called cAMP. This so-called second messenger was discovered in the 1950s. Until now, experimental observations have assumed that cAMP diffuses freely – i.e., that its concentration is basically the same throughout the cell – and that one signal should therefore encompass the entire cell.
“But since the early 1980s we have known, for example, that two different heart cell receptors release exactly the same amount of cAMP when they receive an external signal, yet completely different effects are produced inside the cell,” reports Dr. Andreas Bock. Together with Dr. Paolo Annibale, Bock is temporarily heading the Receptor Signaling Lab at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) in Berlin.
Like holes in a Swiss cheese
Bock and Annibale, who are the study’s two lead authors, have now solved this apparent contradiction – which has preoccupied scientists for almost forty years. The team now reports in Cell that, contrary to previous assumptions, the majority of cAMP molecules cannot move around freely in the cell, but are actually bound to certain proteins – particularly protein kinases. In addition to the three scientists and Professor Martin Falcke from the MDC, the research project involved other Berlin researchers as well as scientists from Würzburg and Minneapolis.
“Due to this protein binding, the concentration of free cAMP in the cell is actually very low,” says Professor Martin Lohse, who is last author of the study and former head of the group. “This gives the rather slow cAMP-degrading enzymes, the phosphodiesterases (PDEs), enough time to form nanometer-sized compartments around themselves that are almost free of cAMP.” The signaling molecule is then regulated separately in each of these tiny compartments. “This enables cells to process different receptor signals simultaneously in many such compartments,” explains Lohse. The researchers were able to demonstrate this using the example of the cAMP-dependent protein kinase A (PKA), the activation of which in different compartments required different amounts of cAMP.
“You can imagine these cleared-out compartments rather like the holes in a Swiss cheese – or like tiny prisons in which the actually rather slow-working PDE keeps watch over the much faster cAMP to make sure it does not break out and trigger unintended effects in the cell,” explains Annibale. “Once the perpetrator is locked up, the police no longer have to chase after it.”
The team identified the movements of the signaling molecule in the cell using fluorescent cAMP molecules and special methods of fluorescence spectroscopy – including fluctuation spectroscopy and anisotropy – which Annibale developed even further for the study. So-called nanorulers helped the group to measure the size of the holes in which cAMP switches on specific signaling pathways. “These are elongated proteins that we were able to use like a tiny ruler,” explains Bock, who invented this particular nanoruler.
The team’s measurements showed that most compartments are actually smaller than 10 nanometers – i.e., 10 millionths of a millimeter. This way, the cell is able to create thousands of distinct cellular domains in which it can regulate cAMP separately and thus protect itself from the signaling molecule’s unintended effects. “We were able to show that a specific signaling pathway was initially interrupted in a hole that was virtually cAMP-free,” said Annibale. “But when we inhibited the PDEs that create these holes, the pathway continued on unobstructed.”
A chip rather than a switch
“This means the cell does not act like a single on/off switch, but rather like an entire chip containing thousands of such switches,” explains Lohse, summarizing the findings of the research. “The mistake made in past experiments was to use cAMP concentrations that were far too high, thus enabling a large amount of the signaling molecule to diffuse freely in the cell because all binding sites were occupied.”
As a next step, the researchers want to further investigate the architecture of the cAMP “prisons” and find out which PDEs protect which signaling proteins. In the future, medical research could also benefit from their findings. “Many drugs work by altering signaling pathways within the cell,” explains Lohse. “Thanks to the discovery of this cell compartmentalization, we now know there are a great many more potential targets that can be searched for.”
“A study from San Diego, which was published at the same time as our article in Cell, shows that cells begin to proliferate when their individual signaling pathways are no longer regulated by spatial separation,” says Bock. In addition, he adds, it is already known that the distribution of cAMP concentration levels in heart cells changes in heart failure, for example. Their work could therefore open up new avenues for both cancer and cardiovascular research.
Text: Anke Brodmerkelwww.mdc-berlin.de
Research / 25.08.2020
Eckert & Ziegler: Gallium-68-Generator erhält Zulassung für Kanada
Die Eckert & Ziegler Radiopharma GmbH hat von der kanadischen Gesundheitsbehörde Health Canada die Marktzulassung für ihren pharmazeutischen 68Ge/68Ga-Generator GalliaPharm® erhalten.
„Wir freuen uns, GalliaPharm® nun in Kanada anbieten zu können. Mittlerweile sind die Generatoren von Eckert & Ziegler in immer mehr Ländern erhältlich. Wenn sich in den kommenden Jahren Gallium-basierte Diagnosen auf breiter Front durchsetzen, sind wir als Lieferant dafür bestens gerüstet“, erklärt Dr. Lutz Helmke, Vorstandsmitglied der Eckert & Ziegler AG und verantwortlich für das Segment Medical. „Da es weltweit momentan viele klinische Studien mit sogenannten Theranostika gibt, erwarten wir eine steigende Nachfrage sowohl nach dem diagnostischen Radioisotop Gallium-68 als auch dem therapeutischen Radioisotop Lutetium-177.“
GalliaPharm® wird bereits erfolgreich für die Diagnose von neuroendokrinen Tumoren und demnächst auch für Prostatakrebs (Ga-68-PSMA) verwendet.
Galliumgeneratoren bieten eine preiswerte Alternative zur radioaktiven Markierung von Biomolekülen mit Gallium-68 im Rahmen der PET, einer bildgebenden Untersuchungsmethode, mit denen die An- oder Abwesenheit von krankem Gewebe nachgewiesen wird. Das Verfahren kommt vor allem bei der Diagnostik von Krebs, Herzinfarkten oder neurologischen Erkrankungen zum Einsatz. Bisher werden zur Markierung der Biomoleküle meist die Radioisotope Fluor-18 oder Kohlenstoff-11 benutzt. Hierfür sind Millioneninvestitionen für Großgeräte (Zyklotrone) erforderlich. Der 68Ge/68Ga-Generator dagegen hat in etwa die Größe einer Thermoskanne und kann wesentlich preiswerter bezogen werden, was in den nuklearmedizinischen Kliniken und Praxen Kosten senkt und Flexibilität erhöht.
Über Eckert & Ziegler.
Die Eckert & Ziegler Strahlen- und Medizintechnik AG gehört mit über 800 Mitarbeitern zu den weltweit größten Anbietern von isotopentechnischen Komponenten für Strahlentherapie und Nuklearmedizin. Die Eckert & Ziegler Aktie (ISIN DE0005659700) ist im TecDAX der Deutschen Börse gelistet.