News

Innovation / 11.10.2021
Eckert & Ziegler Acquires 53,000 Square Feet Facility for Expansion of Contract Development and Manufacturing Services

Eckert & Ziegler Strahlen- und Medizintechnik AG (ISIN DE0005659700, TecDAX) has received from the Berlin City Government a 66-year long-term lease for an industrial property with 53,000 square feet (5,000 square meters) of factory floor located at the north eastern city limit of Berlin. The group plans to use the facility for the expansion of its contract development and manufacturing services that it provides, among others, for a variety of cancer therapeutics and radio diagnostics. Up to 10 mm EUR will be invested during the next years into the renovation of the site, the set-up of new laboratories, production and clean rooms meeting Good Manufacturing Standards for the pharmaceutical industry, and the creation of high-tech workplaces. Due to its proximity to a thermal power station, the new site is expected to meet highest energy efficiencies.

“We are encouraged to see companies in our industry developing so many exciting new radiopharmaceuticals and are eager to provide a top-tier development and manufacturing service to support their efforts”, explained Dr. Lutz Helmke, COO of Eckert & Ziegler’s medical division. “We may also use the site later to produce proprietary drugs and diagnostics”.

The acquisition and build-up of the new facility represent a cornerstone of Eckert & Ziegler’s global capacity expansion program, which is scheduled to absorb up to 100 mm EUR until the end of the decade. It will also benefit Eckert & Ziegler sites in the United States and China. Production processes developed and validated in Berlin shall be duplicated there, so that customers in the pharmaceutical industries can receive the components for their radiopharmaceuticals in an identical, standardized manner.

About Eckert & Ziegler.
Eckert & Ziegler Strahlen- und Medizintechnik AG with more than 800 employees is a leading specialist for isotope-related components in industry, science, nuclear medicine and radiation therapy. The company also offers a broad range of services and products for the radiopharmaceutical industry, from early development work to contract manufacturing and distribution. Eckert & Ziegler shares (ISIN DE0005659700) are listed in the TecDAX index of Deutsche Börse.

Source: Press release EZAG
Eckert & Ziegler Acquires 53,000 Square Feet Facility for Expansion of Contract Development and Manufacturing Services

Research / 30.09.2021
Lighting up tumor cells

© Matthias Schmitt, MDC
© Matthias Schmitt, MDC

MDC PhD student Matthias Jürgen Schmitt is being honored with the Curt Meyer Memorial Prize of the Berlin Cancer Society for his achievements in cancer research. He employs molecular reporters to investigate how glioblastoma – the deadliest brain tumor of all – becomes resistant to therapies.

The Curt Meyer Memorial Prize of the Berlin Cancer Society, which is endowed with €10,000, commemorates Senate Councillor Dr. Curt Meyer (1891–1984), who as a physician and health policymaker was committed throughout his life to educating people about cancer and preventing and fighting the deadly disease. This year’s prize goes to Matthias Jürgen Schmitt of the Max Delbrück Center for Molecular Medicine (MDC). The award ceremony will take place on October 1, 2021, at the annual meeting of the German Society for Hematology and Medical Oncology in Berlin. “Although the prize was presented to me, it recognizes the success of our entire team. And we’re tremendously thrilled that the jury has honored our work – work into which we have expended a lot of energy and even some frustration,” says Matthias Schmitt. “We’re also proud that our young lab was recognized, especially considering that most previous award winners were much further along in their scientific careers.”

Resistance is crux of problem

Matthias Schmitt is a PhD student in Dr. Gaetano Gargiulo’s Molecular Oncology Lab at the MDC. Together with Yuliia Dramaretska and Juan Carlos Company Nevado he has developed molecular reporters to study how glioblastomas manage to become resistant to any therapy – and how this may be prevented. These resistance mechanisms must be elucidated before new therapeutic options for this form of cancer can be developed. “In the past 20 years, not a single new effective drug has come onto the market. And that’s despite the fact that no other type of tumor is so well molecular biologically characterized as glioblastoma,” Schmitt stresses.

Um neue Therapieoptionen für diese Krebsform entwickeln zu können, müssen diese Resistenzmechanismen aufgeklärt werden. „In den vergangenen 20 Jahren kam kein einziges neues wirksames Medikament auf den Markt. Und das, obwohl keine andere Tumorart molekularbiologisch so gut charakterisiert ist“, betont Matthias Schmitt.

The problem is that most studies to date have focused on the biopsy and molecular characterization of the entire tumor. Yet the composition of a glioblastoma changes at the single-cell level over time, particularly when the tumor returns after an initially successful therapy. In this process the tumor cells often transition to the most aggressive subtype. Molecular reporters can now make this “identity change” visible.

Light signals from the cell

Molecular reporters are synthetic copies of DNA sequences that regulate the activity of those genes that initiate or stop cell transformation. “We have virtually combined the complete ‘regulome’ of these signature genes into a small piece of DNA and fused it to a fluorescent protein,” the molecular biologist explains. “When the cell’s state changes, certain transcription factors become active and bind to the corresponding target genes – and to our reporter. And then the cell lights up.”

The cells of origin for glioblastoma likely develop from neural stem cells and from glial cells, the supporting tissue of the brain. They strongly infiltrate into surrounding tissue during this process. In Germany alone, about 4,800 people are newly diagnosed with this very aggressive cancer every year. The diagnosis is still a death sentence. That’s because even if the standard therapy – surgical removal of the tumor followed by radiation and chemotherapy – is initially successful, the tumor invariably returns, and patients die within a few months. Drugs that are used successfully to treat other forms of cancer do not reach this tumor at all because they cannot cross the blood-brain barrier.

Molecular reporter exposes collaborators

New single-cell technologies have revealed just how heterogeneous a glioblastoma is. “We were able to see that there are many different cell types at different stages, and that a one-size-fits-all therapy is not possible,” Schmitt explains. As if it weren’t complicated enough that diverse genetic, epigenetic and transcriptional factors play a role in resistance development, cells in the immediate tumor microenvironment also get involved in the process.

With the help of molecular reporters, Schmitt and his colleagues were able to visualize how cells of the innate immune system actually “protect” the tumor cells instead of fighting them. They help the tumor cells change their identity to the most aggressive subtype of glioblastoma, the subtype that is maximally resistant to therapies. “We now know that if you attack one cell type with chemotherapy, the composition of the tumor changes to another cell type,” says Schmitt. “One possible approach would be to use this evasive maneuver to reduce the number of cell states and force the tumor to transition into the least aggressive type.”

The researchers can now track in real time how individual tumor cells respond to specific therapies. The team wants to find out if and how it is possible to stop immune cells from protecting tumor cells. The concept of fluorescent reporters also happens to be applicable not only to tumors, but also to many other biological questions

Co-award winner: Dr. Laura Schmalbrock of Charité

Matthias Jürgen Schmitt shares this year’s Curt Meyer Memorial Prize with Dr. Laura Schmalbrock from the Department of Hematology, Oncology and Tumor Immunology at Charité – Universitätsmedizin Berlin. She is being honored for her work on acute myeloid leukemia (AML), the most common form of acute leukemia in adults. Her research has examined why some patients do not respond to an established method of therapy involving tyrosine kinase inhibitors in combination with chemotherapy or why they suffer a relapse of the disease.

Text: Catarina Pietschmann

Further information

Source: MDC
Lighting up tumor cells

Innovation, Patient care / 27.09.2021
Nantes University Hospital Doses First Patients with Eckert & Ziegler’s Novel Ga-68 Imaging Agent PENTIXAFOR

The Centre Hospitalier Universitaire de Nantes (CHU), the French university hospital serving the greater Nantes/Saint-Nazaire metropolitan area, has started to dose first patients with PENTIXAFOR, an innovative imaging compound for the initial staging of cancer patients with symptomatic multiple myelomas. The Ga-68 based radio-diagnostic promises to significantly improve the patient management for early forms of the disease by identifying the optimal therapeutic alternative.

To investigate the potential of PENTIXAFOR the CHU will recruit, on its own account, up to 45 patients in a so-called investigator-initiated study (ISS). Eckert & Ziegler (ISIN DE0005659700, TecDAX), the owner of the rights to the underlying chemokine 4 receptor (CXCR4), supports the CHU team under Professor Caroline Bodet-Milin by providing the compound in exchange for access to certain data.

PENTIXAFOR is being developed by Eckert & Ziegler’s subsidiary Pentixapharm GmbH also on its own as a superiorly sensitive diagnostic for a portfolio of rare blood cancers, among them myelomas and lymphoma. In spring 2021 the European Medicine Agency gave Eckert & Ziegler green light to leapfrog into a phase III clinical examination, thereby allowing her to cut a range of time-consuming evaluation steps. The clinical tests are scheduled to start next year and will involve about 500 patients worldwide.

Given the potential of PENTIXAFOR for improved patient stratification, academic groups like CHU have decided to move ahead on their own and to test PENTIXAFOR right away. To speed up the PENTIXAFOR marketing authorization, Eckert & Ziegler closely cooperates with such initiatives and supports them where feasible.

Multiple myeloma is a form of blood cancer that affects the bone marrow. It is caused by the malignant proliferation of plasma cells in the bone marrow. Globally, multiple myelomas annually affect about half a million people and result in about 100,000 deaths.

Principal Investigator Professor Caroline Bodet-Milin for the PENTIMYELO study stated, “The PENTIXAFOR-PET may improve sensitivity and specificity of PET imaging in symptomatic Multiple Myeloma patients, as compared with FDG-PET. An improved sensitivity of PENTIXAFOR may allow visualization of bone marrow lesions and extra-medullary disease not detected by FDG commonly generating a significant number of false negative results. Moreover, PentixaFor may allow to determine new prognostic value at baseline or during therapy evaluation.”

“The fact that one of the leading centers in France like the CHU has decided to work on the PENTIXAFOR on its own indicates the immense interest among haematologists in the potential of PENTIXAFOR,” comments Dr. Jens Kaufmann, co-founder and general manager of Pentixapharm. “We are delighted to have Professor Françoise Kraeber-Bodéré and Professor Caroline Bodet-Milin of the nuclear medicine department as the principal investigators in these tests.”

Professor Françoise Kraeber-Bodéré is Head of the department of Nuclear Medicine at the University Hospital in Nantes, France and an expert of the Oncology committee of the French Society of Nuclear Medicine (SFMN) as well as of the Oncology and Therapy committee of the European Association of Nuclear Medicine. She is on the scientific board of the French Lymphoma research group LYSA and expert for PET in lymphoma and myeloma.

Professor Caroline Bodet-Milin is senior physician in the department of Nuclear Medicine at the University Hospital in Nantes, France and an eminent expert on PET lymphoma and myeloma.

This project is supported by several cancer research associations, among them Siric ILIAD and IRON Labex.

About Eckert & Ziegler.
Eckert & Ziegler Strahlen- und Medizintechnik AG with more than 800 employees is a leading specialist for isotope-related components in nuclear medicine and radiation therapy. The company offers a broad range of services and products for the radiopharmaceutical industry, from early development work to contract manufacturing and distribution. Eckert & Ziegler shares (ISIN DE0005659700) are listed in the TecDAX index of Deutsche Börse.

Research / 24.09.2021
BR50: Strengthen the science metropolis Berlin

With a position paper developed under the umbrella of Berlin Research 50, the non-university institutions of Berlin emphasize what is important for science in Berlin. They state ten demands that should be implemented by the future senate to strengthen Berlin as science metropolis.

Berlin has a unique diversity and spatial density of research institutions. The capital city’s non-university research landscape in particular is diverse and covers a wide range of topics. Together with the universities that make up the Berlin University Alliance (BUA), non-university research institutions are key location factors.

During the last years, the Berlin senate strongly supported the interest of science and research in the capital. This commitment should be continued and even be expanded. To achieve this, it is crucial to now pave the way, claimed Berlin Research 50 (BR50) an initiative that was formed in spring 2020. This is essential to strengthen Brain City Berlin and the Berlin-Brandenburg region as research location.

The institutions state that it is necessary to intensify the already existing cooperation between the non-university institutions and with the universities, universities of applied sciences, and the Charité and to strengthen the important role of the Einstein Foundation in terms of the cross-institutional scientific col-laboration.

Ten key points

During a general assembly that took place on September 9th 2021 at the Max Delbrück Center for Molecular Medicine in Berlin Buch, the BR50 institutions agreed on a joint position paper. Within three sections they name 10 key points that are important for the non-university research and that should be addressed by the future senate on state level as well as on the national level:

Attracting the best minds to the metropolitan region

   1. Simplification and promotion of joint professorships
   2. Equal rights for junior research group leaders
   3. International network and diversity as location factors in a global research economy

Ensuring framework conditions for excellent research

   4. Taxation of research cooperation hampers science
   5. Promotion of infrastructure for excellent research
   6. Ensuring of adequate spatial arrangements for research

Recognising and promoting diversity in science

   7. Honest and realistic communication on animal experimental research
   8. Expansion of support for small and individual projects
   9. The Berlin-Brandenburg Metropolitan Region as a healthy place to live
 10. Venture capital for a start-up science in Berlin

Attract cutting edge scientists from all over the world

“The research in Berlin is extraordinary diverse and make the capital shine, while the contribution of the non-university institutions, under the umbrella of BR50, is more visible than ever.” States Thomas Sommer, founding coordinator of the Unit Life sciences in BR50 and scientific director of the MDC (in-terim). “We envision to strengthen the connection of the scientists beyond all institutional and discipli-nary borders, because interdisciplinarity is a requirement for good science. “

„Our society has to face huge challenges“, states Michael Hintermüller, founding coordinator of the Unit Technology and Engineering in BR50 and director of the Weierstrass Institute for Applied Analy-sis and Stochastics at the Forschungsverbund Berlin e.V.: “With BR50 we have the chance to promote future topics like artificial intelligence and quantum technology, technological sovereignty, health, cli-mate change and biodiversity by a better exploitation of the synergies of all research institutions in Berlin.”

“To upgrade Berlin towards a worldwide leading research metropolis, it is essential to have new programs that attract cutting edge scientists from all over the world to Berlin enhancing the diversity in science”, states Ulrich Panne, founding coordinator of the Unit Natural Sciences in BR50 and presi-dent of the Bundesanstalt für Materialforschung und -prüfung (BAM). “And, frameworks for state-of-the-art laboratories and IT infrastructure need to be established and usable by all research institutions in Berlin.“

“Science and science politics can function on solidarity only. That is essential to create understanding and trust – a necessary basis for investments, innovation and visions” emphasizes Jutta Allmendinger, founding coordinator of the Unit Social Sciences and Humanities in BR50 and president of the Berlin Social Science Center (WZB) „BR50 is a strong bridgehead and enables science politics that works on national and international level for the well-being of science and society while setting a strong signal for Berlin as science metropolis.“

Further information

 

Source: Press Release MDc
BR50: Strengthen the science metropolis Berlin

Research / 16.09.2021
Downtime at the nerve cell’s protein factories

A team led by MDC researcher Marina Chekulaeva has figured out why protein production slows down in the nerve cells of people suffering from Charcot-Marie-Tooth disease. This discovery could lead to a new therapeutic approach, the scientists report in the journal "Nucleic Acids Research".

Charcot-Marie-Tooth disease (CMT) is a rare hereditary condition. It occurs when genetic changes disrupt the transmission of nerve signals from the brain to the muscles of the extremities, particularly those of the lower limbs. This leads to a gradual loss of muscle tissue in the lower legs. Early symptoms of the disease, which include pain and difficulties walking, usually appear in childhood and adolescence. In Germany alone there are an estimated 30,000 people living with CMT.

Enzymes become altered

“We have known for some time that mutations in genes encoding enzymes called aminoacyl-tRNA synthetases (aaRSs) can cause CMT,” explains Dr. Marina Chekulaeva, head of the Non-coding RNAs and Mechanisms of Cytoplasmic Gene Regulation Lab at the Berlin Institute for Medical Systems Biology (BIMSB), which is part of the Berlin-based Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC).

These enzymes are required for cellular protein production, which takes place in ribosomes, the cell’s protein factories. Their job involves aminoacylation binding an amino acid to another molecule, a so-called tRNA. This enables the individual amino acids to be linked together at the ribosomes to form a protein chain according to the genetic blueprint stored in the DNA.

Translation is impaired by mutations

“The paradox is that these mutations do not disrupt aminoacylation activity, but they do interfere with translation – the production of proteins at the ribosomes,” says Chekulaeva. “To understand this mechanism, my team and I took a close look at how mutations in glycyl-tRNA synthetase affect translation processes.” This enzyme is altered in patients with a common form of CMT disease known as CMT type 2D (CMT2D).

For their work, the researchers used ribosome profiling to evaluate ribosomal activity in detail. “This technique helps us determine things like the exact codon where protein production is halted, and quantify the frequency at which this occurs,” explains Samantha Mendonsa, the study’s first author and a doctoral student in Chekulaeva’s lab.

Protein chains are too short

“We found that the gene alteration in CMT patients initially results in a shortage of glycyl-tRNA available for translation,” says Mendonsa. “This causes ribosomes to stall their protein production at the sites where the amino acid glycine is to be added to the growing protein chain.” Elongation or lengthening of the protein chain is thus halted. “The pause in elongation at the glycine sites also induces an integrated stress response, leading to a disruption of translation initiation,” she reports. Protein production is reduced as a result.

Mendonsa and Chekulaeva are convinced that their findings can provide new avenues for therapies against CMT, for which there is currently no causal treatment. “One possibility would be the administration of tRNA to overcome its shortage in the nerve cells, thus alleviating ribosome pausing,” says Chekulaeva. “Another approach could be to use relevant therapeutic agents to suppress the integrated stress response.” Yet she says pursuing these avenues further is now a task for clinical researchers.

Open questions

“Our team is now interested, for example, in the still unanswered question of how and why ribosome pausing impairs the function of the motor and sensory nerve fibers that connect the brain and lower limbs,” Chekulaeva says. An answer to that question will likely be of great benefit to people with CMT.

Text: Anke Brodmerkel

 

Source: Press Release MDC
Downtime at the nerve cell’s protein factories

Research / 13.09.2021
COVID-19: What is driving the escalating hyperinflammation

© Soyoung Lee, Charité
© Soyoung Lee, Charité

The severity of COVID-19 is primary result of a dysregulated immune response. A cellular stress response mechanism plays a major role in the derailed immune response: senescence, report Clemens Schmitt and his colleagues in “Nature“. This suggests novel treatment path.

Cellular senescence is a tissue-protective mechanism which is triggered in response to stress and injury. It results in the programmed cessation of cell division, thereby also protecting against cancer. Senescent cells release pro-inflammatory messengers which are important in wound healing. When present in excess or produced for too long, these inflammation modulators promote age-related diseases like diabetes and atherosclerosis. Sparse evidence that senescence may also be triggered by viral infections has, until now, received little attention.

A team of researchers from Charité – Universitätsmedizin Berlin, the Max-Delbrück-Center for Molecular Medicine (MDC), Johannes Kepler University (JKU) Linz and Kepler University Hospital (KUK) led by the oncologist Professor Clemens Schmitt has now shown in “Nature“ that this process plays a crucial role in triggering a veritable avalanche of inflammatory mediators, which contribute to the lung damage associated with COVID-19. Drugs capable of selectively eliminating senescent cells were shown to mitigate COVID-19-related lung damage in animal models, in addition to significantly reducing inflammation. “In our view, the early use of specific substances which disrupt this inflammatory overreaction holds enormous potential as a new treatment strategy for COVID-19,” says the cancer specialist.

Infection drives mucosal cells into senescence

In addition to his position as Director of the Molecular Cancer Research Center (MKFZ), Clemens Schmitt is Head of the MDC’s “Cancer Genetics and Cellular Stress Responses” research group and Research Group Lead at Charité’s Department of Hematology, Oncology and Tumor Immunology on Campus Virchow Klinikum. He is also the Head of Hematology/Oncology at the KUK and holds a professorship at the JKU Linz. Schmitt´s research into COVID-19 benefits from his long-standing expertise in the field of senescence, in particular as it pertains to cancer. Working alongside his team of researchers, he has been using both cell-based models and animal models to study the role of senescence in the body’s immune response to SARS-CoV-2 infection.

In their article, the researchers show that the cellular stress-response program initiates an avalanche-like inflammatory response which culminates in the pneumonia typically seen in COVID-19. Simply put, the cascade begins inside SARS-CoV-2-infected cells of the upper respiratory tract, where viral entry into mucosal epithelial cells triggers a cellular stress response which activates their senescence program. Once senescent, the mucosal epithelial cells produce ample amounts of pro-inflammatory messengers. These, in turn, attract specific immune cells known as macrophages, which infiltrate the mucosa in order to remove senescent cells.

Due to the presence of the pro-inflammatory factors, however, the macrophages are themselves driven into the senescent state and release now large quantities of such factors themselves. Senescent macrophages can then infiltrate the lungs, where they may trigger senescence in other cells, such as the extremely sensitive cells lining the lung’s small blood vessels. Thrombogenic substances produced in response to this insult result in microthrombosis, i.e., the formation of tiny blood clots which obstruct the lung’s small blood vessels. Blood flow and oxygen exchange are severely impaired.

Interrupt the cascade early on

“The cellular stress program is an important driver of such escalating hyperinflammation which plays a major role in producing many of the characteristic features of COVID-19 pneumonia, such as vascular damage and microthrombosis,” explains the study’s first author, Dr. Soyoung Lee, a researcher based at the MDC and Charité’s Department of Hematology, Oncology and Tumor Immunology as well as the MKFZ on Campus Virchow Klinikum. “It was therefore a logical step to test whether we might be able to mitigate disease severity through early targeting of cells affected by virus-induced senescence.”

The team used animal models to study the effects of four distinct drugs which attack senescent cells in a targeted manner: navitoclax, fisetin, quercetin and dasatinib. Two of these senolytics are plant-based compounds; the other two are approved as or tested for cancer therapy. When used in hamsters and mice, all four substances – some used on their own, others in combination – achieved varying degrees of success in normalizing the hyperinflammation cascade and mitigating lung injury. The research team was able to refer to data from two smaller clinical studies which had already been completed. A combined analysis of the available data suggested that one of the senolytics tested was also able to reduce the risk of severe COVID-19 in humans.

Clinical studies test dose and side effects

“These results are extremely encouraging,” says Schmitt, who also conducts research at the German Cancer Consortium (DKTK). He adds: “Just like other therapeutic agents, however, senolytics can have side effects. Many questions therefore remain to be answered before we can consider them as a potential treatment against COVID-19. For instance: what is the effective dose? At which point and for how long will these substances need to be administered? What side effects are associated with their use? Might older people derive more benefit from senolytics than younger patients? After all, aging is associated with an increase in the number of cells which are ready to enter senescence. This needs to be explored in further clinical studies, some of which are already underway in a number of institutions across the globe.”

While the researchers await the results of these clinical COVID-19 studies with great interest, they are also looking beyond the current pandemic. “Our study has shown that different types of cells initiate senescence not only in response to an infection with SARS-CoV-2, but also in response to other viruses,” explains Lee. “Our hope is therefore that our findings will be of relevance to other infectious diseases in which the body’s immune response plays a crucial role in determining disease severity.”

Photo: Human nasal mucosa cells which have started their senescence program in response to SARS-CoV-2 infection. The cells were stained using a standard test for evaluating senescence which produces a characteristic blue color.© Soyoung Lee, Charité

Source: A joint press release by Charité, the MDC, JKU Linz and the Kepler University Hospital
https://www.mdc-berlin.de/news/news/covid-19-was-die-lawine-der-entzuendung-antreibt

Research / 09.09.2021
Disease genes help early brain development

Photo: AG Hammes, MDC
Photo: AG Hammes, MDC

If the cerebral hemispheres of the forebrain fail to divide properly in an unborn child, this results in holoprosencephaly. An MDC team led by Annette Hammes has discovered candidate genes that can positively influence the severity of this congenital malformation of the forebrain, as the researchers now report in the journal Development.

Holoprosencephaly (HPE) affects around one to four in every 1,000 unborn babies, and occurs when the cerebral hemispheres of the forebrain fail to divide or only partially divide. It is the most common malformation of the forebrain in humans and is associated with facial disfigurements, such as cleft lip and cleft palate or eyes that are very close together – even to the extent that the two eyeballs merge. The majority of fetuses affected die while still in the womb.

The exact causes of HPE are not yet fully understood. In addition to environmental pollutants and illness of the expectant mother, genetic factors can play a role – including mutations in the genes of the so-called Sonic Hedgehog (SHH) signaling pathway. This pathway controls the embryonic development of organs and the nervous system. Gene defects and a resulting loss of function of LRP2, an SHH co-receptor, result in brain defects that manifest themselves very differently. “We wanted to know why the severity of this disease varies so much,” says Dr. Annette Hammes, head of the Molecular Pathways in Cortical Development Lab at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC). “While some sufferers have no or only mild symptoms, others have to live with severe deformities – even if the two patients are related to each other and we can therefore assume that the disease is caused by the same gene mutation.”

Disease genes restore the SHH pathway

Researchers have long assumed that there are genes that positively influence this malformation or even prevent it altogether. The Hammes Lab team has now identified two new candidates: “ULK4 and PTTG1, also known as securin,” says co-lead author Dr. Nora Mecklenburg, who was a postdoctoral researcher with Hammes at the time of the study. ULK4 is a gene that has so far been associated with schizophrenia and bipolar disorder, while PTTG1 is mainly researched in connection with cancer. In the journal Development, the scientists explain how these proteins can restore an impaired SHH pathway. Nine years of work went into the study, which the journal classifies as a “research highlight.”

But the results were also partly down to chance. Hammes and her team had been studying mice with LRP2 mutations for many years, together with the MDC lab led by Professor Thomas Willnow. “We know that LRP2 influences the formation of the neural tube in early embryogenesis, and it is out of this that the nervous system later develops,” explains the neuroscientist. Without LRP2, the SHH pathway is not sufficiently activated and malformations of the neural tube occur at a very early stage of pregnancy – often resulting in miscarriage. When the scientists crossed the LRP2 mutants of the commonly used black-coated mouse strain (known as “Black 6” for short) with another mouse strain with white coats, the result was very surprising: The white-coated offspring did not show any malformations of the brain or face – despite having a mutation in the SHH co-receptor LRP2. The team concluded that there must be as-yet-unknown factors that influence the SHH pathway, and set out to find them.

RNA analysis with high-throughput sequencing

To do this, Mecklenburg first bred the different mouse strains and examined the animals with regard to their disease characteristics, signaling pathways and genetic makeup. Together with her co-lead authors Franziska Witte, then a doctoral student in Professor Norbert Hübner’s MDC lab, and Izabela Kowalczyk, a doctoral student with Hammes, she sequenced and analyzed the RNA of embryonic cells of the different strains using high-throughput methods. The three scientists discovered that, despite having a similar genome sequence, the cells have completely different transcriptomes – meaning the genes are read very differently. “The extent of the differences even between the wild types of the two mouse strains at this early stage of embryonic development really surprised us,” says Mecklenburg.

The researchers conducted further studies and found that, in the white-coated LRP2 mutants, as well as in the wild types of this strain, certain genes, including ULK4 and PTTG1, are strongly upregulated compared to the Black 6 mice. To see if this affects the SHH pathway, they introduced the genes into cells lacking LRP2 function. “We were able to see that they significantly boost the Sonic Hedgehog signaling pathway,” says Kowalczyk. Their conclusion: “More ULK4 and PTTG1 are produced in the LRP2 mutants with the white mouse ancestors. They compensate for the missing LRP2, restore a sufficiently strong SHH pathway, and prevent the malformations from occurring.” This finding casts the disease genes ULK4 and PTTG1 in a completely new light: While high levels of expression can trigger diseases in the adult organism, they can actually positively influence the development of an embryo. The scientists were also able to pinpoint the location from which these factors amplify the SHH pathway – the antenna-like projections of the neuroepithelial cells, which are the cells that line the inside of the neural tube.

Decoding – and maybe even preventing – genetic diseases

“The fact that we have identified these candidate genes that modulate the SHH pathway in mice takes our knowledge of holoprosencephaly and other genetic diseases one step further,” says Hammes. “With this knowledge, we may even find a way to prevent them.” But there is still a long way to go until then, and the next step for her team is to explore what role the newly discovered SHH pathway modifiers play – not only during embryonic development, but also in the adult brain. The scientists have already located PTTG1 in the cytoskeleton of neurons – a protein network in the cytoplasm that gives the cells stability. The team is currently investigating what role the gene plays in this location.

Text: Jana Ehrhardt-Joswig

Source: Press Release MDC
https://www.mdc-berlin.de/news/news/disease-genes-help-early-brain-development

Research / 02.09.2021
Dr. Michael Frieser is named new Administrative Director of the Berlin Institute of Health at Charité (BIH)

Dr. Michael Frieser © BIH
Dr. Michael Frieser © BIH

On June 24, 2021, the BIH Governing Board confirmed Dr. Michael Frieser as the new Administrative Director of the Berlin Institute of Health at Charité (BIH). He succeeds Andrea Runow, who has held the post since January 1, 2019, and is now retiring. Dr. Michael Frieser, 55, who currently heads the Administration Division at the Paul-Ehrlich-Institut in Langen, brings more than 20 years of experience in science administration to the position. He will take up the new post on September 1, 2021.

Christian Luft, State Secretary at the Federal Ministry of Education and Research (BMBF), expressed his delight at the confirmation of Dr. Michael Frieser: “We are thrilled that in Dr. Michael Frieser we are gaining an experienced scientific manager for the BIH. We are confident that together with Professor Baum he will continue to drive the BIH forward on its successful course. We wish him all the best in his new role.”

Steffen Krach, the Permanent Secretary for Higher Education and Research of the State of Berlin, concurred that the appointment of Dr. Michael Frieser as the BIH’s new Administrative Director was an excellent choice: “With his many years of experience in science administration, Dr. Frieser is eminently qualified for the role in the Board of Directors of the Berlin Institute of Health at Charité. I wish him together with Professor Baum every success in advancing the strategic development of the BIH. With the successful integration into Charité and the finalization of leadership changes, the BIH is now ideally positioned going forward to strengthen Berlin as a health and research hub on an enduring basis, while also translating scientific discoveries more quickly into benefits for patients.”

A wealth of experience in relevant areas

In his new role Frieser will be in charge of all business and administrative operations at the BIH while, together with Professor Christopher Baum, Scientific Director and Chair of the BIH Board of Directors, also being responsible for management of the Institute. Christopher Baum, who is also the Chief Translational Research Officer of Charité – Universitätsmedizin Berlin, welcomes his new colleague to the Board of Directors: “I very much look forward to working with Dr. Michael Frieser. He brings a wealth of experience from an area that is extremely relevant for the BIH: The Paul-Ehrlich-Institut is closely involved in the authorization of vaccines and novel drugs, which also play a major role at the BIH. His experience will also help us to work even more effectively in this future-oriented field.”

Dr. Michael Frieser is also looking forward to his new duties: “The BIH’s mission of quickly translating findings from the lab to patients is something that is very close to my heart. I’m pleased to be able to bring to bear my experience in Berlin.”

An administrative specialist with a PhD in biology

Dr. Michael Frieser studied at the Federal University of Applied Administrative Sciences in Cologne, graduating with a degree in public administration in 1988. He then studied biology at Friedrich-Alexander University of Erlangen-Nuremberg (FAU). His thesis, which he completed in the clinical research groups of the Max Planck Society, dealt with rheumatology and connective tissue research. He earned his doctorate from 1994 to 1996 at the FAU’s Institute for Experimental Medicine with a dissertation on the endothelium, the innermost cellular layer of blood vessels. Immediately thereafter, he joined the Paul-Ehrlich-Institut (PEI), Federal Institute for Vaccines and Biomedicines, in the Hessian city of Langen, where he initially headed its Information Technology Unit. He held various other positions at PEI before becoming the head of the Administration Department in 2003.

Dr. Michael Frieser is married and has two children, aged 13 and 16.

Research / 01.09.2021
Johanna Quandt-Professorship for Kathrin de la Rosa

Stiftung Charité Foundation and the Berlin Institute of Health at the Charité are continuing their format for recruiting outstanding female scientists. MDC researcher Kathrin de la Rosa is among the four new Johanna Quandt Professors. The immunologist will continue to lead her research group here.

Stiftung Charité and the Berlin Institute of Health at Charité (BIH) are establishing a number of new BIH Johanna Quandt Professorships in Berlin for the second time. The professorships were advertised worldwide and proved to be extremely well demanded. Not only was this international call for applications explicitly designed to promote women in science, but it also was open to all topics. Prospective candidates were invited to apply for their own professorship in Berlin creating an innovative concept. "The open topic approach by the Johanna Quandt Professorships dispenses with being restricted to specific subjects and, by doing so, promotes genuine competition for the best ideas and most promising research approaches," states Dr. Jörg Appelhans, Chair of the Executive Board of Stiftung Charité, summing up the selection process. Through the collaboration between the private Stiftung Charité and the publicly funded Berlin Institute of Health, up to three million Euros will be made available for each of the new professorships over the first five years. "The joint initiative with Stiftung Charité allows us to endow the professorships, which have also attracted candidates from leading universities, such as from the USA and Canada," states Professor Dr. Christopher Baum, Chair of the BIH Board of Directors and Chief Translational Research Officer of Charité – Universitätsmedizin Berlin.

Cooperation between Charité and MDC

With all female professors having been made a binding offer of tenure, the sustainability of the professorships is guaranteed. In order to bring about the corresponding long-term perspectives, Charité – Universitätsmedizin Berlin and the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) are working closely together on the appointments.

The new BIH Johanna Quandt Professors are:

  • Prof. Dr. Sarah Hedtrich from the University of Vancouver in Canada: she is appointed Johanna   Quandt   Professor   for   Translational   Human   Organ   Models   at  Charité  – Universitätsmedizin Berlin and its Department of Infectious Diseases and Respiratory Medicine. Her research will mainly focus on complex organ models of human skin and lung, while also establishing alternatives to conventional animal models for the development of new drugs and therapies.
  • Dr. Kirsten Kübler from the Massachusetts General Hospital of Harvard Medical School and the American Broad Institute, a joint institution of the Massachusetts Institute of Technology (MIT) and Harvard University: her Johanna Quandt Professorship for Early Cancer Development and Prevention is endowed at Charité – Universitätsmedizin Berlin and its Department of Hematology, Oncology and Cancer Immunology. In her research, the clinician will focus primarily on the molecular changes during cancer development, aiming at improving early detection of cancer.
  • Dr. Kathrin de la Rosa: the  group leader at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) is appointed Johanna  Quandt  Professor  for Immune Mechanisms in Translation. As part of her professorship, the immunologist, who was recently awarded a Starting Grant by the European Research Council, will deepen the research into the production of B cells to defend against viruses, such as SARS-CoV-2 or HIV. The scientist will continue to head her research group “Cancer & Immunology / Immune Mechanisms and Human Antibodiesat” the MDC and will also be based on Campus Buch.

All three BIH Johanna Quandt Professors will start their new appointments in the next few weeks. A fourth Johanna Quandt Professorship is expected to be filled in the near future. Together with the three Johanna Quandt Professors already selected in 2017, they form a new promising generation of highly interdisciplinary life scientists.

Stiftung Charité receives its funding for the professorships from the Johanna Quandt Private Excellence Initiative. The initiative is one of the largest single private funds for promoting science in Germany. As part of the Private Excellence Initiative, Stiftung Charité now supports nigh on 500 people at all scientific and clinical career stages, ranging from students to Nobel Prize winners.

Further information

Press Release MDC
https://www.mdc-berlin.de/news/press/johanna-quandt-professorship-kathrin-de-la-rosa

Innovation, Patient care / 26.08.2021
Eckert & Ziegler Starts Technetium-99 Delivery in Brazil

Eckert & Ziegler (ISIN DE0005659700, TecDAX), has started the delivery of Technetium-99 generators in Brazil. The subsidiary Eckert & Ziegler Brasil Comercial Ltda. had recently received a license from the Brazilian health authority ANVISA as the first and only private company to import and distribute technetium generators. Two leading hospitals in the greater Sao Paulo area are among the first customers, and further orders have already been placed.

Technetium generators are a core component for a nuclear medicine diagnostic procedure called SPECT, which is used to detect medical abnormalities. The generators need to be replaced regularly because the radioactive material in them has a short half-life. In Brazil, the SPECT market has a volume of about 100 million Euro per year. Eckert & Ziegler already supplies around 500 hospitals and clinics in this country with medical products and radioisotopes and now hopes to tap into the generator market. SPECT is often used to detect cardiac diseases, tumors, and metastases.

About Eckert & Ziegler.
Eckert & Ziegler Strahlen- und Medizintechnik AG with more than 800 employees is a leading specialist for isotope-related components in nuclear medicine and radiation therapy. The company offers a broad range of services and products for the radiopharmaceutical industry, from early development work to contract manufacturing and distribution. Eckert & Ziegler shares (ISIN DE0005659700) are listed in the TecDAX index of Deutsche Börse.
Contributing to saving lives.

Research / 17.08.2021
Slow version of the glutamate receptor AMPA discovered

The glutamate receptor AMPA was previously known for its lightning-fast transmission of excitation. All the more surprising, therefore, are the results that researchers from the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) in Berlin have now made: AMPA-receptors can also be extraordinarily slow. The discovery of the new type of receptor puts synaptic signaling in a whole new light. The groundbreaking findings were recently published in the journal Cell Reports.

The glutamate receptor AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) ensures that neurotransmitter signals are transferred from brain cell to brain cell at enormous speed. The fact that the receptor performs this vital task in a few milliseconds and is thus faster than all other glutamate receptors was considered certain.
Now it looks like the textbooks will have to be rewritten. Scientists from the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) in Berlin have discovered in mouse brains that there are also extraordinarily slow AMPA-receptors. These remain active for 500 milliseconds after stimulation - in other words, they are about 100 times slower than the "original". These are not isolated cases: About two-thirds of all hippocampal pyramidal cells express slow AMPA-receptors.

Two new AMPA-receptors identified
"Our results are a small revolution in biophysics and neuroscience," says Heisenberg Professor Dr. Andrew Plested, head of the Molecular Neuroscience and Biophysics group at the FMP and member of the Cluster of Excellence "NeuroCure". "This is because, for the first time, we were able to demonstrate that, in addition to the lightning-fast AMPA-receptors, there are at least two other types that operate in a much slower mode." This had already been suspected, he said, but had never been shown in such detail in brain tissue.

AMPA-receptors are vital for our brain function. It is still unclear what significance the now discovered slow AMPA-receptors with their synaptic potential of more than 100 milliseconds have for cognitive processes such as thinking, speaking, calculating or remembering. This exciting question will have to be explored further.
Researchers are still not entirely sure whether AMPA-receptors take on different properties by being able to switch between fast and slow modes - or whether they are fundamentally different types. The researchers suspect that there are fast, slow and multifunctional AMPA-receptors.

"Based on our data, we are currently assuming multiple receptor types, which offers some really interesting new functions for this type of glutamate receptor," said Niccolò Pampaloni, Ph.D., first author of the study published in Cell Reports.

Unstable process with dangerous aspects
In this context, the research team has made another spectacular discovery: According to current doctrine, the response of the AMPA-receptor is exclusively determined by the signaling from the pre-synaptic cell, and the post-synaptic cell is merely a passive receptor. However, the researchers found robust evidence that slow AMPA-receptors in the postsynaptic cell control the duration and strength of synaptic signal transmission. For this purpose, they apparently use auxiliary proteins.

But this could also have dangerous aspects, says Niccolò Pampaloni, who is funded by an EMBO stipend. "We're dealing with a very unstable feedback process. If somehow acts in the wrong way, this could lead a runaway excitation that could be linked to epilepsy, for example. We also don't know what happens once this process gets out of control - for example, due to an accident, a stroke or some other event in which a lot of glutamate is released."

New chapter opened in neuroscience
The impact of the slow AMPA current regarding brain function and pathologies can only be answered in the next step. First of all, it must be clarified whether humans actually possess these newly-discovered AMPA receptors. The researchers plan to investigate this crucial question shortly using human tissue samples. A cooperation with the Charité –Universitätsmedizin via the Cluster of Excellence "NeuroCure" has already been initiated.

Based on the current data, the Berlin research team assumes that slow AMPA-receptors are widely distributed in the mammalian brain, beyond the hippocampus. Biophysicist Plested: "We hope we’ve opened a new chapter with our discovery, which both basic researchers and neuroscientists will be able to exploit."

Publication:
Niccolò P. Pampaloni, Irene Riva, Anna L. Carbone, Andrew J.R. Plested. Slow AMPA receptors in hippocampal principal cells. Cell Reports, DOI: 10.1016/j.celrep.2021.109496

Press Release FMP
https://www.leibniz-fmp.de/press-media/press-releases/press-releases-single-view/slow-version-of-the-glutamate-receptor-ampa-discovered

Innovation / 12.08.2021
Eckert & Ziegler with Strong First Half of 2021

Eckert & Ziegler Strahlen- und Medizintechnik AG (ISIN DE0005659700, TecDAX), achieved a new record result in the first half of 2021 with a net profit of € 22.3 million or € 1.08 per share. Revenues of the Group amounted to € 89.5 million and were thus 7% above the previous year's level.

Although a large part of this growth is due to income from the sale of the tumor irradiation business, the development of the operating business in both segments is also extremely encouraging. The analysis of the operating result, which rose from € 19.0 million in the previous year to € 29.4 million, clearly illustrates this. Approximately half of the increase of € 10.4 million compared with the first half of 2020 (€ 5.4 million) results from the increase in the balance of other operating income and expenses, while a further € 5.0 million is attributable to improvements in the operating result.

Despite the deconsolidation of the tumor irradiation business and the associated loss of this revenue, the Medical segment was able to increase its sales revenues by a total of € 3.2 million or 8% to € 41.5 million.  The main growth driver continued to be the Radiopharmaceuticals business, which includes pharmaceutical radioisotopes, plant engineering, and project business. Sales revenues from laboratory equipment also increased.

At € 50.3 million, the Isotope Products segment achieved sales revenues that were € 3.2 million or around 7% higher than in the first six months of 2020. Following the slumps in connection with the Covid and oil crises last year, the segment was thus able to grow again as expected.

With around € 22 million, the Eckert & Ziegler Group achieved earnings in the first half of 2021 that exceeded original expectations. The Executive Board therefore expects the Group result to exceed the forecast for net income in fiscal year 2021 published at the beginning of the year by around 20%. As already published in the ad-hoc announcement of July 27, 2021, the Executive Board is therefore increasing the target for net income from € 29 million to  € 35 million, which corresponds to an EPS of around € 1.70.

The complete quarterly report can be viewed here:
https://www.ezag.com/fileadmin/user_upload/ezag/investors-financial-reports/englisch/euz221e.pdf

About Eckert & Ziegler.
Eckert & Ziegler Strahlen- und Medizintechnik AG with more than 800 employees is a leading specialist for isotope-related components in nuclear medicine and radiation therapy. The company offers a broad range of services and products for the radiopharmaceutical industry, from early development work to contract manufacturing and distribution. Eckert & Ziegler shares (ISIN DE0005659700) are listed in the TecDAX index of Deutsche Börse.

Research / 11.08.2021
Understanding lung damage in patients with COVID-19

© Dietert, Gruber, Freie Universität Berlin
© Dietert, Gruber, Freie Universität Berlin

A severe course of COVID-19 disease is not caused by the direct destruction of the lung due to the multiplication of the virus. As researchers from Berlin report in the journal Nature Communications, inflammatory processes and the endothelium of the lung are involved.

Researchers from around the globe have spent the past 18 months trying to understand COVID-19, the disease caused by the SARS-CoV-2 coronavirus. Capable of causing acute lung failure, the disease is known to wreak havoc on both the lungs and other organs and organ systems. Unfortunately, drug-based treatment options remain limited. One of the difficulties has been the fact that COVID-19 is caused by an errant and sometimes exaggerated immune response. In order to identify therapeutic targets, researchers need to gain a detailed understanding of the underlying mechanisms, both in terms of how they work and where in the body they occur. Patient-centered approaches are rather limited in their scope. This particularly applies to the study of disease mechanisms during the early phase of infection. Biomaterials, which are needed for this type of research, can usually be harvested only after a patient has been admitted to hospital. Furthermore, it is virtually impossible to obtain lung tissue samples from patients with mild or moderate disease and pneumonia, as the harvesting procedure would place these patients at too great a risk. What is left, then, is the analysis of tissues harvested from COVID-19 patients after their death.

Under the leadership of Professor Martin Witzenrath, Deputy Head of Charité’s Department of Infectious Diseases and Respiratory Medicine, the researchers used available patient samples to obtain valuable information on both disease mechanisms and disease progression. The researchers searched for a suitable model which might enable them to also study compartments of the lungs not easily accessible in patients but necessary in order to study the early phase of the disease. Hamster models have proven extremely useful, both as part of international research efforts into COVID-19 and research pertaining to SARS-CoV-1. “We wanted to know whether we could use these models to develop new treatment options and tried to replicate findings from patient samples. We were remarkably successful in this regard,” says Witzenrath, the study’s co-last author. “We were primarily interested in the lung’s endothelial cells, which line the pulmonary blood vessels and form a barrier there. In severe COVID-19 cases, this barrier becomes dysfunctional, a development which eventually results in lung failure.”

Syrian hamster is most important animal model for COVID-19

Working alongside researchers from the MDC’s Berlin Institute for Medical Systems Biology (BIMSB), virologists and veterinary surgeons from Freie Universität Berlin, as well as data experts from the Berlin Institute of Health (BIH), the researchers were able to describe the detailed characteristics of SARS-CoV-2 infection in an animal model. They subsequently corroborated their findings using data sets pertaining to patient samples. The purpose of this analysis is to make what is currently the most important, non-transgenic animal model for the study of COVID-19 available for research aimed at developing future treatments. Hamsters contract the same virus variants as humans. They also develop similar disease symptoms, and severe disease will result in damage to the lungs. Symptoms and progression of COVID-19, however, vary between different species of hamster. While symptoms usually remain moderate in Syrian hamsters, Roborovski hamsters will develop severe disease.

The reasons for this and the processes which take place in the cells of the lungs were demonstrated as part of experiments conducted at the BIMSB. These included single-cell analyses during which individual cells obtained from a particular sample were loaded onto a chip, where they were first barcoded and then encapsulated into minute droplets of aqueous fluid. Once prepared, single cells can undergo RNA sequencing, a process used to establish the sequence of genetic building blocks which a cell has just read. Thanks to barcoding, this RNA was later identifiable as originating from a particular cell, enabling the researchers to determine cellular function at the single-cell level with a high degree of accuracy. “We were able to observe how certain cells involved in lung immunity – namely monocytes and monocyte-derived macrophages – ingest the virus and subsequently show a very pronounced response. They send out biological messengers which then elicit a very strong inflammatory response. In our model, this is quickly brought under control by T cells, another type of immune cell which is dispatched for this very purpose. In severe COVID-19, however, this does not happen,” explains the study’s co-first author Dr. Geraldine Nouailles, a researcher at Charité’s Department of Infectious Diseases and Respiratory Medicine. She adds: “A fast and efficient T cell response is crucial to successful recovery from COVID-19.”

While COVID-19 prompts the immune system to go into overdrive, SARS-CoV-2 initially displays a low rate of replication in the lungs and respiratory tract. “The destruction of lung tissue seen in severe COVID-19 is not a direct result of viral propagation inside cells, but of the strong inflammatory response,” explains fellow co-first author Dr. Emanuel Wyler, a researcher at the MDC. He adds: “This also appears to apply to the cells of the vasculature, in particular the lung’s endothelial cells. They show a very strong response to the virus but are neither infected by it nor destroyed in the process.” If the disease is severe, blood vessels can become obstructed and vessel walls unstable, resulting in acute lung failure. It does not appear likely, however, that this blood vessel damage also plays a part in moderate COVID-19. “That COVID-19 activates the endothelium – a type of protective barrier lining blood vessels which, amongst other things, also controls a range of processes in the lung’s micro blood vessels – did not come as a surprise. What did come as a surprise, however, was that these cells are also the active driver of inflammation,” says Witzenrath. “Given their key role in disease progression, these cells could be targeted using one of two therapeutic strategies. One is to use substances which are capable of sealing the endothelial barrier. The other is to use substances which calm the endothelium. One of these is already the target of research conducted in our Collaborative Research Center SFB-TR84, where we were able to show that it is effective in pneumonia and ventilated patients.” Other anti-inflammatory drugs currently being tested as treatments for COVID-19 target the immune response itself. They are also effective against monocytes and macrophages and temper their activity.

Now that their model has been validated, the researchers hope to use it to help develop safe and effective treatments for patients with COVID-19. The aim is to reduce the number of patients who develop severe lung injury. The multidisciplinary team of researchers are currently analyzing the responses of different cell types observed in Roborovski dwarf hamsters. The researchers want to establish why the infection produces severe disease in these animals, and why it is not self-limiting as is the case in Syrian hamsters. “We hope this will guide us to a possible explanation for why some people develop severe COVID-19 but others do not,” says Geraldine Nouailles. As a first step, the researchers will need to decipher the dwarf hamster’s genome. The fact that hamsters have traditionally been regarded as somewhat exotic by the animal research community explains the existence of numerous knowledge gaps. “Information from our current study has enabled us to close some of these gaps. This represents major progress, including in terms of a more conscious and targeted approach to the use of animals in medical research,” explains co-last author Dr. Jakob Trimpert, a virologist and veterinary surgeon from Freie Universität Berlin. In addition to developing the COVID-19 hamster models, Dr. Trimpert and his team also worked with Freie Universität Berlin’s Department of Veterinary Pathology. Performing the necessary histopathological analyses (microscopic examination of infected lung tissue) under the leadership of Prof. Dr. Achim Gruber, the team’s work represents a crucial contribution to the study’s published findings.

Photo: The cells which line the blood vessels, known as the endothelium (arrowhead icon), are not infected. However, the endothelium’s strong response to the virus triggers an influx of inflammatory cells, primarily T cells (arrow pointer). Bars: 50µm © Dietert, Gruber, Freie Universität Berlin

Source: Joint press release by Charité – Universitätsmedizin Berlin, the MDC and Freie Universität Berlin
https://www.mdc-berlin.de/news/press/understanding-lung-damage-patients-covid-19

Research / 10.08.2021
A defective potassium channel disrupts the brain's navigation system

Fig. Modified from Gao et al., 2021
Fig. Modified from Gao et al., 2021

The potassium channel KCNQ3 is required for our brain to generate accurate spatial maps. In mice, defects in KCNQ3 function have measurable effects on the internal navigation system.

The findings of a research team including researchers from the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) in Berlin, now appeared in Nature Communications, are also relevant for Alzheimer's-type dementia research.

Among other physiological processes, potassium is required for muscle and nerve cell excitability. Potassium ions cross the outer cell membrane via a variety of ion channels and thereby generate electrical currents. Prof. Thomas Jentsch's team at the Leibniz Research Institute for Molecular Pharmacology (FMP) in Berlin identified the genes encoding the potassium channel family KCNQ2-5 two decades ago and demonstrated that mutations in KCNQ2 and KCNQ3 can cause hereditary epilepsy in humans. Pharmaceutical companies were able to develop targeted anti-epileptic drugs as a result of this pioneering research.

Now, teams of molecular biologists led by Thomas Jentsch and neurophysiologists supervised by Alexey Ponomarenko (formerly a member of FMP, now professor at Friedrich-Alexander-Universität Erlangen-Nürnberg) have discovered that KCNQ3 may also play a role in Alzheimer's disease and other cognitive disorders.

Normally, the transmitter acetylcholine inhibits neuronal potassium flow, which is necessary for the cortex's excitability and thus for memory and attention. It is well established that Alzheimer's patients gradually lose this so-called cholinergic neuromodulation.

The current study examined the role of KCNQ3 channels in the neuromodulation of the brain's navigation system. The so-called place fields, a discovery for which a Nobel Prize was awarded several years ago, serve as an internal space map for the brain. “We found how various signals generated by place cells under the control of KCNQ3 channels interact with brain rhythms to form precise spatial maps,” says Alexey Ponomarenko.

The knock-out mice with a defective KCNQ3 channel generated by Thomas Jentsch's group revealed a different picture: whereas the activity patterns of place cells in healthy mice were structured in time and space, in knock-out mice, the synaptic transmission by single or nearly simultaneous multiple (burst) signals of place cells was disorganized. “When bursts are fired, they typically have a certain rhythm. In the mutants, on the other hand, the bursts are not controlled by the rhythm, but are fired at completely random times or phases of the rhythm, as Ponomarenko explains. "This effectively suppresses single action potentials and creates an imbalance in the activity patterns of place cells."

Recordings using 15 micrometers thin silicon probes implanted in the hippocampus of freely behaving rodents, together with optogenetic experiments, provided exciting insights into brain function. Additionally, the American colleagues demonstrated that the absence of the KCNQ3 channel resulted in a significant decrease in neuronal potassium currents (here M-currents).

“While the data to date are insufficient to guide clinical applications, our findings suggest that the KCNQ3 channels could be a potential target for future drug research to treat Alzheimer's-type and other dementias,” Prof. Ponomarenko emphasizes, “at least in the early stages, when place cells are likely still present but cholinergic neuromodulation has already subsided.” Additional research is required to gain a better understanding of KCNQ3's role in the brain.

Source: Pressemitteilung Forschungsverbund e.V.
A defective potassium channel disrupts the brain's navigation system

Innovation / 09.08.2021
Eckert & Ziegler Receives Manufacturing Authorization for Thorium and Lutetium Compounds

Eckert & Ziegler Radiopharma GmbH in Braunschweig, a subsidiary of Eckert & Ziegler Strahlen- und Medizintechnik AG (ISIN DE0005659700, TecDAX), has now received manufacturing authorization from the Lower Saxony authorities for several thorium and lutetium compounds in accordance with the German Medicines Act. This authorization enables Eckert & Ziegler to supply its customers in the pharmaceutical industry with therapeutic radioisotopes for clinical trials and beyond. The radioisotopes are the central active ingredients in a series of innovative cancer drugs that are currently being tested in advanced phases by numerous drug manufacturers.

Obtaining the manufacturing authorization also entitles the Eckert & Ziegler Group to milestone payments for successful technology developments. The profits from these milestones, however, have already been accounted for in the recently updated guidance for 2021.

“Due to the large number of studies in which lutetium-177 is being clinically tested worldwide, we expect an increasing demand for this isotope and related services in the coming years. With the new technology and production facilities in Europe, Asia, and North America, we see ourselves as being excellently positioned to meet this demand," explained Dr. Lutz Helmke, member of the Executive Board of Eckert & Ziegler AG.

Radiotherapeutic agents that are coupled with lutetium-177 prior to injection are currently under development for several types of cancer. Lutetium-177-based drugs for the treatment of metastatic prostate cancer are already in the clinical phase III trials. Therapeutic agents for other tumor types are also awaiting approval. In addition to its efficiency, the advantage of lutetium treatment is that it can be coupled with very precise diagnostics. The carrier substance of the therapeutic agent can be linked to a diagnostic radioisotope, for example gallium-68. Using special devices, so-called PET scanners, the response rate for the patient and thus the usefulness of treatment can be predicted with high precision in advance.

economic development, Innovation / 03.08.2021
Eckert & Ziegler Takes over Brazilian Isotope Specialists – Strengthening their Presence in South America

Eckert & Ziegler (ISIN DE0005659700, TecDAX) acquired Ambientis Radioproteção, based in Sao Paulo, Brazil, effective July 31st, 2021 via its subsidiary Eckert & Ziegler Brasil Isotope Solutions Ltda (EZBIS). The business with annual sales in the low single-digit million range and 24 employees and specialists have been integrated into EZBIS´s Special Transportation Business Unit.

Ambientis has 25 years of experience in radiation protection services and holds Brazil’s and LATAM´s only ISO-17025 certified counting laboratory. The company will allow EZBIS to expand its products and services offerings to the Latin American market and to expand the laboratory testing provided to this market. Ambientis´ Laboratory will be integrated into the Eckert & Ziegler’s counting laboratory global network as it has its own regional radiological protection structure and all the required authorizations to handle substances based on isotope technology.

“Eckert & Ziegler is focusing on organic growth as well as strategic acquisitions in the expansion of its business. This acquisition is a further step in our growth strategy in South America, one of the world’s most dynamic healthcare markets. EZBIS and Ambientis have multiple business synergies and their combined capabilities will help to expand our market opportunities not only for the Industrial segment but also for the Radiopharma and Nuclear Medicine segments in the region,” said Claudia Goulart, President of Brasil Isotope Solutions of Eckert & Ziegler AG.

About Eckert & Ziegler.
Eckert & Ziegler Strahlen- und Medizintechnik AG with her 800 employees is a leading specialist for isotope-related components in nuclear medicine and radiation therapy. The company offers a broad range of services and products for the radiopharmaceutical industry, from early development work to contract manufacturing and distribution. Eckert & Ziegler shares (ISIN DE0005659700) are listed in the TecDAX index of Deutsche Börse.

02.08.2021
Berlin start-up T-knife raises $110 million

Dr. Elisa Kieback Co-founder of T-knife (© T-knife)
Dr. Elisa Kieback Co-founder of T-knife (© T-knife)

T-knife, a spin-off from the MDC and Charité, has raised 110 million U.S. dollars from international investors. The Berlin-based biotech company is developing novel immunotherapies against cancer that focus on teaching a patient’s T cells to recognize and fight solid tumors.

The Berlin biotech company T-knife is taking off: The young company announced on August 2, 2021, the closing of a $110 million Series B round of financing. The round was led by Fidelity Management & Research Company, LLC., with participation from new investors Life Sciences Partners, Qatar Investment Authority (QIA), Casdin Capital, Sixty Degree Capital and CaaS Capital as well as existing investors RA Capital Management, Versant Ventures and Andera Partners. The company, which was spun out of the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) with support of Charité – Universitätsmedizin Berlin, is developing novel immunotherapies against cancer that focus on teaching a patient’s T cells to recognize and fight solid tumors.

Further information: T-knife website

T-knife will use the proceeds from this financing to expand its scientific team, increase production capacity, and add additional innovative and differentiated T-cell receptor therapies (TCR-T) to its pipeline. Series B financing rounds are all about taking start-ups to the next level beyond the development stage.

Fighting tumors with T cells

T cells monitor our body and protect it from diseases such as viral infections. Infected cells can be recognized by the viral antigens that appear as typical markers on their surface. If a T cell detects an antigen with the help of its receptor, it either destroys the infected cell or triggers a wider immune response. Cancer cells also have special antigens on their surface, but the problem is that the immune system often does not recognize them as malignant and therefore does not fight them. The new T-cell therapy aims to change this: The researchers are teaching the patients’ T cells to identify cancer cells as invaders by equipping them with new T-cell receptors (TCR).

T-knife is developing next-generation adoptive T-cell therapies to treat solid tumors. The company is using mouse strains whose T cells express only human T-cell receptors (TCRs) to identify and build a portfolio of innovative TCR-T-cell therapy programs. T-knife’s lead program, TK-8001, is a novel TCR-T product candidate. It targets solid tumors that carry the antigen MAGE-A1 – a typical distinguishing feature on the surface of cancer cells. In the fourth quarter of 2021, researchers aim to begin enrolling patients in the TK-8001 IMAGE1NE Phase I/II clinical trial; T-knife plans to seek clinical trial approval for additional development programs in 2022.

Decades of basic research paved the way

Decades of research by T-knife co-founder Professor Thomas Blankenstein and his team at the MDC in cooperation with Charité laid the groundwork for this next generation of T-cell therapies. To help realize his vision of using genetically modified immune cells to cure cancer, the MDC technology transfer team and Ascenion, a company that specializes in technology transfer, worked closely with Blankenstein for many years. They patented and further developed the invention and prepared and guided the establishment of T-knife.

The leap from science to business was made in 2015: Professor Thomas Blankenstein, Dr. Elisa Kieback and Holger Specht, Investment Director at IBB Beteiligungsgesellschaft, founded T-knife as a spin-off from the MDC. In 2018 the founders converted T-knife into a limited liability company; Ascenion stepped in. The venture capital firms Boehringer Ingelheim and Andera Partners provided €8 million in initial financing. That was enough to hire a team of 15 employees and set up the first independent offices and labs on the Berlin-Buch campus. In 2020 T-knife launched a second round of financing and raised an impressive €66 million.

That made T-knife one of the best-funded start-ups in the German biotech sector. There has been no stopping T-knife ever since. Being well-funded enables the company to search for more TCR candidates to fight different types of cancer. Yet the 450 square meters on the Berlin-Buch campus are starting to get cramped. At the end of 2020, 20 people were working there. That number grew to 40 by the first half of 2021, and it is expected to double again by the end of this year. T-knife has also set up a presence in the biotech stronghold of San Francisco.

Unique selling point in a growing field

Our TCRs have several advantages over those produced by conventional methods. This could open up new treatment opportunities for many cancer patients, provided that the data from our studies are confirmed in clinical trials.

“The team has established for the first time a system that enables in vivo development of human TCRs that attack cancer-associated antigens. That is a unique selling point and potentially an important breakthrough in the rapidly growing field of adoptive T-cell therapies,” says Dr. Christian Stein, CEO of Ascenion. “We are thrilled that we now have a sound financial basis for translating these outstanding discoveries into tangible benefits for patients.”

Ascenion holds shares in T-knife and has an observer seat on the company’s board of directors. Profits from the future sale of shares will go towards funding further translational research – particularly at the MDC and Charité – via Ascenion’s parent company, the LifeScience Foundation for the Promotion of Science and Research.

“Our TCRs have several advantages over those produced by conventional methods. This could open up new treatment opportunities for many cancer patients, provided that the data from our studies are confirmed in clinical trials,” says Thomas Blankenstein, head of the MDC’s Molecular Immunology and Gene Therapy Lab and former director of Charité’s Institute of Immunology. “We thank all our partners who have supported us for many years through all the ups and downs along this incredible journey.”

 

Further information

02.08.2021
T-knife Therapeutics Announces $110 Million Series B Financing to Advance Pipeline of T-cell Receptor Therapies

Plan to initiate the IMAG1NE Phase 1/2 clinical study of TK-8001, a TCR-T cell therapy for MAGE-A1 positive solid tumors, in 2021

SAN FRANCISCO and BERLIN, Aug. 02, 2021 (GLOBE NEWSWIRE) — T-knife Therapeutics, Inc., a next-generation T-cell receptor company developing a pipeline of innovative therapeutics for solid tumor patients, today announced the successful completion of a $110 million Series B financing. The financing was led by Fidelity Management & Research Company, LLC., with participation from other new investors including, LSP, Qatar Investment Authority (QIA), Casdin Capital, Sixty Degree Capital, and CaaS Capital, along with existing investors RA Capital Management, Versant Ventures and founding investor Andera Partners. The company plans to use proceeds from the financing to expand its scientific team, increase manufacturing capacity and advance its pipeline of T-cell receptor (TCR) engineered T cell therapies (TCR-T).

“Over the past year we have made substantial progress toward our goal of building a leading TCR-T company focused on delivering clinically meaningful benefits for patients with solid tumors,” stated Thomas M. Soloway, Chief Executive Officer of T-knife. “We are excited to have the support of this group of dedicated life sciences investors to help us fulfill our mission, and we welcome Dr. Karin Kleinhans of LSP to our board of directors.”

“T-knife has an elegant and differentiated approach to identifying potent, cancer-specific TCRs with naturally optimized affinity and specificity profiles, creating a next-generation platform for this promising therapeutic field,” said Alex Mayweg, Chairman of T-knife and Managing Director at Versant Ventures. “We are pleased to be progressing TK-8001 toward the clinic and to advance our broader portfolio of product candidates.”

T-knife is leveraging its proprietary HuTCR transgenic mouse platform to discover and develop a portfolio of TCR-T programs to treat patients with solid tumors. T-knife’s lead program, TK-8001, is a novel TCR-T product candidate targeting MAGE-A1 positive cancers. T-knife plans to begin enrolling patients in the TK-8001 IMAG1NE Phase 1/2 clinical study in the fourth quarter of 2021 and is planning to submit INDs/CTAs for additional product candidates in 2022.

“The field of TCR-T holds significant promise to change the treatment paradigm for many cancer patients,” said Karin Kleinhans, PhD, Partner at LSP who joined T-Knife’s board in connection with the Series B financing. “We are highly encouraged by the progress being made at T-knife to advance its important next-generation therapies.”

Olivier Litzka, Partner at Andera Partners, commented, “As a founding investor, it is gratifying to witness the continued success at T-knife. The completion of the Series B financing is an important milestone that will enable us to execute on our vision of building a leading transatlantic immuno-oncology company.”

About the HuTCR platform
T cells play a key role in the immune response by directly recognizing and eliminating infected, foreign or altered cells, such as cancer cells. To do this, they use their T-cell receptors (TCRs) to scan the surface of other cells for foreign antigens presented on Human Leukocyte Antigen (HLA) complexes. Cancer cells can be recognized by mutated or viral antigens expressed only in the tumor, or self-antigens normally expressed during embryonic development and in non-somatic adult tissues. Genetic engineering of T cells with TCRs recognizing antigens aberrantly or over-expressed in cancers can redirect these T cells to the tumor, potentially offering curative responses to cancer patients.

The ability to identify potent cancer-specific TCRs has been limiting for the field of TCR-T. In the case of self-antigens, T cells bearing those TCRs are eliminated during T cell development to avoid recognition and attack of healthy tissues. For non-self tumor antigens, such as those derived from viral sequences or mutations, the very low T cell frequency in the blood has limited TCR discovery efforts.

To overcome these challenges, T-knife has developed transgenic mice (HuTCR mice) carrying the human TCRαβ gene loci and expressing multiple human HLAs. Immunizing HuTCR mice with human tumor antigens, for which mice are not tolerant, allows for the identification of both CD4+ and CD8+ T cells with TCRs that have optimized affinity / specificity profiles capable of mediating significant anti-tumor activity. The TCRs from HuTCR mice are of higher affinity for tumor self-antigens than TCRs isolated from human donors and are naturally optimized to maintain a high specificity profile, making HuTCR mice a powerful high-throughput platform for rapidly generating TCRs with best-in-class potential.

About T-Knife Therapeutics, Inc.

T-knife is a next-generation T-cell receptor (TCR) company developing a pipeline of therapeutics for solid tumor patients. The company leverages its proprietary humanized T-cell receptor (HuTCR) mouse platform to produce fully human TCRs, naturally selected in vivo for optimal affinity and specificity.

T-knife is developing a pipeline of potential first/best-in-class TCR therapeutics against targets with high unmet medical need, including cancer testis antigens, viral antigens and commonly shared neoantigens. T-knife was founded by leading T-cell and immunology experts using technology developed at the Max Delbruck Center for Molecular Medicine together with Charité University Hospital in Berlin. For additional information, please visit the company’s website at www.t-knife.com.

 

Research / 22.07.2021
Anton Henssen honored with Berlin science award

Photo of Anton Henssen. Credit: Wiebke Peitz, Charité
Photo of Anton Henssen. Credit: Wiebke Peitz, Charité

Dr. Anton Henssen, a scientist and physician at the ECRC, has received the Young Investigator Award of the 2020 Berliner Wissenschaftspreis for his cutting-edge research into childhood cancers. The award was presented by the Governing Mayor of Berlin at a ceremony on July 22 in front of the Rotes Rathaus.

Anton Henssen has been awarded the 2020 Berliner Wissenschaftspreis in the Young Investigator category. The pediatric oncologist is a group leader at the Experimental and Clinical Research Center (ECRC ), a joint institution of the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) and Charité – Universitätsmedizin. Henssen studies the causes of rare pediatric tumor types such as neuroblastoma. Here he focuses on the role played by small DNA rings – a completely new genetic mechanism of cancer formation – and uses technologies like single-cell analysis. His goal is to one day be able to treat his young patients better with personalized therapies. In addition to conducting research on the Buch campus, Henssen works at Charité as a physician in the Department of Pediatric Oncology and Hematology. His research, according to an official statement, is deeply embedded in the scientific fabric of the capital region and is an outstanding example of the impact that application-oriented research can have.

The Young Investigator Award, which includes a €10,000 cash prize, is given each year in conjunction with the Berliner Wissenschaftspreis to early career researchers who are 35 years old or younger. The award recognizes innovative research in a future-oriented field that could particularly benefit Berlin as a science and business location. The Berliner Wissenschaftspreis promotes outstanding achievements in science and research that have been made in Berlin. A central aim is to lay the foundation for the further economic development of Berlin. The 2020 award, which is being presented for the thirteenth time and is endowed with €40,000, goes this year to Professor Christian Drosten. The presentation of the award had been postponed in fall 2020 due to the pandemic and has now taken place for as part of Wissensstadt Berlin 2021.

“The recognition goes to a team”

“I am delighted and very honored to receive this award,” Henssen said after the presentation ceremony. “Even though the award was presented to me, the recognition goes to a team of international collaboration partners, because the research done by my lab would not have been possible without such teamwork.”

Berlin’s Governing Mayor and Senator for Higher Education and Research Michael Müller stressed: “Through his cutting-edge research, Henssen is laying important groundwork that will allow us to achieve new breakthroughs in the diagnosis and treatment of childhood cancers. The two award winners show through their research just how strong Berlin science is, and our city can be rightly proud of that.”

Professor Thomas Sommer, interim Scientific Director of the MDC, said: “I am absolutely delighted and congratulate Anton Henssen on this great award. In my view, Henssen ideally combines basic research and direct application. He brings his knowledge and experience as a clinical oncologist to his laboratory work, while also using his innovative research approaches and findings to help children afflicted with cancer. I sincerely wish Henssen and his team much success on this path.”

About the award winner

Anton Henssen, a pediatric oncologist, grew up in Düsseldorf and has since late 2018 been working at the Berlin-based Experimental and Clinical Research Center (ECRC), a joint institution of the Max Delbrück Center for Molecular Medicine and Charité – Universitätsmedizin Berlin. Henssen, 35, received his PhD from RWTH Aachen University in 2013 following neuroscience training at Forschungszentrum Jülich. He was deeply involved in treating childhood cancers for the first time as a junior physician at the University Hospital Essen. During a research stay in the United States at Memorial Sloan Kettering Cancer Center in New York (2013 to 2016), he specialized in DNA sequencing of childhood cancers.

In 2016 he came to Berlin to work in the Clinician Scientist Program of the Berlin Institute of Health at Charité (BIH) and Charité – Universitätsmedizin Berlin. Since the end of 2018 Henssen has led the Emmy Noether Research Group “Genomic Instability in Pediatric Cancer” at the ECRC, which is also a guest group at the MDC. Since 2020 his research has been funded by a Starting Grant from the European Research Council (ERC). In addition to conducting research on the Buch campus, Henssen works at Charité as a physician in the Department of Pediatric Oncology and Hematology.

Press Release of the MDC:
https://www.mdc-berlin.de/news/press/anton-henssen-honored-berlin-science-award

Research / 16.07.2021
The new old-fashioned way

Photo: Claudia Wüstenhagen/Berlin Partner
Photo: Claudia Wüstenhagen/Berlin Partner

When Rudolf Virchow started studying medicine in Berlin in October 1839, the theory of the four humors of antiquity was still the mainstay of medical belief. Barely two decades later, the textbooks had to be rewritten: Virchow, who had since received his doctorate in medicine, succeeded in showing that the entire human body consists of cells – tiny units that can undergo disease reflecting morphological alterations.. Virchow’s revolutionary “cellular pathology” offered an entirely new understanding of causes of disease. His teachings, valid to this day, laid the foundation for modern, science-based medicine.

And yet, by today’s standards, the prerequisites for such a momentous discovery were modest. Virchow examined tissue samples under a simple microscope with the aid of a mirror and sunlight. To make cell structures visible, he stained tissue with dyes mixed together for him by chemists. Using this method, the “father of cellular pathology” managed to diagnose 20 diseases, including leukemia and thrombosis.

21st century physicians and scientists still use staining techniques to identify morphological patterns of cells, the detailed diagnosis of cancer being a prominent example. Only today, the dyes are fluorescent and the equipment differs somewhat from that of the 19th century. A glance at the Screening Unit at the FMP in Berlin-Buch shows just how far things have progressed: The state-of-the-art technology features a fully automated confocal microscope equipped with two cameras that automatically records 1,000 morphological characteristics for each individual cell. Given that almost 400 experiments can be performed simultaneously on one test plate (the FMP compound library has 200 of them), no fewer than 400 million data sets are generated in one run per single test plate alone. Not even a mastermind like Rudolf Virchow would have been able to analyze such huge volumes of data. The high-resolution microscope is therefore connected to a fleet of supercomputers that use artificial intelligence to detect tiny changes in cells and assign them to specific classes or diseases.

“We work in the tradition of Virchow, but using computer power that was unimaginable back then,” explained Dr. Jens von Kries, Head of the Screening Unit. “Virchow 2.0” is the term he gives to the concept of computer-aided pattern recognition, which is ideal for both drug discovery and disease diagnosis.

The team led by von Kries is currently using the new technology for cell toxicity profiling. The researchers want to find out which of the 70,000 chemical substances in their compound library are toxic. This classification should make drug screening assisted by robotic arms even more efficient
in the future. “Virchow 2.0” is soon to be used for personalized medicine. When cancer patients have developed resistance to drugs, for example, researchers can use tissue samples to search for alternative medications. Requests to this effect have already been received from Virchow’s long-time workplace – Charité. According to Jens von Kries, there are plans for further fields of application, and machine pattern recognition still has further potential.

“Virchow pushed the boundaries,” he remarked, “and we are trying to do the same using current technological means.”
 

Translation: Teresa Gehrs
 

Research / 05.07.2021
A glitch in the heart’s protein factory

Picture: Mariana Guedes Simoes / AG Panakova
Picture: Mariana Guedes Simoes / AG Panakova

MDC researchers have discovered a previously unknown cause of cardiac hypertrophy. As they report in the journal “Genome Biology”, genetic variation results in heart cell ribosomes not working properly. This disrupts protein production, which in turn causes the heart to grow too large.

An abnormal increase in heart muscle mass is considered the most common cause of sudden cardiac death. Now, a team of scientists led by Professor Norbert Hübner, head of the Genetics and Genomics of Cardiovascular Diseases Lab at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) in Berlin, has figured out what’s behind this hypertrophy. Another MDC research group – the “Non-coding RNAs and Mechanisms of Cytoplasmic Gene Regulation Lab”, led by Dr. Marina Chekulaeva – was also involved in the study.

The scientists have uncovered a complex molecular mechanism that interferes with the overall protein production in the ribosomes of heart cells. As a result, the heart does not get the proteins it needs. This production defect, in turn, promotes abnormal growth of heart muscle cells. The study, which involved 19 researchers from six countries, has been published in the journal “Genome Biology”.

The entire protein production is impaired

“We wanted to find out how natural genetic variation, which is present in every living being, can contribute to the development of complex diseases,” says Dr. Sebastiaan van Heesch, who is the study’s co-last author along with Hübner. Until June 2020 the Dutchman was a postdoc in Hübner’s lab at the MDC. He has since set up his own lab back in his home country, at the Prinses Máxima Center for Pediatric Oncology in Utrecht.

“It was already known that differences in the genome can influence whether and how genes are read in the cell nucleus,” says van Heesch. This process, known as transcription, is the first step in protein production. Scientists were also aware that certain changes in the DNA can lead to the production of defective heart proteins. “But the fact that genetic variants can affect the heart’s entire protein production by interfering with cellular protein factories – the ribosomes – was new and rather surprising,” says van Heesch.

Particularly devastating for long proteins

“In our study, we worked with a group of rats for which we know all the genetic variants and we also know that about half of the animals in this panel of hybrid strains develop heart disease,” reports Dr. Jorge Ruiz-Orera, a scientist from the same group. Ruiz-Orera is co-lead author of the study along with Dr. Franziska Witte, who was a doctoral student in Hübner’s lab during the first years of the study and now works at the Berlin-based research firm Nuvisan.

“To find out more about the reasons behind the rats’ cardiac hypertrophy, we looked for a link between the animals’ DNA and the function of their ribosomes. That’s where translation, or protein production, takes place,” says Ruiz-Orera. The researchers also examined whether errors in protein production could be related to the known enlargement of the hearts.

In these investigations, the team came across an altered region in the rats’ genome that results in a defect in overall protein synthesis. However, this defect affects long and short proteins differently. “The effect is not as devastating in short proteins,” explains Ruiz-Orera. “But long proteins, such as the important muscle protein titin, are produced much less efficiently. We were able to show that this has a negative effect on the assembly of sarcomeres, the smallest functional unit of the muscle fiber.” Ultimately, this defect leads to a thickening of the heart chambers and heart failure.

Similar effects even seen in yeast cells

“What is especially remarkable is that similar genetic variants also have the same effects on protein synthesis in other species – for example, in mice, humans, and even in unicellular organisms like yeast,” reports Hübner. This shows, he says, just how widespread the genetically determined defect is in the cellular protein factories, how little it has changed over the course of evolution, and how important a role it plays in the development of complex diseases that also affect humans.

“The mechanism we uncovered may explain why some people are genetically predisposed to develop cardiac hypertrophy,” says Hübner. “In addition, our work lays the groundwork for future studies on the genetic predisposition to complex diseases that can affect organs other than the heart.”

Text: Anke Brodmerkel

Further information

Literature

Franziska Witte, Jorge Ruiz-Orera et al. (2021): “A trans locus causes a ribosomopathy in hypertrophic hearts that affects mRNA translation in a protein length-dependent fashion”. Genome Biology, DOI: 10.1186/s13059-021-02397-w

Research / 17.06.2021
Probing deeper into tumor tissues

A tumor section, with a mass spectrometer visible in the background. © Corinna Friedrich, MDC / Charité
A tumor section, with a mass spectrometer visible in the background. © Corinna Friedrich, MDC / Charité

Researchers at the MDC, the BIH and Charité have developed methods for performing comprehensive analyses of fixed tumor tissue samples. These analyses make it possible to shed new light on the clinical course of various cancer types, as the team reports in Nature Communications.

Today as they did 100 years ago, doctors diagnose cancer by taking tissue samples from patients, which they usually fix in formalin for microscopic examination. In the past 20 years, genetic methods have also been established that make it possible to characterize mutations in tumors in greater detail, thus helping clinicians select the best treatment strategy.

Even tiny tissue samples can be used to detect proteins

Now, a group of researchers from the Berlin-based Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), the Berlin Institute of Health (BIH), Charité – Universitätsmedizin Berlin and the German Cancer Consortium (DKTK) have succeeded in analyzing in detail more than 8,000 proteins in fixed samples of lung cancer tissue using mass spectrometers.

“Using the methods we have developed, it has become possible to conduct an in-depth analysis of molecular processes in cancer cells at the protein level – and to do so in archived patient samples that are collected and stored in large numbers in everyday clinical practice,” says Dr. Philipp Mertins, head of the Proteomics Platform at the MDC and the BIH. “Even very small tissue samples, such as those obtained in needle biopsies, are sufficient for our experiments.”

The study, published in the journal Nature Communications, is considered a major success for the Multimodal Clinical Mass Spectrometry to Target Treatment Resistance (MSTARS) research project, which has been funded by the German Federal Ministry of Education and Research (BMBF) to the tune of around €5.7 million since 2020.

The team of researchers, led by Mertins and Professor Frederick Klauschen from the Institute of Pathology at Charité, has been able to show that proteins – unlike the frequently studied yet quite sensitive RNA molecules – remain stable in the samples for many years and can be precisely quantified. “In addition, the proteins that are present in the tumor tissue map disease progression especially well,” says lead author Corinna Friedrich, a PhD student in the labs of Mertins and Klauschen. “This is because they provide information about such things as which of the genes that promote or inhibit tumor growth are particularly active in the cells.”

The methods promise to help identify the best treatment for each tumor

The picture gained from the team’s analysis of two forms of lung cancer – adenocarcinomas and squamous cell carcinomas – has also become so detailed because the researchers have not only uncovered a great many of the proteins present in the cell, but have also quantified more than 14,000 phosphosites. With the help of phosphorylation, a mechanism that regulates the reversible attachment of phosphate groups to proteins, the cell controls almost all biological processes by switching certain signaling pathways on or off.

“Our paper thus provides a good basis for gaining a better understanding of disease progression in lung cancer and also in other types of cancer,” says Klauschen, who, along with Mertins, is co-corresponding author of the study. Klauschen has since become director of the Institute of Pathology at Ludwig-Maximilians-Universität München, but continues to conduct research at Charité. “The methods we have developed will also enable us to better explain in the future why a very specific therapy works for some patients but not for others,” adds the pathologist. This will, he says, make it easier, to find the best treatment option for each patient.

Methods also suitable for researching cardiovascular diseases

Mertins also hopes that the mass spectrometric analysis of the proteome in tissue samples will pave the way for the discovery of not only new biomarkers for therapeutic decisions and patient survival predictions, but also other molecular structures that could serve as targets for future drugs.

And, according to the researcher, there is yet another plus to the new approach: “Our methods are not only suitable for researching cancer, but can also be applied very broadly.” For example, the Proteomics Platform has already successfully analyzed the proteome of fixed immune cells from COVID-19 patients. The authors have also provided guidelines on which mass spectrometric methods are best suited for different types of clinical studies.

Next on the agenda for the MDC platform is the mass spectrometric analysis of additional fixed immune cells as well as fixed cardiovascular tissue for the presence of proteins and phosphosites. “The aim here is to get a better understanding of infectious and cardiovascular diseases,” explains Mertins, “so that one day it might be possible to treat these diseases in a much better way than has so far been the case.”

Text: Anke Brodmerkel

Literature

Corinna Friedrich et al (2021): “Comprehensive micro-scaled proteome and phosphoproteome characterization of archived retrospective cancer repositories,” in: Nature Communications, DOI: 10.1038/s41467-021-23855-w

Source: Joint press release by the MDC, the BIH and Charité
https://www.mdc-berlin.de/news/press/probing-deeper-tumor-tissues

Research / 14.06.2021
$7 million to advance cardiovascular research

Copyright: Boulder Universit
Copyright: Boulder Universit

Diverse messenger RNAs are produced in cells by “alternative splicing.” The Leducq Foundation is now supporting a transatlantic network dedicated to investigating this process in heart muscle cells and how changes in this process contribute to disease. Professor Michael Gotthardt of the MDC and Professor Leslie Leinwand of the University of Colorado Boulder are coordinating the project.

Despite advances in prevention and therapy, cardiovascular diseases are still one of the leading causes of death worldwide. Scientists have only recently begun to understand the key role of alternative splicing – the “stitching together” of messenger RNA during gene transcription – in cardiovascular diseases. The Leducq Foundation is providing 7 million U.S. dollars over the next five years to support the Cardiac Splicing as a Therapeutic Target (CASTT) project, which is comprised of six European and U.S. researchers. They will focus on examining the regulation and disease relevance of alternative splicing in different types of heart cells.

“Our goals include mapping the path from splicing factor discovery to drug development, and creating a database that will make it easier in the future to incorporate complex splicing information into heart disease diagnostics,” says Professor Michael Gotthardt, group leader at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) and the European coordinator of CASTT. Professor Leslie Leinwand, biologist and founder of several successful BioPharma companies who is the North American Coordinator adds: “The Leducq Foundation allows us, as scientists and clinicians, to think outside the box of what is traditionally considered effective treatments for heart disease. It enables us to connect different research directions from animal models to patients with innovative genomic and computational approaches."

Other network members include Professor Euan Ashley, a cardiologist at Stanford University; Professor Maria Carmo-Fonseca, a cell and oncobiologist at the University of Lisbon; Professor Benjamin Meder, a cardiologist at Heidelberg University Hospital; and Professor Lars Steinmetz, a geneticist at the EMBL Heidelberg and Stanford University.

Splicing errors can cause heart disease

Heart muscle cells require a variety of proteins so that they can develop, contract, transmit electrical impulses to neighboring cells, and respond to external influences such as stress. The blueprints for producing these proteins are contained in the genes and are transcribed into messenger RNA (mRNA), which then carries this information to the cell’s protein factories – the ribosomes.

Some cells, especially those of higher organisms, use a trick to produce a wide variety of protein molecules. The genes of these cells do not only encode one particular protein, but

can serve as the blueprint for several proteins. Genes usually contain alternating coding segments called exons, and non-coding regions called introns. The latter can be removed as needed during transcription, while exons can be linked together in a variable fashion. This creates mRNAs with different exon compositions. This process, known as “alternative splicing,” is executed by the spliceosome – a complex machinery made up of splicing factors and splicing regulators. Errors in the splicing process can lead to heart disease. “While remodeling processes dominate in the embryonic heart, allowing the heart to grow and mature, the most important processes at work in the adult heart are those that ensure effective pumping,” explains Gotthardt. “In diseased hearts, however, we see gene expression patterns that partly transition back toward the embryonic state in terms of protein formation. As a result, the heart no longer operates within the normal range.”

A heart for large meals

The researchers work both clinically as well as experimentally with human cell lines, artificial heart tissue, and animal models. In addition to mice, this includes Burmese pythons, because this powerful strangler is one of only a few living creatures capable of rapidly growing the size of its heart – within a day of swallowing its large prey. This increases blood flow and speeds up the distribution of nutrients throughout the reptile’s body. The organ then shrinks back to its original size when digestion is completed. “We want to elucidate the very specific regulation of splicing processes in the python heart because we think these findings could be of therapeutic use – for example, in patients suffering from hypertrophic cardiomyopathy, which involves a thickening of the heart muscles,” says Leinwand, chief scientific officer for the BioFrontiers Institute at University of Colorado Boulder.

The Leducq Foundation was created in 1996 in Paris by industrialist Jean Leducq and his wife Sylviane to drive forward transatlantic collaboration on cardiovascular disease and stroke research. Since then, the foundation has supported more than 70 international networks in these areas, involving more than 800 investigators at more than 100 institutions in 25 countries.

Text: Catarina Pietschmann

 

Source: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
https://www.mdc-berlin.de/news/press/7-million-advance-cardiovascular-research

 

Research, Innovation, Patient care / 10.06.2021
Founder Kieback gets T-knife off to a flying start

Dr. Elisa Kieback, co-founder and Chief Technology Officer of T-knife (Photo: © T-knife)
Dr. Elisa Kieback, co-founder and Chief Technology Officer of T-knife (Photo: © T-knife)

Best-funded start-up in Germany’s biotech sector

A young Berlin-based company called T-knife is a rising star in Germany’s biotech sector. Co-founder Dr. Elisa Kieback, along with colleagues, has catapulted the joint spin-off from the MDC and Charité to the top of the German biotech start-up universe.

Dr. Elisa Kieback says, for about a year, she has felt like “she’s on a rocket launch pad.” In 2015, the now 40-year-old researcher and entrepreneur teamed up with Professor Thomas Blankenstein of the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) and Holger Specht, Investment Director at IBB Beteiligungsgesellschaft, to found T-knife as a spin-off from the MDC and Charité. This leap from science to business was preceded by almost 20 years of basic research at the MDC – that’s how long Blankenstein has been working to realize his vision of curing cancer with the help of genetically modified immune cells, known as T cells.

For about ten years Blankenstein carried the idea of a spin-off around with him. He met Elisa Kieback in 2004 when he served as the second examiner for her doctoral thesis. “She is an exceptionally intelligent, motivated, organized and hard-working young scientist who has dedicated herself to T-cell receptor (TCR) gene therapy,” is how Blankenstein describes his co-founder. In 2015, the biologist moved from Professor Wolfgang Uckert’s lab to Blankenstein’s team and coordinated the first clinical trial on TCR gene therapy, which began in January this year at Charité –Universitätsmedizin Berlin. “When she learned that I was planning a spin-off from the MDC, she was eager to be part of it. I immediately agreed, and it is a decision I’ll never regret,” Blankenstein recalls. The name T-knife is as old as the founding idea itself. It is derived from genetically modified T cells – cells of the immune system – that are designed to cut tumors from healthy tissue much like a precision surgical knife.

Until 2018 T-knife existed only on paper. “Setting up the company as a joint venture was important because it allowed us to take the first organizational steps, such as hiring a law firm,” says Kieback. Then the founders converted T-knife into a limited liability company, Holger Specht dropped out and the technology transfer company Ascenion stepped in. The venture capital firms Boehringer Ingelheim and Andera Partners provided €8 million in initial financing. This enabled Kieback to hire a team of 15 employees and set up the first independent offices and labs on the Berlin-Buch campus. In 2020, she launched a second round of financing and raised an impressive €66 million – again from Andera Partners and Boehringer Ingelheim but also from US-based venture capitalists Versant Ventures and RA Capital Management. That made T-knife the best-funded start-up to date in the German biotech sector. She also brought Thomas Soloway on board as chief executive officer and Camille Landis as chief financial officer. Kieback herself is chief technology officer, which means she oversees product and platform development, while Blankenstein sits on the supervisory board.

There has been no stopping T-knife ever since. Being well-funded enables Kieback and her team to search for more TCR candidates to fight different types of cancer. The researchers have discovered several promising antigens that appear in tumors. “We will now produce and test suitable receptors,” says Kieback. Yet the 450-square-meter-space that T-knife moved into on the Berlin-Buch campus is starting to get cramped. At the end of 2020, 20 people were working there. That number grew to 40 by the first half of 2021. “The number will double again by the end of this year,” Kieback estimates. Besides, T-knife is opening a new office in Berlin-Mitte for the team responsible for clinical trials.

Off to the U.S. – and around the globe

T-knife has also set up a presence in the biotech stronghold of San Francisco. For one thing, most of the capital invested in T-knife comes from the United States. “If we want to take a long-term view and position ourselves well for further rounds of funding or for an IPO, then we have to be attractive to U.S. investors,” Kieback explains. For another thing, she is seeking to conduct clinical trials in U.S. hospitals. “The United States currently has more scientific expertise in advancing T-cell therapies into clinical trials compared to Germany,” she adds. Last but not least, Kieback hopes this move will lead to faster approval and quicker access to the U.S. market.

But that doesn’t mean she’s turning her back on Germany. “Berlin has a lot going for it as a science city,” Kienback enthuses, adding that the numerous universities and research institutes and the research hospital Charité produce many researchers that T-knife can recruit. San Francisco, she says, is the key to breaking into the U.S. market – but Kieback wants to enter the global market.

A unique technology with huge potential

She is confident this goal can be achieved. “The technology Thomas Blankenstein developed is unique,” she explains confidently. “Even people without a background in biotech recognize very quickly that it’s something very special and novel – with great potential both medically and economically.” It was this fact, Kieback says, that enabled her to win over investors. She also knows it would have been impossible without the large injection of money. “This form of therapy is very capital-intensive,” she explains. The German Federal Ministry of Education and Research provided €4 million in funding for the clinical trial that she got up and running at Charité. “That seems like a lot, and it’s great support,” she says. “But in the field of cell therapeutics, that amount doesn’t go very far if you want to develop a real product that will benefit a large number of people.” The clinical trial, the monitoring, the production of the patient-specific cell products – that’s completely new territory and extremely costly. “Because of the need to raise money for further development,” she says, “we had no choice but to start the company.” Financing is now in place until 2023.

Inventors need entrepreneurs

Kieback is totally comfortable in her new role as an entrepreneur. She is also convinced that the research world “needs to be more open to the fact that entrepreneurship is necessary if inventions are to make the leap from research to practice.” Besides, she continues to do research, albeit with a different focus: away from basic research, which formed the basis, and towards new product candidates and ultimately new therapeutics.

She has always wanted to go into research, so she decided to study biology in Heidelberg after finishing her Abitur. After an Erasmus year in Scotland, Kieback wrote her thesis at the German Cancer Research Center (DKFZ). In 2004, she applied for the PhD program at the MDC in Uckert’s research group on cellular gene therapy. “Gene therapy absolutely fascinated me,” she says. “Back in the 2000s, there was a lot of hype about the possibility of curing diseases by fixing broken genes and inserting new genes into cells. That’s what I wanted to do.” For her doctoral work, she developed a sort of safety switch that can stop cell and gene therapy if there are any unwanted side effects.

A role model for women in science and business

At some point she decided explore new career paths, leading her to apply for a study coordinator position in Blankenstein’s research group. “It was an all-around job and had the great advantage of providing a glimpse into many areas,” she recalls. When she heard of Blankenstein’s spin-off plans, she was immediately excited and eager to get on board. She enjoys building teams, identifying strengths and weaknesses, and encouraging and supporting people in their careers. One thing is very important to her: “Being a role model for women in science and business. I never thought I’d care about this, but my experience at T-knife has shown me how much it matters.” She is also keen to find out if the T-knife technology really works for patients. That is something only clinical data will tell. “We are committed to creating the best possible conditions for testing our platform in an optimal way. That’s what’s been driving me,” she stresses.

The breathtaking pace at which T-knife is growing requires constant change. You need a good amount of perseverance. Kieback admits that it is not always easy to manage if the number of employees doubles – from 20 to 40 – in a short time . “But I’m someone who thrives more on activity than stagnation. I become frustrated when things stand still,” she says, laughing a little.

There is no question of standing still for the time being. In July she will give birth to her second child. But if things do indeed slow down a little next year, she hopes to find time again for her hobby, dancing. It is a fitting pastime as it combines hard work with agility and lightness of foot.

Text: Jana Ehrhardt-Joswig

Further information

T-knife website

Blankenstein Lab

Molecular Immunology and Gene Therapy

"A long and winding road"  – a film with Thomas Blankenstein, Elisa Kieback, Mathias Leisegang, Antonio Pezzutto and Wolfgang Uckert. (with English subtitles)

Innovation, Patient care / 08.06.2021
Eckert & Ziegler: Affiliate Receives Additional NIAID Funding to Advance Pharmaceutical Development

Myelo Therapeutics GmbH, an affiliate of Eckert & Ziegler (ISIN DE0005659700, TecDAX) focused on developing medical countermeasures (MCM) and therapies for cancer supportive care, announced that the U.S. National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, extended their contract to advance the development of the new chemical entity Myelo001. The extension into year two of the three-year contract provides an additional $2 million to Myelo Therapeutics to develop clinical-stage Myelo001 as an oral formulation MCM for the treatment of Hematopoietic Acute Radiation Syndrome (H-ARS). The total contract, initially awarded in April 2020, is valued at up to $ 6.2 million over three years if all options are exercised.

The additional funds will advance the development of Myelo001 as an H-ARS monotherapy, and in polypharmacy regimens in laboratory models ranging from rodents to larger animals toward an Investigational New Drug Application (IND) with the U.S. Food and Drug Administration (FDA). The candidate MCM development program is funded in whole or in part by the Radiation and Nuclear Countermeasures Program (RNCP), NIAID, part of the National Institutes of Health (NIH), in the Department of Health, and Human Services (HHS), under Contract No. 75N93020C00005. Only a select number of companies are funded by the RNCP, based on a highly competitive application process.

About Acute Radiation Syndrome
ARS, also known as radiation toxicity or radiation sickness, is an acute illness that presents after exposure of large portions of the body to high levels of radiation, like those that might be experienced during a radiological or nuclear incident. The primary manifestation of ARS is the depletion of hematopoietic stem and progenitor cells, constituting one of the major causes of mortality. The U.S. government encourages development of new drugs to treat bodily injuries resulting from ARS.

About Myelo Therapeutics
Myelo Therapeutics is a pharmaceutical company based in Berlin, Germany, that is developing innovative treatments in areas of high unmet medical needs, such as Chemotherapy-Induced Myelosuppression (CIM), Radiation-Induced Myelosuppression (RIM), and ARS. Myelo's lead candidate, Myelo001 is a clinical-stage, adjuvant cancer therapy for treatment of chemotherapy - and radiotherapy-induced myelosuppression. It is delivered as an oral tablet formulation and is stable at room temperature for at least three years. Preclinical and clinical studies have shown that Myelo001 has both prophylactic and therapeutic efficacy at reducing hematopoietic symptoms caused by radiation and chemotherapy. Eckert & Ziegler is one of Myelo's largest shareholder and has funded a substantial portion of the Myelo001 development activities. www.myelotherapeutics.com.

About Eckert & Ziegler.
Eckert & Ziegler Strahlen- und Medizintechnik AG with her 800 employees is a leading specialist for isotope-related components in nuclear medicine and radiation therapy. The company offers a broad range of services and products for the radiopharmaceutical industry, from early development work to contract manufacturing and distribution. Eckert & Ziegler shares (ISIN DE0005659700) are listed in the TecDAX index of Deutsche Börse.

Research / 07.06.2021
Tracking RNA through space and time

One-cell zebrafish embryo: The MDC research lab found numerous localized genes at this early stage of development. Much of their genetic information flows into the precursor cells of the later germ cells © AG Junker, MDC
One-cell zebrafish embryo: The MDC research lab found numerous localized genes at this early stage of development. Much of their genetic information flows into the precursor cells of the later germ cells © AG Junker, MDC

A research team at the MDC has succeeded in tracking genes through space and time within a one-cell zebrafish embryo – even before cell division occurs. They have now described a method in the journal “Nature Communications” that may one day allow scientists to measure cell response to drugs, for example, in organoids.

The “miracle of life” is most obvious at the very beginning: When the fertilized egg cell divides by means of furrows into blastomeres, envelops itself in an amniotic sac, and unfolds to form germ layers. When the blastomeres begin to differentiate into different cells – and when they eventually develop into a complete organism.

“We wanted to find out whether the later differences between the various cells are already partly hard-wired into the fertilized egg cell,” says Dr. Jan Philipp Junker, who heads the Quantitative Developmental Biology Lab at the Berlin Institute for Systems Biology (BIMSB) of the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC). Junker and his team are investigating how cells make decisions and what dictates whether they become nerve, muscle, or skin cells. This involves creating cell lineage trees that allow them to determine the lineage and cell type of thousands of individual cells from an organism. Using these lineage trees, they can understand how and by what mechanisms cells come together to form a functioning organism or how they respond to perturbations.

Blueprints for different cell types already exist in the one-cell embryo

Yet this search for clues by means of cell lineage trees begins at a later stage – namely, when cell division and differentiation is already under way. What’s more, the observations cover long time periods. In their current study, which has just been published in the journal “Nature Communications”, Junker and his team focus on a very short time period: the first hours after fertilization, from the one-cell stage to the process of gastrulation – the formation of the germ layers – of the embryo. The scientists wanted to know whether the one-cell embryo already contains parts of the blueprint for the multitude of different cell types that later develop from it. To do this, they studied zebrafish and clawed frog embryos. Researchers had previously succeeded in finding individual genes whose RNA is localized at specific sites within one-cell zebrafish embryos. The Berlin scientists have now shown that there are many more such genes. “We have discovered ten times more genes whose RNA is spatially localized in the fertilized egg cell than previously known,” explains Karoline Holler, lead author of the study. “Many of these RNA molecules are later transported into the primordial germ cells. This means that the program for subsequent cell differentiation is hard-wired into the fertilized egg cell.”

New approaches in transcriptomics

State-of-the-art methods of single-cell transcriptomics provide a good understanding of cell differentiation. Scientists order individual cells according to the similarity of their transcriptome – the complete collection of RNA molecules present in a cell – and can use the patterns that emerge to decipher how the cells became what they are. However, they cannot use this method to reconstruct the earliest stages of embryonic development, because here the spatial arrangement of RNA

molecules is crucial. His team instead used a specialized technique called tomo-seq, which Junker developed at the Hubrecht Institute in the Netherlands in 2014. It enables scientists to spatially track RNA molecules within the cell. This is achieved by cutting embryos of the model organisms into thin slices. It is then possible read the RNA profiles on the cut surfaces and convert them into spatial expression patterns. Holler refined the tomo-seq technique to now measure the spatial distribution of the transcriptome within the fertilized egg cell.

The scientists used another new technique to study which localized genes later contribute to which cells. “We labeled the RNA molecules so as to be able to track them over different developmental stages. This allows us to observe the RNA not only in space but also over time,” explains Junker. In this way, the scientists can distinguish the RNA transferred to the embryo by the mother from the RNA produced by the embryo itself. This RNA labeling method, called scSLAM-seq, was fine-tuned at BIMSB in the labs of Professor Markus Landthaler and Professor Nikolaus Rajewsky, enabling it to be applied in living zebrafish. “Labeling RNA molecules allows us to measure with high precision how gene expression changes in individual cells, for example, after an experimental intervention,” explains Junker.

How do drugs affect cell differentiation?

RNA labeling opens up completely new avenues for studying such things as the mechanism of action of drug therapies. “We can use it in organoids to investigate how different cell types respond to substances,” explains the physicist. The method, Junker says, is not suitable for long-term processes of change. “But we can see which genes change within five to six hours after treatment, providing a pathway to understanding how we might influence cell differentiation.”

Spatial analysis also has medical relevance: Looking further into the future, it could be useful for studying those diseases that result from mislocalized RNA, such as cancer or neurodegenerative diseases. In such diseases a large number of molecules are transported through the cell. “If we understand these transport processes, then we may be able to identify risk factors for these diseases,” explains Holler. But, for now, that is a long way off. “There is still much work to be done before the one-cell zebrafish embryo can be used as a model system for studying human neurodegenerative diseases,” stresses Junker.

The scientists next want to uncover the mechanisms involved in RNA localization: How does the detected RNA differ from other transcripts in the cell? Junker’s team plans to work with Professor Irmtraud Meyer’s lab at BIMSB to characterize the sequence features of the localized RNA. With the help of algorithms, they hope to predict whether the localized genes share a two- or three-dimensional fold. They are also working on further developing their method so that it can be used in other systems than the one-cell zebrafish embryo.

Text: Jana Ehrhardt-Joswig

Further information

How cells make decisions

Science / May 04, 2020

Innovation / 03.06.2021
Eckert & Ziegler and Telix Pharmaceuticals Enter Co-Promotion Agreement for Prostate Cancer Diagnostic in the United States

Eckert & Ziegler (ISIN DE0005659700, TecDAX) and Telix Pharmaceuticals (Telix) will cooperate closely in the commercialization of GalliaPharm® (68Ge/68Ga Generator) and investigational product Illuccix® (Kit for the preparation of Ga-68 PSMA-11 injection) in the United States. An agreement to this effect has now been signed by the two companies. Illuccix® is a preparation for imaging prostate cancer by positron emission tomography (PET) and is currently under review for regulatory approval in the United States and multiple markets worldwide.

Eckert & Ziegler and Telix will expand their existing collaboration to further develop access to Ga-68 supply in the United States. The parties will both promote the combination of GalliaPharm® and Illuccix® to national radiopharmacy networks, commercial and hospital-based nuclear pharmacies, and other target institutions.

"After previously being granted distribution rights for Germany, our home market, the latest collaboration marks another important milestone for our 68Ga generator GalliaPharm® and our nuclear medicine activities”, explained Dr Harald Hasselmann, Eckert & Ziegler Executive Director and responsible for the Medical segment. “We are pleased to have Telix as a partner and to be able to jointly provide leading edge diagnostic products to prostate cancer patients in the USA.”

“This important cooperation between EZAG and Telix sales teams is highly complementary to our efforts in rolling out 68Ga-PSMA imaging across the US. Subject to FDA approval, we will together raise awareness of this state-of-the-art imaging modality and facilitate coast-to-coast access for US men living with prostate cancer.”, added Telix Americas President Dr Bernard Lambert.

Following regulatory approval, Illuccix® will be offered as a cold kit preparation for the diagnosis of prostate cancer. For this purpose, Illuccix® enables PSMA-11 to be radio-labelled with the radionuclide 68Ga directly before injection by medical personnel. After preparing the radiopharmaceutical and injecting it into the patient, sites exhibiting prostate cancer are localized and imaged via the presence of the prostate-specific membrane antigen.[1],[2]

Prostate cancer is the most common type of cancer in men in the United States, with approximately 210,000 cases in 2020, a significantly higher incidence than either lung cancer (116,000 new cases) or bowel cancer (82,000 new cases).[3] Prostate cancer was also the second most common cause of cancer death in men, with over 32,000 men dying from the disease in the United States in 2020. More than 812,000 American men were estimated to be living with prostate cancer in 2020.

[1] Fendler W et al. JAMA Oncol. 2019; 5(6): 856-863.
[2] Hofman M et al. The Lancet. 2020; 395: 1208-1216.
[3] IARC Global Cancer Observatory, 2020.

About Eckert & Ziegler
Eckert & Ziegler Strahlen- und Medizintechnik AG with around 800 employees, is one of the world's largest providers of isotope-related components for nuclear medicine and radiation therapy. The company offers services for radiopharmaceuticals at its worldwide locations, from early development to commercialization. Eckert & Ziegler shares (ISIN DE0005659700) are listed in the TecDAX index of Deutsche Börse.
Contributing to saving lives.

About Telix Pharmaceuticals
Telix is a clinical-stage biopharmaceutical company focused on the development of diagnostic and therapeutic products using Molecularly Targeted Radiation (MTR). Telix is headquartered in Melbourne, Australia with international operations in Belgium, Japan, and the United States. Telix is developing a portfolio of clinical-stage products that address significant unmet medical needs in oncology and rare diseases. Telix is listed on the Australian Securities Exchange (ASX: TLX). For more information visit www.telixpharma.com and follow Telix on Twitter (@TelixPharma) and LinkedIn.

About Illuccix®
Telix's lead investigational product, Illuccix® (TLX591-CDx) for prostate cancer imaging, has been accepted for filing by the U.S. FDA, and is under priority evaluation by the Australian Therapeutic Goods Administration (TGA). Telix is also progressing marketing authorisation applications for Illuccix® in the European Union and Canada. None of Telix's products have received a marketing authorisation in any jurisdiction.

Eckert & Ziegler AG Contact:
Karolin Riehle, Investor Relations
Robert-Rössle-Str. 10, 13125 Berlin, Germany
Tel.: +49 (0) 30 / 94 10 84-138, karolin.riehle@ezag.de, www.ezag.com

Telix Pharmaceuticals Contact:
Dr. Stewart Holmstrom, Investor Relations
Suite 401, 55 Flemington Road, North Melbourne, VIC 3051, Australia
Email: stewart.holmstrom@telixpharma.com

economic development, Innovation / 18.05.2021
Eckert & Ziegler Granted Exclusive Distribution Rights by Telix Pharmaceuticals for Prostate Cancer Diagnostic

Eckert & Ziegler (ISIN DE0005659700, TecDAX) has signed an agreement with Telix Pharmaceuticals (Telix), an Australian-headquartered company, for the exclusive distribution of Illuccix® (Kit for the preparation of Ga-68 PSMA-11 injection) in Germany. Illuccix® is a preparation for imaging prostate cancer with positron emission tomography (PET), currently under review for regulatory approval in multiple markets worldwide, including Germany.

“Illuccix® is anticipated to be one of the most important imaging products for prostate cancer. Widespread approval of a preparation for the diagnosis of prostate cancer is urgently needed and we are pleased to have Telix, a pioneer in bringing this drug to market, as a partner," explained Dr Harald Hasselmann, Eckert & Ziegler Executive Director and responsible for the Medical segment. "Together with our other products, we will be able to offer nuclear medicine practices and clinics in Germany a fully comprehensive product portfolio for the production of Ga-68 PSMA, once approval has been attained."

“We are pleased to have entered this commercial distribution agreement with Eckert & Ziegler so that, subject to German regulatory approval, we will together be able to deliver a commercial product to German patients living with prostate cancer as efficiently as possible. Partnering with such a capable and patient-centric leader in nuclear medicine uniquely aligns with Telix’s mission of helping patients with cancer live longer, better quality lives”, explained Telix Chief Executive Officer Dr Christian Behrenbruch.

Illuccix® is offered as a so-called kit preparation for the diagnosis of prostate cancer. For this purpose, Illuccix® enables PSMA-11 to be labelled with the radionuclide Ga-68 directly before injection by medical personnel. After preparing the radiopharmaceutical and injecting it into the patient, tumours that show the so-called prostate-specific membrane antigen can be localised by PET.[1],[2]

Prostate cancer is the most common type of cancer in men in Germany, with approximately 68,000 cases in 2020, a significantly higher incidence than either lung cancer (38,000 new cases) or bowel cancer (31,000 new cases). Prostate cancer was also the second most common cause of cancer death in men, with over 15,000 men dying from the disease in Germany in 2020. More than 290,000 German men were estimated to be living with prostate cancer in 2020. 

(1) Fendler W et al. JAMA Oncol. 2019; 5(6): 856-863.
(2) Hofman M et al. The Lancet. 2020; 395: 1208-1216.
(3) IARC Global Cancer Observatory, 2020.

About Eckert & Ziegler.
Eckert & Ziegler Strahlen- und Medizintechnik AG with more than 800 employees, is one of the world's largest providers of isotope-related components for nuclear medicine and radiation therapy. The company offers services for radiopharmaceuticals at its worldwide locations, from early development to commercialization. Eckert & Ziegler shares (ISIN DE0005659700) are listed in the TecDAX index of Deutsche Börse.

About Telix Pharmaceuticals
Telix is a clinical-stage biopharmaceutical company focused on the development of diagnostic and therapeutic products using Molecularly Targeted Radiation (MTR). Telix is headquartered in Melbourne, Australia with international operations in Belgium, Japan, and the United States. Telix is developing a portfolio of clinical-stage products that address significant unmet medical needs in oncology and rare diseases. Telix is listed on the Australian Securities Exchange (ASX: TLX). For more information visit www.telixpharma.com 

About Illuccix®
Telix’s lead investigational product, Illuccix® (TLX591-CDx) for prostate cancer imaging, has been accepted for filing by the U.S. FDA, and is under priority evaluation by the Australian Therapeutic Goods Administration (TGA). Telix is also progressing marketing authorisation applications for Illuccix® in the European Union and Canada. None of Telix’s products have received a marketing authorisation in any jurisdiction.

economic development, Innovation / 17.05.2021
Eckert & Ziegler: Record Income Due to Sale of Division and Strong Core Business

One-off effects from the deconsolidation of the tumor irradiation business, a waning of the Corona slump, and continued strong demand in particular for pharmaceutical radioisotopes more than doubled net profit at Eckert & Ziegler Strahlen- und Medizintechnik AG (ISIN DE0005659700; TecDAX) in the first quarter of 2021. With sales revenues of 44 million EUR (PY: 44), the Berlin-based technology company posted a net profit of 13.8 million EUR, 8.8 million EUR more than in the same period of the previous year

6.8 million EUR of the quarterly profit were booked as a one-off in the Medical Segment due to the deconsolidation of the tumor irradiation business. Another 4.9 mm EUR of net income (36% more than last year) was generated in this segment in particular through stronger sales of pharmaceutical radioisotopes, but also of laboratory devices and nuclear production equipment. The performance in these sub-segments more than compensated a weak start in the project business (services for companies). The Industrial segment returned to pre-Corona profitability and closed the quarter with a net income of EUR 2.5 million. The holding, the group’s third segment, where pre-clinical development expenses are booked, showed a loss of 0.4 mm EUR.

Although almost half (48%) of the 2021 annual income goal of EUR 29 million was already achieved in the first quarter, the Executive Board for now sticks to the guidance published in March due to the ongoing pandemic, the travel restrictions that continue to hamper business, and the extended delivery times for preliminary products, for example in plant construction.

The complete quarterly report can be viewed here:
https://www.ezag.com/fileadmin/user_upload/ezag/investors-financial-reports/englisch/euz121e.pdf

Innovation / 28.04.2021
Eckert & Ziegler Signs Long-Term Supply Agreement with Sirtex Medical on Yttrium-90 for Treating Liver Cancer

Eckert & Ziegler AG (ISIN DE0005659700, TecDAX) and Sirtex Medical (Sirtex) have executed a long-term supply agreement for the use of EZAG’s Yttrium-90 in Sirtex SIR-Spheres® Y-90 resin microspheres for liver cancer. The arrangement has an initial term of five years and guarantees Eckert & Ziegler a substantial share of Sirtex’s rising global demand. It supplements the existing broad-based supply agreement that Sirtex and Eckert & Ziegler have been operating since 2009. The Eckert & Ziegler sales forecast for the 2021 financial year remains unaffected.

"This agreement cements our long-term relationship and makes it easier for both parties to plan accordingly. The order once again underlines our strong market position and competence as a leading production partner for the pharmaceutical industry", explains Dr. Lutz Helmke, member of the Executive Board of Eckert & Ziegler AG and responsible for the Medical segment. “With our geographic expansion strategy, we offer our customers a reliable and worldwide supply of high-quality radioisotopes.”

"With its global manufacturing network, Eckert & Ziegler is an ideal partner for us to supply yttrium-90 worldwide. Our therapy is used in more than 50 countries to treat liver cancer, and with our recently announced prospective, multi-center study for the treatment of hepatocellular carcinoma, we have the potential to expand our FDA-approved indication for the use of SIR-Spheres® in the U.S.," explains Kevin R. Smith, CEO of Sirtex Medical.

From its production facilities in Braunschweig, Germany, and Boston (MA), USA, Eckert & Ziegler supplies the Sirtex sites in Frankfurt, Boston and Singapore with yttrium-90.

Radioembolisation or selective internal radiotherapy (SIRT) uses tiny radioactive beads inserted directly into the liver tumours. The clinical data of this form of therapy, which has been used since 2002, is becoming increasingly convincing. In February 2021, the renowned British National Institute for Health and Care Excellence (NICE) issued a positive recommendation for the treatment of advanced liver carcinomas with SIR-Spheres® Y-90 resin microspheres. Every year, around 840,000 people worldwide develop liver cancer (source: Globocan, 2018).

To meet the increasing demand for radiopharmaceutical substances, Eckert & Ziegler is currently expanding its production sites. A new GMP facility will be added to the Boston (MA), USA site at the end of 2021. In Berlin, a new GMP facility with a total area of around 270 m² will be ready for operation in the first quarter of 2022. In Jintan (China), Eckert & Ziegler is investing up to EUR 50 million in the construction of a production facility for radiopharmaceuticals.

This expansion strategy positions Eckert & Ziegler as a global partner to the radiopharmaceutical industry, offering complete early development services, including process development and scale-up, CMC development, manufacturing and packaging, product release and stability programmes. This will enable the company to be a radiopharmaceutical contract manufacturer of phase I, II and III clinical scale products and for commercial use.

About Eckert & Ziegler.
Eckert & Ziegler Strahlen- und Medizintechnik AG with more than 800 employees, is one of the world's largest providers of isotope-related components for nuclear medicine and radiation therapy. The company offers services for radiopharmaceuticals at its worldwide locations, from early development to commercialization. Eckert & Ziegler shares (ISIN DE0005659700) are listed in the TecDAX index of Deutsche Börse.

www.ezag.com