News

Innovation / 12.05.2022
Eckert & Ziegler with Sales Growth in the First Quarter of 2022

Eckert & Ziegler Strahlen- und Medizintechnik AG (ISIN DE0005659700, TecDAX) increased its sales by 13% to EUR 49.9 million in the first quarter of 2022. The net profit of EUR 6.7 million or EUR 0.32 per share was below the previous year's quarter. This earnings gap compared to the previous year is due to a one-off effect of around EUR 6.8 million in the first quarter of 2021, in which the Group sold its tumour irradiation business at a profit. Despite the pandemic and the war in Ukraine, the Q1 figures reflect a stable start to the year.

Revenue in the Medical segment was EUR 20.1 million in the first quarter, EUR 1.2 million or 5% below the previous year's figure. Taking into account the loss of sales of EUR 1.1 million due to the deconsolidation of the tumour irradiation business, the sales level was maintained compared to the previous year.

The Isotope Products segment achieved revenue of EUR 29.8 million, which is EUR 7.0 million or about 31% higher than in the first three months of 2021, due to rising oil and gas prices and an associated exceptional demand in radiometric components for energy companies. Around EUR 1.9 million of the increase is attributable to the acquisition of the Argentinian company Tecnonuclear SA in January 2022.

The results of the first quarter of 2022 are in line with the expectations of the Executive Board. The forecast for the 2022 financial year published in March remains unaffected. The Executive Board continues to expect sales of around EUR 200 million and a net profit of around EUR 38 million. The forecast is subject to the assumption that the developments in Ukraine do not result in any major disruptions.

The complete quarterly report can be viewed here: https://www.ezag.com/fileadmin/user_upload/ezag/investors-financial-reports/englisch/euz122e.pdf

About Eckert & Ziegler.
Eckert & Ziegler Strahlen- und Medizintechnik AG with more than 900 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.
 

Innovation / 11.05.2022
Eckert & Ziegler Cooperates with Czech Research Center UJF to Produce Pharmaceutical Alpha Radioisotopes

Eckert & Ziegler AG (ISIN DE0005659700, TecDAX), a specialist in medical radioisotopes, has entered into a long-term cooperation agreement with the Nuclear Physics Institute of the Czech Academy of Sciences (Ústav jaderné fyziky, UJF) to produce the alpha emitter Actinium-225. The agreement envisions Eckert & Ziegler to provide the UJF research center with several million euros for investments in equipment and hot cells, as well as radium-226 as a starting material for experiments and irradiations. In return, the Eckert & Ziegler group gets exclusive access to the capacities of a pilot unit being built within the next two years close to Prague and joint rights to the process steps developed for a large-scale Ac-225 commercial production.

Actinium-225 is used as an active ingredient in cancer treatment. The radioisotope emits powerful, high-energy cascade of alpha particles with short penetration depths that enable precise treatment of tumor cells, including difficult-to-target micro metastases, with minimal impact on surrounding healthy tissue. For this purpose, Actinium-225 is combined with a suitable carrier (e.g. antibody or peptide) that specifically binds to cancer cells to selectively target them. Currently, Actinium-255-based radiopharmaceuticals are being tested in many clinical indications, including prostate tumors, colorectal cancer, and leukemia. Specialists expect the demand for Actinium-225 to increase exponentially over the next decade.

"The collaboration with Eckert & Ziegler helps to create efficient plants for the production of therapeutic radiopharmaceuticals in the European Union," explained Dr. Petr Lukáš, Director of the UJF. "Corona and the recent political crises in the East of Europe show how vulnerable global supply chains can get and how important it can be for producers of novel radiopharmaceuticals to develop parts of their value chain with local partners," added Prof. Dr. Ondřej Lebeda, Head of the Department Radiopharmaceuticals of the UJF.

"With UJF, we have a competent partner for the complex tasks involved in the production of Actinium-225 just 90 minutes by car from our site in Saxony," added Dr. Lutz Helmke, Executive Director and COO of the Medical segment. "We are gaining a valuable ally in the attempt to expand our leading position in the global market for therapeutic radioisotopes. As a starting material, we are drawing on a stock of radium-226 that we have accumulated in our recycling business during the take-back of medical radiation sources. This reprocessing of the sources, by the way, provides an example of how well recycling concepts work within the industry."

About Eckert & Ziegler.
Eckert & Ziegler Strahlen- und Medizintechnik AG with more than 900 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.

www.ezag.de

Research, Innovation, Patient care / 25.04.2022
Where science turns into business

Dr. Christina Quensel presented the Campus Berlin-Buch together with the campus stakeholders (Photo: Peter Himsel)
Dr. Christina Quensel presented the Campus Berlin-Buch together with the campus stakeholders (Photo: Peter Himsel)

On April 25, 2022, Federal Commissioner for East Germany, Minister of State Carsten Schneider, and Governing Mayor of Berlin Franziska Giffey visited Campus Berlin-Buch to see how the “Zukunftsort” (place of the future) is developing.

Following the invitation of Campus Berlin-Buch, the Federal Commissioner for Eastern Germany, Minister of State Carsten Schneider, and Berlin Mayor Franziska Giffey, visited the science and technology hub on April 25th, 2022. They were accompanied by Pankow District Mayor Sören Benn. On campus, the guests gained insights into the BiotechPark Berlin-Buch.

The research campus is one of Berlin's eleven “Zukunftsorte“ (places of the future), attracting excellent scientists from all over the world. Berlin-Buch stands for the future of medicine. For decades, research and healing, invention and therapy have been combined at the health location Berlin-Buch. Established companies work alongside life science start-ups, and teams of doctors and researchers cooperate closely with each other.

Internationally renowned research institutions such as the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) and the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), the Charité – Universitätsmedizin Berlin, the Berlin Institute of Health in the Charité (BIH) as well as biotechnology companies and clinics form a network. Building on the first spin-offs at the beginning of the 1990s, the campus is now one of the largest biotech parks in Europe. With a clear focus on biomedicine, it represents the entire value chain from knowledge to development to the production of marketable innovations and has outstanding growth potential.

The investments are worthwhile

"Since 1992, more than 600 million Euros have been invested in research and biotech infrastructure on the campus by the EU, the federal government and the state. And on our campus it is evident that these investments are worthwhile," said Dr. Christina Quensel, Managing Director of Campus Berlin-Buch GmbH. "By closely combining basic and clinical research, state-of-the-art technology platforms and with the goal of bringing biomedical findings into application, science is turning into business in Berlin-Buch."

A visible sign of the continuing growth is the new construction of the “BerlinBioCube” start-up center in the BiotechPark. The "BerlinBioCube" will open in 2023 and offer 8,000 square meters of space for start-ups in biotechnology, medical technology and related fields. When it is completed next year, around 30 biotech start-ups will be able to work in state-of-the-art laboratories and offices and start their business operations. Dr. Ulrich Scheller, Managing Director of Campus Berlin-Buch GmbH, and Dr. Quensel explained plans for the expansion of the campus, the extension of the biotech park to neighboring areas in the city and for the increased establishment of biotech companies.

During their campus tour, the politicians met with researchers and successful entrepreneurs. They visited the laboratories of T-knife, one of the most successful start-ups in the biotech scene, whose technology for novel immune therapies against cancer is based on decades of basic research at the Max Delbrück Center for Molecular Medicine.

One of the world’s best

In a discussion at the corporate headquarters of Eckert & Ziegler Strahlen- und Medizintechnik AG, the guests discussed current issues of business development in technology and start-up centers, questions and best-practice examples of value-creating networking between research and business, the expansion of the regional transport infrastructure and the coordinated development of commercial and residential building potential areas at the future location of Berlin-Buch with representatives from companies and research institutions on the campus.

"The Berlin-Buch campus with its numerous players from science and the health industry is an example of successful transformation into a modern technology hub for clinical research, molecular medicine and molecular pharmacology. Buch proves how targeted innovation management leads to success and global networking when it is supported by active settlement and funding policies that involve business and science and that think transport and living and working together. Thank you to all our hosts for inspiring impressions," said Franziska Giffey.

Minister of State Carsten Schneider also thanked the campus actors. "Today, we gained highly exciting insights into the biotech sector in Berlin-Buch. Innovative research and work is being done here. This makes the Berlin-Buch campus one of the world's best," explained Schneider. "With the research funding from the federal government, we are creating long-term structures."

Research, Patient care / 13.04.2022
COVID-19 therapy: better in combination than alone

© Judith Bushe/ Anne Voß, FU Berlin
© Judith Bushe/ Anne Voß, FU Berlin

More and more drugs are available for the treatment of COVID-19. Researchers from Charité, FU and MDC in Berlin have investigated the mechanisms of action of antiviral and anti-inflammatory substances. In the journal "Molecular Therapy" they describe that a combination of both works best.

SARS-CoV-2 infections continue to result in hospitalizations. According to estimates by the Robert Koch Institute, the current COVID-19 hospitalization rate is approximately six to seven per 100,000 of the resident population. Hospitalized COVID-19 patients now have access to a range of drugs which can reduce the severity of the disease or, in the most severe cases, reduce the risk of death. Some of these drugs target the virus itself; others fight the inflammation associated with infection.

First-line treatments include monoclonal antibodies and dexamethasone, a drug with strong anti-inflammatory properties. Antibody treatments neutralize the virus by sticking to the surface of its spike protein, preventing it from entering human cells. This type of treatment is used within seven days after symptom onset. Hospitalized COVID-19 patients who require oxygen therapy usually receive dexamethasone, a glucocorticoid which, for approximately 60 years, has been used to treat inflammatory conditions caused by an overactive immune response. In COVID-19, too, the drug has been shown to reliably dampen the body’s inflammatory response. However, as the drug is associated with various side effects, including an increased risk of fungal infections, it should only be used in a specific and targeted manner.

Severe course in the dwarf hamster

Researchers from Charité, the Berlin Institute of Medical Systems Biology (BIMSB) at the Max Delbrück Center for Molecular Medicine (MDC) and FU Berlin have now studied the mechanisms of action of both types of treatment. “We uncovered evidence to suggest that combination therapy of antibodies and dexamethasone is more effective than either of these treatments alone,” says first author Dr. Emanuel Wyler, a researcher at the MDC’s ‘RNA Biology and Posttranscriptional Regulation’ research group, which is led Prof. Dr. Markus Landthaler.

As not all lung compartments can be studied using lung tissue samples obtained from patients, the research group’s first step last year was to search for a suitable model. That task fell to co-last author Dr. Jakob Trimpert, a veterinarian and research group leader at the FU Berlin’s Institute of Virology, who subsequently developed COVID-19 hamster models. As animals which both contract the same virus variants as humans and develop similar disease symptoms, hamsters have proven the most important non-transgenic model for the study of COVID-19. Symptoms and progression, however, vary between different species of hamster. While symptoms usually remain moderate in Syrian hamsters, for example, Roborovski hamsters will develop severe disease reminiscent of that seen in COVID-19 patients requiring intensive care.

Interplay of signalling pathways

“In the current study, we tested the effects of single and combined antiviral and anti-inflammatory therapies for COVID-19, meaning we used the existing models with monoclonal antibodies, dexamethasone, or a combination of the two,” explains Dr. Trimpert. The FU Berlin’s veterinary pathologists then examined infected lung tissue under a microscope to establish the extent of lung tissue damage. Dr. Trimpert and his team also determined the quantities of infectious virus and viral RNA present in the tissues at various time points. This enabled the researchers to check whether and how viral activity might change over the course of treatment. “Thanks to a detailed analysis of various COVID-19 parameters, which is only possible in an animal model, we were able to improve our understanding of the basic mechanisms of action of two important COVID-19 drugs. Moreover, we found clear evidence of the potential benefits associated with a combination therapy of monoclonal antibodies and dexamethasone”, says Dr. Trimpert.

Using single-cell analyses, the researchers demonstrated the drugs’ effects on the complex interplay of various cellular signaling pathways and the number of immune cells present. 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, the single cells underwent RNA sequencing, a process used to establish the sequence of genetic building blocks which a cell has just read. Thanks to barcoding, this RNA is 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 that the antibodies are effective at reducing the amount of virus present,” explains Dr. Wyler. He adds: “This was not much use in our model, though.” This is because it is not the virus that damages the lung tissue, but the strong inflammatory response triggered by the virus. The immune cells fighting the invading pathogens release messenger substances to call in reinforcements. When these defensive forces arrive in large numbers, the lungs can become clogged. “Obstructed blood vessels and unstable vessel walls can subsequently result in acute lung failure,” explains Dr. Wyler.

Well known drug as a gamechanger?

A surprise came in the shape of the well-known drug dexamethasone. “This anti-inflammatory exerts a particularly strong effect on a specific kind of immune cell known as neutrophils,” says the study’s co-last author Dr. Geraldine Nouailles, Research Group Leader at Charité’s Department of Infectious Diseases and Respiratory Medicine. Neutrophils are a type of white blood cell responsible for mounting a prompt response to viral and bacterial infections. “The corticosteroid preparation suppresses the immune system and prevents the neutrophils from producing messenger substances which would attract other immune cells,” explains Dr. Nouailles. She continues: “This makes the drug extremely effective at preventing an escalation of the immune response.”

The best treatment outcomes were achieved when the researchers administered a combination of antiviral and anti-inflammatory treatments. “This type of combination therapy is not included in existing clinical guidelines,” emphasizes Dr. Nouailles. “What is more, current guidance stipulates that, in high-risk patients, antibody therapy can only be given in the first seven days following symptom onset. In clinical practice, dexamethasone is only used once a patient requires oxygen therapy, i.e., at an extremely advanced stage of the disease. Its use in combination, however, opens entirely new treatment time windows.” This new approach must now be evaluated in clinical trials before it can be adopted in clinical practice.

Text: Jana Ehrhardt-Joswig

Photo:

Images at x 600 magnification showing: healthy lung tissue with open alveoli (left); severe SARS-CoV-2 infection with tissue damage and immune cells (center); visibly reduced level of destruction and improved gas exchange following combination therapy (right).© Judith Bushe/ Anne Voß, FU Berlin

Source: A joint press release by Charité, the MDC and FU Berlin
COVID-19 therapy: better in combination than alone

Innovation, Patient care / 08.04.2022
Eckert & Ziegler: Radboud University Medical Center Netherlands to Image First Patient with PENTIXAFOR

Radboud University Medical Center (RUMC) in Nijmegen, one of the largest centres of excellence in the Netherlands for adrenal diseases, treated the first patient with primary aldosteronism with the Ga-68-based diagnostic PENTIXAFOR as part of the CASTUS study.

Developed by PentixaPharm, PENTIXAFOR is an innovative imaging PET tracer that targets the chemokine-4 receptor (CXCR4) and is used to diagnose various oncological and inflammatory diseases. The Ga-68-based PET radiodiagnostic is expected to have the potential to significantly improve the diagnosis of these disorders and to direct patients to the appropriate therapy.

Primary aldosteronism (PA), also known as Conn’s disease, is an abnormality of the adrenal gland characterised by either a unilateral aldosterone-producing adenoma (APA) or bilateral adrenal hyperplasia (BAH). Regardless of the location of the pathological tissue, adrenal tumours cause hypersecretion of aldosterone, which leads to hypertension and is therefore closely associated with high vascular morbidity. The prevalence of PA in patients with hypertension, about 20 million patients in Germany, is about 5.9 %. The number of unreported cases is even higher due to the complicated and invasive standard diagnosis by adrenal vein sampling (AVS).

The CASTUS study is a clinical research programme aiming to evaluate the accuracy of PENTIXAFOR in the diagnosis of primary aldosteronism. The Ga-68-based PET radiodiagnostic will be used to detect the unilateral or bilateral nature of aldosterone hypersecretion in primary aldosteronism. This distinguishing feature determines patient management and medical therapy. Compared to the previous diagnostic procedure, in which hormone levels are measured on the adrenal gland using a complex invasive catheterisation procedure, PENTIXAFOR is a non-invasive diagnostic method. In order to investigate the potential of PENTIXAFOR, the RUMC is recruiting up to 300 patients.

RUMC has started imaging the first patient with PENTIXAFOR with great success. High-resolution images show the potential of the non-invasive PET radiodiagnostic PENTIXAFOR. One of the investigators of the CASTUS study, Professor J. F. Langenhuijsen explained: "The high sensitivity of PENTIXAFOR allows us to determine the location of the adrenal tumour much more accurately and may replace the previous, invasive gold standard AVS for diagnosis in the future. Further studies are needed to determine the promising prognostic value of PENTIXAFOR at baseline or during treatment evaluation."

"The fact that one of the leading centres in the Netherlands, such as RUMC, has decided to work on PENTIXAFOR itself shows the great interest in finding a new diagnostic for adrenal disease and could pave the way for additional therapeutic alternatives. The CASTUS trial provides PentixaPharm with the opportunity to enter another therapeutic area in addition to its core development strategy in oncology," commented Dr Hakim Bouterfa, founder and managing director of PentixaPharm GmbH. "We are pleased to have Professor J. F. Langenhuijsen, Professor J. Deinum and Professor M. Gotthardt as principal investigators for this study."

Eckert & Ziegler (ISIN DE0005659700, TecDAX), the owner of the rights to the underlying [68Ga]Ga-PentixaFor PET compound, is supporting the RUMC team by providing PENTIXAFOR. In return, Eckert & Ziegler receives access to the study results. PENTIXAFOR is being developed by Eckert & Ziegler subsidiary PentixaPharm GmbH as a highly sensitive diagnostic for a portfolio of haemato-oncological malignancies, including myeloma and lymphoma.

In 2021, the European Medicines Agency (EMA) gave Eckert & Ziegler the green light to jump directly into a phase III clinical trial for PENTIXAFOR, allowing the company to save a number of time-consuming evaluation steps. Since end of December, the Phase III study design has been submitted for review in Amsterdam. However, the EMA recently had to postpone the start of the review, which was scheduled for March 7, 2022, by two months because an "exceptionally high number of applications" faced a pool of reviewers decimated by Corona and its processing capacities were insufficient. The phase III clinical trial is expected to start approximately 5 months after the start of the review and will include about 500 patients in a PAN cancer trial with European participation.

The CASTUS study is sponsored by ZonMW, the Dutch national organisation for health research and innovation in healthcare.

About Eckert & Ziegler.
Eckert & Ziegler Strahlen- und Medizintechnik AG with more than 900 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.
 

Source: Press release EZAG
Eckert & Ziegler: Radboud University Medical Center Netherlands to Image First Patient with PENTIXAFOR

Research / 06.04.2022
High-ranking naked mole-rats are more resilient

Encounters in the tunnel are status contests: the higher-ranking animal moves over its inferior. © Colin Lewin
Encounters in the tunnel are status contests: the higher-ranking animal moves over its inferior. © Colin Lewin

Naked mole-rats are full of surprises. The latest is that higher-ranked mole-rats most likely have an immunological advantage over animals with lower social status, a discovery made by Professor Gary Lewin’s lab at the MDC. The team is now reporting its findings in Open Biology.

Naked mole-rats not only look strange, they have a strange lifestyle, too: they spend their entire lives underground. They also feel very little pain, rarely develop cancer and are exceptionally long-lived for a rodent – living up to 37 years. All this makes the hairless burrow-dwellers prime candidates for scientific study.

For nearly 20 years, Professor Gary Lewin at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) has been researching these extraordinary animals. “The naked mole rats live in strictly organized colonies,” Lewin says. “Each animal knows its rank and the tasks it has to perform.” Now Lewin’s team in the Molecular Physiology of Somatic Sensation Lab, together with scientists at the German Cancer Research Center (DKFZ), Freie Universität Berlin and the University of Pretoria, has made a new discovery: The researchers report in Open Biology that naked mole-rats of higher social rank have a larger spleen. The organ plays a key role in the immune system and is involved in the formation, maturation and retention of immune cells. “This could mean that higher-ranking animals have better built-in defenses than animals below them on the social hierarchy,” says lead author Dr. Valérie Bégay of Lewin’s team.

No sign of disease, despite an enlarged spleen

The shriveled sausages on four legs are so special that Bégay carefully examines each naked mole-rat used in an experiment. She noticed that some of the animals had a much larger spleen than others. That got her wheels turning. “We initially thought that the animals with the larger spleens were sick,” the researcher recounts. That’s because the organ swells up when the body fights inflammation and disease, as many types of immune cells are manufactured and stored there. “But we couldn’t find anything, not even inflammatory markers in the blood or any other evidence of disease,” she reports. “There had to be another explanation for the enlarged spleen.”

With the help of Dr. Alison Barker, Bégay found out that spleen size is linked to the animal’s social status. The scientist, who recently studied mole-rat dialects, is very experienced in conducting behavioral research experiments. They determined rodent rank by having two naked mole-rats run towards each other in a tube. “The higher-ranked animal will always climb over the lower-ranked animal,” Barker says. “It keeps the upper hand, so to speak.”

Higher-ranking animals cope better with disease

It was through this method that the researchers learned that the higher-ranked animals had enlarged spleens. Bégay then studied the organs at the molecular level. She used RNA sequencing and tissue sample analysis to classify the different immune cells in the spleen. This showed that the number of macrophages is increased in the enlarged organs. Macrophages act as the body’s defense soldiers. They kill invading pathogens by surrounding and swallowing them. That’s why they are also called scavenger cells. “The enlarged spleen might enable the higher-ranked animals to fight infections better and deal with inflammation and injury more easily,” Bégay explains.

A stronger immune system in higher-ranking animals is not unique to naked mole-rats. In macaques, too, the higher-ranked group members are better equipped to fight disease. But instead of an enlarged spleen, the monkeys have a differently organized system of immune protection. “It really surprised us that there could be such large differences in spleen size without disease being present,” Lewin says. “The rank of a naked mole-rat depends on how it behaves in the group. The size of the spleen is linked in turn to rank. This would ultimately mean that behavior directly affects the physical characteristics of the immune system, or vice versa.”

The queen never experiences menopause

The researchers also suspect that the spleen influences an animal’s longevity. Successful naked mole-rats – that is, those able to get their way with other colony members – live longer. The queen does not typically die of old age, but is usually killed during a “coup” – namely, when another female gathers male followers around her and removes the old queen. “Up until her last day, the queen is fertile,” says Lewin. “She never experiences menopause – as if her organism did not age.” This suggests at the very least that a strong immune system slows down the aging process. Mammals do not usually produce offspring until the end of their lives: they have a post-reproductive lifespan.

The scientists are now asking new questions. For instance, which comes first: the larger spleen or the higher rank? This has not yet been determined. The only thing that is clear is that naked mole-rats are not born into their social status, but work their way up. The desire for sex may be their driving force: Only the highest-ranking members – the queen and two to three pashas – are allowed to reproduce. “This could be a selection mechanism,” Lewin says. “By allowing only the most successful to mate, it ensures that the animals with the strongest immune systems pass on their genes.” Lewin also hopes to gain new insights into cancer. Naked mole-rats have a very efficient defense system against the disease. Whether the spleen plays a role in this remains to be seen. First, the scientists must conduct further cell analysis. “We are still at the very beginning,” he stresses.

Text: Jana Ehrhardt-Joswig

Source: Press Release MDC
High-ranking naked mole-rats are more resilient

Research, Education / 05.04.2022
Science you can touch

Claudia Jacob (Photo: Peter Himsel)
Claudia Jacob (Photo: Peter Himsel)

Claudia Jacob is a trained biologist who has a passion for explaining how things work. As head of the Life Science Learning Lab (Gläsernes Labor) on Campus Berlin-Buch, she gives schoolchildren a hands-on opportunity to explore the life sciences – from conducting lab experiments to discussing ideas with scientists – and perhaps even a chance to become a scientist themselves one day.

When she welcomes new participants to a neurobiology course, Claudia Jacob has the schoolchildren put on special glasses and then lets them play with various balls in the foyer of the Max Delbrück Communications Center. Laughter spreads rapidly through the group as they realize how awkward and clumsy they have become. The glasses change the angle of vision, making throwing and catching virtually impossible – this is what it feels like when our brains and nervous systems aren’t working properly. “Starting the course with this activity sparks curiosity in the subject matter,” Jacob says. She heads the Life Science Learning Lab (Gläsernes Labor), a youth education center at the science and biotechnology park Campus Berlin-Buch. It is run jointly by the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) and Campus Berlin-Buch GmbH. The learning laboratory also receives support from numerous funding institutions and sponsors, including the campus-based company Eckert & Ziegler.

Jacob has led the Life Science Learning Lab since 2015. After training as a chemical-biological research assistant, she studied biology and environmental management. She financed her studies with a part-time position at Freie Universität Berlin. While working with younger students, Jacob noticed that she liked to explain things. So she became a lecturer – and eventually joined the Life Science Learning Lab, becoming its head in 2004. “The lab is a real gem,” she says. In this interview, she explains why this is so.

Here schoolkids can learn to CRISPR

When was the Life Science Learning Lab launched?

Claudia Jacob: The Life Science Learning Lab opened its doors in 1999. The idea for the lab came from MDC founding director Prof. Detlev Ganten: It was originally conceived as an information center to keep the general public abreast of developments in genetic engineering and biotechnology. Scientists were to conduct experiments together with citizens, and explain to visitors what happens on Campus Berlin-Buch, what basic research is and how science works. However, teachers quickly expressed a need for opportunities to conduct extracurricular experiments. And so the Life Science Learning Lab soon became one of the largest student labs in Germany. Every year some 14,000 students and teachers, mainly from Berlin and Brandenburg, visit us.

What does the Life Science Learning Lab offer?

Claudia Jacob: We have a total of six laboratories in which we offer more than 20 experimental courses for schoolchildren and secondary school students. The courses cover topics such as molecular biology, cell biology, neurobiology, chemistry, radioactivity and ecology. We are one of the few student labs in Germany where young people can conduct experiments with CRISPR-Cas9. We also offer experiments for elementary school kids and, in our research garden, even for small children of kindergarten age. In addition, we have working groups in which students can learn about careers in the life sciences and do experiments on things like biodiversity, 3D printing and natural science phenomena. There are also vacation courses that enable young people to get acquainted with lab work, and which include a tour of a real research lab and a chance to talk with scientists.

Creating understanding, generating enthusiasm

So you are promoting, so to speak, the life sciences to young people?

Claudia Jacob: Our aim is to get children and young people interested in the life sciences and, ideally, get them excited about these subjects. And yes, we do offer advice on study and training options. Not everyone has to go to university. There are many traineeships here on campus. In addition to biology and chemistry lab technicians, you can also become an animal keeper, an IT specialist for systems integration, a medical laboratory assistant or an office administration clerk. For one project, we portrayed an animal keeper who enthusiastically explains how important her job is for scientific research and how highly animal welfare is regarded in the campus’s labs. Young people can also complete a Voluntary Ecological Year at the Life Science Learning Lab. This allows them to find out if a scientific profession is right for them. But our work with young people goes beyond that.

In what way?

Claudia Jacob: As part of the Collaborative Research Centre “Scaffolding of Membranes: Molecular Mechanisms and Cellular Functions” (SFB 958) – the spokesperson is Prof. Stephan Sigrist of Freie Universität Berlin (FU) – there is a subproject on public relations headed by Prof. Petra Skiebe-Corrette and Prof. Dirk Krüger, both also of the FU. The Life Sciences Learning Lab and the NatLab of the FU are involved. PhD students in SFB 958, FU students studying to become teachers, schoolchildren, schoolteachers and interested members of the public can participate in the project to learn how science communication works. The PhD students are creating short videos for this purpose. In another subproject of SFB 958, the research lab of Prof. Oliver Daumke of the MDC is developing an experiment on the crystallization and X-ray structure analysis of membrane proteins. This experiment will be integrated into our existing neurobiology courses for schoolchildren as well as those of the NatLab at the FU. The videos will help the kids gain insights into membrane research.

Teaching the teachers – and TV editors too

The courses of the Life Science Learning Lab are not just targeted at schoolchildren?

Claudia Jacob: No. We also offer continuing education courses and lectures for biology and chemistry teachers. We are currently experiencing a surge of interest, especially because of the shortage of teachers. In addition, our Life Science Learning Lab Academy offers further education opportunities for life science professionals. These feature courses on topics ranging from PCR technology and good clinical practice to refresher courses for project managers and biological safety and patent law officers. One course covers what career paths are available in science. The lecturers come from the MDC, the FMP, and sometimes from business and industry.

That’s quite a lot.

Claudia Jacob: But that’s not the whole of it. Film and television have started turning to us as experts. We recently received an inquiry from ZDF, a German television network, about vaccine production. The editors wanted to know whether they had portrayed the laboratory situation correctly. I was very glad about this! I always get annoyed when I see labs on TV where glass flasks bubble, hiss and steam, since this has nothing to do with reality.

Do you regularly work with scientists at the MDC?

Claudia Jacob: Of course, and we want to intensify our work with them. The ideas and impulses from the research labs are very important to us. For instance, when we cover the topic of Alzheimer’s disease in the neurobiology course, it’s great that Prof. Thomas Willnow is able to give me a section of a brain specimen. Other times a nice story is all we need.

Personal stories make kids more receptive to the topics

Can you give an example?

Claudia Jacob: Stories that help us illustrate the research in an interesting way. For instance, we know that Prof. Willnow originally comes from cardiovascular research and stumbled onto the topic of Alzheimer’s more or less by chance. Today he is an expert in this field. Students usually find it very exciting to hear personal stories like these.

Has the coronavirus changed things at the Life Science Learning Lab?

Claudia Jacob: Now, as a result of the lockdown, we often deal with young people who have never seen the inside of a lab or held a pipette in their hands. We also offered video experimental courses for the first time during this phase. It was a big experiment for us too. We had to rearrange the whole lab, as it was no easy task to find space for the lighting and the camerawoman. A colleague did the experiments at home, joining us virtually via video conferencing. That was an exciting experience. But I’m very glad that our courses are being held again on campus in our labs. Face-to-face encounters are simply better.

Imparting scientific knowledge is more important than ever

Do you get feedback on the courses?

Claudia Jacob: Many students tell us that we are better equipped than the universities. We’re a bit proud of that. When I joined the Life Science Learning Lab, it wasn’t like that. We applied for lots of grants and financed better equipment that way. We often hear from parents that the research vacation programs, which we also offer for the children of campus employees, were a great experience for their children – that makes us very happy of course. Then there are the many teachers who have been coming to us with their pupils for years. But we often see the same young people more than once, too. After a course, it is not uncommon for pupils to ask if they can do an internship with us to prepare for the presentation exam in the tenth grade. We are happy to arrange this for them. For instance, we once had a pupil who wanted to use microscopic analysis to determine which starch – corn, potato or rice starch – was most suitable for ecological diapers. Rice starch proved to be best suited. I also hear time and again from the staff at our training center that most of the applicants had been to the Life Science Learning Lab as schoolchildren. I assume that means they liked it here.

What do you especially like about your work?

Claudia Jacob: It’s important to me to teach young people to be scientifically literate – especially today when there are so many science skeptics out there who are offering up their own invented truths on the internet. For many people it is very difficult to distinguish between real facts and so-called alternative facts. I hope that I can help in this respect.

Jana Ehrhardt-Joswig conducted the interview.

First published here https://www.mdc-berlin.de/news/news/science-you-can-touch

Source: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
Science you can touch

Research / 01.04.2022
Award-winning science communication

F.l.t.r.: Stephanie Sturm, Jana Schlütter, Jutta Kramm, Karoline Knop, Felix Petermann; from top to bottom: Anke Brodmerkel, freelance writer and author of the text, Christina Anders, Silvio Schwartz, © Felix Petermann, MDC
F.l.t.r.: Stephanie Sturm, Jana Schlütter, Jutta Kramm, Karoline Knop, Felix Petermann; from top to bottom: Anke Brodmerkel, freelance writer and author of the text, Christina Anders, Silvio Schwartz, © Felix Petermann, MDC

One of the MDC's most cited press releases last year revealed that naked mole-rats speak in different dialects. The communications team now has another reason to feel proud of this particular press release, because it has won first prize in this year's Award for Science Communication presented by science information service idw (Informationsdienst Wissenschaft).

The communications department at the Max Delbrück Center for Molecular Medicine (MDC) has been recognised for its media work in 2021, having won first prize in the idw Award for Science Communication. The award is presented by idw in recognition of press releases that are of high professional quality, outstanding news value and high scientific importance. The news that naked mole-rat colonies develop their own dialects – just as German speakers communicate not only in standard German but also in Bavarian or Saxon, for example – resonated with the international media last year. It was reported in Die Zeit, GEO magazine, New Scientist and Flemish daily De Standaard, and was covered by the German radio station Deutschlandfunk as well as the BBC and ARTE. To accompany its award-winning press release, the MDC communications team also produced a variety of video, image and audio material for the media. “There's still a lot of interest in this subject,” says deputy head of communications Jana Schlütter. “Even today, we're still receiving enquiries on the topic.” In total, 84 press offices in Germany, Austria, Switzerland and Italy nominated themselves for the idw award.

The jury explained that its decision was based on the fact that the press release is “a clearly structured flowing text with an understandable, entertaining and at the same time comprehensive presentation of the interdisciplinary research achievements. Not only do we learn a great deal about how naked mole rats communicate, but the text also brings them closer to us as social creatures. The story put the naked mole rat on the cover of 'Science'. The multimedia package of text, images and – of course, especially important for this topic – sound certainly contributed to the great international media response.”

“Very encouraging”

Jutta Kramm, head of communications at the MDC, commented: “We're absolutely thrilled and we'd like to thank the jury for selecting us for this award. It’s very encouraging. We aim to make basic biomedical research at the MDC accessible, understandable and engaging for everyone and explain the processes involved in scientific research. We don’t exaggerate and we don’t promise too much. At the moment, with science sceptics becoming ever louder, the importance of this is more obvious than ever.”

A team of 14 people at the MDC are responsible for communicating the organisation’s research output to the public – in the form of press releases, photos, videos, exhibitions, social media activities, a newsletter and the MDC website. They also organise scientific conferences and events for the general public, for example during the”'Long Night of the Sciences”, Berlin Science Week, and for schools. The department works hand in hand with MDC researchers and many communications teams at partner institutions in Germany and abroad.

Naked mole-rats are some of the more unusual animal models used at the MDC: they are insensitive to pain, highly resistant to cancer and very long-lived. They form states and in the wild they live in extreme conditions. “This makes them extremely interesting to scientists – and to the public,” says Jana Schlütter. “We also have a responsibility to explain the animal experiments involved and show what purpose they serve.”

High-impact press release

The award-winning press release presents a study by the working group Molecular Physiology of Somatosensory Perception, headed by Professor Gary Lewin. Together with Dr Alison Barker from his team and researchers at the University of Pretoria in South Africa, Lewin used algorithms to analyse the quiet twittering of 166 naked mole-rats. The researchers found that each individual animal had its own distinctive voice and that each colony had its own dialect. This increases cohesion within the

naked mole-rat state while helping to maintain boundaries. “Humans and naked mole-rats seem to be much more alike than anyone could have guessed,” says Lewin. “Naked mole-rats have their own language culture that developed long before humans even existed.”

The second-placed press release came from the Institute for the World Economy. Third prize went to the press office of Philipps Universität Marburg. The first prize is worth €2,000, the second prize €1,000 and the third prize €500.

 Text: Jana Ehrhardt-Joswig

Further information

 

Research / 31.03.2022
Hyper-CEST NMR technique reveals missing structure of a novel container molecule

Hyper-CEST as ultra-sensitive NMR spectroscopy tool reveals two previously "hidden" structures of metal-organic cages. Visualization: Barth van Rossum, FMP
Hyper-CEST as ultra-sensitive NMR spectroscopy tool reveals two previously "hidden" structures of metal-organic cages. Visualization: Barth van Rossum, FMP

Using the Hyper-CEST NMR technique, the team led by Leif Schröder from the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) and the Deutsches Krebsforschungszentrum (DKFZ) has managed to reveal two previously little researched variants of a type of transport container from the class of metal–organic polyhedra (MOPs). The researchers want to use this knowledge to develop a novel type of contrast agent in MR (magnetic resonance) imaging.

The concept of a modular construction system proves useful in many applications for assembling complex structures for specific functions from individual, repeated sub-units. In chemistry, the principle can be used to construct a self-assembling network from smaller molecular units that acts as a transport container of a defined size. For example, several metal ions can be linked with organic molecules. These MOPs (metal–organic polyhedra) are used, for instance, to capture greenhouse gases or to pave the way for more effective chemotherapeutic agents by loading them with certain drugs, which they then release in the tumor. Several aspects of the behavior of these structures have not yet been adequately explored. This is partly because there are not always appropriate techniques available to observe the loading and unloading of these MOPs at the molecular level – often, no differences can be measured between the empty and loaded variants for either the container or its contents.

In cooperation with a team from the University of Oulu in Finland, Leif Schröder’s research group has now investigated MOPs that spontaneously assemble in solution from iron ions and an organic compound to form tetrahedra. In the process, the organic struts can be attached differently to the iron “nodes”. Essentially, this influences the properties of MOPs, such as their capacity to kill tumor cells. In the case of the MOP under study, however, it was previously thought that only one of the three theoretically predicted variants existed. The other two variants were considered too unstable because no analytical methods were able to detect them. Using a new method of magnetic resonance (hyper-CEST NMR), Schröder’s team member Jabadurai Jayapaul has now succeeded in demonstrating that these previously unknown variants do exist. The colleagues from Finland were able to confirm the signals of these “hidden” MOPs using theoretical calculations. Although they only occur in very small proportions, the measurements showed that altering the attachment of struts causes dramatic changes in the loading and unloading of containers. Certain sub-types of containers can be selected to speed up the process. The researchers are now using this knowledge to develop a novel type of contrast agent in MR imaging in which the loading of the container influences the MRI signal. But observations also show that there is greater potential for new insights for further optimizing drug carriers. In other words, the first impression gained of these structures may not always be the right one. A substantial part of their nature may remain hidden until we are able to detect them using far more sensitive methods.

Source:
Jabadurai Jayapaul, Sanna Komulainen, Vladimir V. Zhivonitko, Jiři Mareš, Chandan Giri, Kari Rissanen, Perttu Lantto, Ville-Veikko Telkki, and Leif Schröder; Hyper-CEST NMR of metal organic polyhedral cages reveals hidden diastereomers with diverse guest exchange kinetics; Nature Communications; doi.org/10.1038/s41467-022-29249-w

Research / 23.03.2022
Aid for Ukraine

© Feraye Kocaoglu, MDC
© Feraye Kocaoglu, MDC

Colleagues are donating money for medicines, working groups are offering jobs for Ukrainian researchers, and the student lab is opening its doors to children from Ukraine. The war in Ukraine has inspired great solidarity at the MDC. Overview.

Feraye Kocaoglu is feeling overwhelmed. She hadn't expected so much money and such great willingness to help. Kocaoglu, an assistant to several MDC research groups, is currently organising support actions for Ukrainian refugees. Together with Joanna Kaldrack from the Research Funding department, and at the request of management and the crisis committee of the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), she is coordinating the centre’s activities. The team can be contacted at ukraine@mdc-berlin.de. To quickly collect donations for medicines, only a few days after the Russian invasion Feraye Kocaoglu organised a bake sale at Campus Buch and at the Berlin Institute for Medical Systems Biology, part of the MDC.

Money for prescription medicines

“Many employees baked cakes and gave donations. Rather than set prices, people could pay whatever they wanted for a slice of cake. The action raised a staggering 3,223 euros”, says Feraye Kocaoglu. MDC researchers with a licence to practise medicine are using these funds to procure prescription medicines. The drugs are being transported to Ukraine and distributed locally by the Initiative für Wissensaustausch, Empowerment und Kultur (IWEK). In view of this tremendous success, the two women are now planning a sale of international finger food.

Material donations – toiletries, over-the-counter medicinal products such as painkillers or bandages and non-perishable foods – are being collected at the MDC, with strong support from technical assistant Margareta Herzog. Coordinated by the postdoctoral researcher Oleksandra Kalnytska, Ukrainian volunteers are collecting these donations regularly and transporting them to the border. MDC employees can find further information on a Ukraine aid website on the intranet, including useful options for personal donations. Specific calls for assistance are also posted here, for example a request for furniture donations for a refugee family.

Dr Luiza Bengtsson from the MDC communications team is an expert in knowledge transfer and works closely with the student lab at Campus Buch. Together with colleagues from the Life Science Learning Lab, she is now organising a course for refugee children from Ukraine. “The response to my email survey at the MDC was enormous. It's great to see how many people want to help,” she says. Two dates have already been scheduled: On 13 and 20 April 2022, children from six to twelve years of age are invited to take part in “research holidays” at Campus Buch, which will include activities such as experiments, play and handcrafts.

Offers for Ukrainian researchers 

Dr Joanna Kaldrack and Dr Oksana Seumenicht are looking after funding opportunities for Ukrainian researchers. Because as well as providing rapid humanitarian assistance, the aim is also to help refugee researchers quickly get back to work. The MDC is represented on solidarity lists of various scientific organisations and initiatives. “We advertise ourself as a partner institution for Ukrainian researchers on these lists, for activities such as joint applications for funding,” explains Joanna Kaldrack. Researchers can contact the MDC through the solidarity lists of the European Molecular Biology Organization (EMBO), EU-LIFE, the Bündnis der biowissenschaftlicher Spitzenforschungsinstitute Europas or the Initiative Science for Ukraine. Different MDC working groups have registered with their scientific focus.

Joanna Kaldrack is available to advise interested parties on work opportunities at the MDC. A matching programme is also in the pipeline to connect MDC group leaders with Ukrainian researchers. “It is still unclear how the administrative aspects of these positions will be managed and funded, and the MDC cannot yet offer any specific jobs,” explains Joanna Kaldrack. The refugee initiative of the Helmholtz Association Initiative and Networking Fund is looking after refugees from Ukraine seeking a position in administration or technical assistance. Joanna Kaldrack is helping with applications in this area, too.

Many MDC employees are also getting involved on a personal level. For example, the molecular biologist Dr Emanuel Wyler. He has assisted at Berlin Central Station on several occasions, including providing Ukrainian families with information on Covid: “We have developed an information sheet at the MDC explaining the disease and measures such as 3G in easily understandable terms. Two colleagues have now translated this into Ukrainian and Russian,” explains the researcher. Plans are also in place to distribute the information to major accommodation providers in Berlin that will soon receive people from Ukraine.

Text: Wiebke Peters

Ukrainian aid at the MDC can be contacted centrally at ukraine@mdc-berlin.de. Refugees from Ukraine are welcome to get in touch.

Further Information

Research / 17.03.2022
Two ERC Consolidator Grants go to MDC researchers

Dr. Jan-Philipp Junker (left) and Dr. Darío Lupiáñez © Felix Petermann, MDC
Dr. Jan-Philipp Junker (left) and Dr. Darío Lupiáñez © Felix Petermann, MDC

How can a heart heal itself? And what determines the sex of a living organism? The European Research Council (ERC) has awarded Consolidator Grants to Dr. Jan Philipp Junker and Dr. Darío Lupiáñez to tackle these questions. Each researcher will receive €2 million over five years for their research.

Their labs are right next to each other, and now they have a reason to celebrate together: Dr. Jan Philipp Junker and Dr. Darío Lupiáñez have each been awarded a Consolidator Grant by the European Research Council (ERC). The two junior group leaders at the Berlin Institute for Medical Systems Biology (BIMSB) of the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) are among the 61 grant winners from Germany. Out of the 2,652 researchers from across Europe who applied for the grants this year, 313 were chosen. These highly sought-after grants provide €2 million in funding over a period of five years. They give the best and brightest minds free rein to explore their ideas and advance their projects.

This is the second grant that Jan-Philipp Junker has received from the ERC. “It’s not just about the money, but about the visibility that comes with an ERC grant. It also allows you to think bigger and gives you more flexibility,” says the head of the Quantitative Developmental Biology Lab. Junker has been conducting research at the MDC since 2015. In the project “Heart States,” he wants to look at how the different cells of the zebrafish heart coordinate in a spatial and temporal way and thus enable the organ to heal itself. “The heart also serves as a model for our studies,” he says. “For example, how does a complex system respond to a perturbation?”

When he was a postdoctoral researcher, Dario Lupiáñez had already showed that the three-dimensional structure of the genome has consequences for the biology of an organism. “Back then, we were the first to demonstrate a connection,” says the head of the Epigenetics and Sex Development Lab. He has been conducting research at the MDC since 2017, and the project “3D Revolution” gives him another opportunity to do pioneering work. What interests him is how the way the DNA strand is packaged into the nucleus affects sex development in different animal species. “We want to shed light on the molecular mechanisms that allow species to adapt to their habitats and that drive their evolution,” he says. He will continue his project as a lab head at the Andalusian Center for Developmental Biology (CABD) in Seville starting in 2023.

Here are more details about the projects:

Zebrafish hearts heal themselves

When a human suffers a heart attack, permanent scar tissue is formed and the organ cannot fully recover. In zebrafish the situation is quite different. If the animal’s heart becomes injured, it simply heals itself. Medicine would like to copy this feat – at least some aspects of it. But there is still a long road ahead. Scientists first need to fundamentally understand the processes involved.

Junker’s Heart States project is investigating how the various cells in the heart manage to coordinate in such a spatiotemporal way as to bring about restored organ function. “For example, we have developed a sort of molecular time machine,” he says. This allows his team to track which genes the cells express at two different points in time. “These data show us which cell types in the zebrafish respond to the heart injury and temporarily enter an activated state, as well as the extent of the response.”

In a second step, Junker and his colleagues analyze what happens in each of these cells during this process: What mechanisms trigger the activation and what programs are switched on by the change in cell state? The third step concerns the coordination among the cells. “To orchestrate the healing process in the heart, the cells must communicate with each other,” Junker says. “And this requires us to know which cells were neighbors and whether receptors and ligands were spatially close.” Little by little, Junker’s team hopes to single out the key switches and verify their role in experiments, thereby creating the first comprehensive overview of how cell state transitions lead to the regeneration of a complex organ.

Focusing on a mature organ like the heart is also a gamble for him, Junker says. “My background is in developmental biology. So I’m all the more grateful to Daniela Panáková, who has been researching the zebrafish heart for a long time and who helped us a great deal with her knowledge and ideas during the conceptual phase.” The project is a perfect fit for the MDC, he says. All the expertise and resources needed to study the heart using a systems medicine approach can be found here, such as bioinformatics analyses, spatial transcriptomics and human cardiology. “Of course, it would be great to awaken the regenerative potential of the human heart,” Junker says. “But we will first have to perform experiments on mice: Perhaps mammalian hearts receive the right signals but can no longer respond to them?”

Gender issues have fascinated humans for 3,000 years

In the neighboring lab, Lupiáñez is also exploring a phenomenon that can work quite differently in the animal kingdom than in humans. “With our 3D Revolution project, we aim to answer a question that has fascinated humanity for almost 3,000 years: How is the sex of an individual determined?” Lupiáñez says. Ancient civilizations tried to explain this through mythology. “Now we use genetics.”

Evolution has come up with many different ways to determine sex – and the famous Y chromosome exists only in mammals. In birds, it is the females that carry the decisive chromosome. In amphibians such as frogs, the sex chromosomes are not well differentiated. And in more extreme cases, like turtles, temperature can determine whether an embryo will be male or female. “We will look at the 3D organization of genomes to understand how this rapidly evolving process happens at the molecular level,” Lupiáñez says.

Two meters of DNA are packed into each cell nucleus, which is about 200 times smaller than a pinhead. Yet still it is be able to deliver, on demand, all the information an organism needs for its development and survival. “The packaging is anything but random,” he says. “We have shown that alterations in the 3D organization of the genome can affect its regulation and lead to certain diseases. However, these changes can also contribute to the evolution of species and to a better adaptation to their habitats.”

He and his team will look at the exact time point when the sex is determined during the development of mammals, birds, amphibians and turtles. They will sift through the data and compare what the 3D gene regulatory landscapes have in common and what is susceptible to evolve. “This is unchartered territory; nobody has looked at this before,” Lupiáñez says. One reason is that the capability to read, interpret and modify genomes has constrained researchers in the past. “Now we have novel tools to link genomic variation to phenotypes,” he adds. “And the ERC grant will allow us to scale our efforts up. I am immensely grateful to my team who made great efforts in producing the necessary preliminary data.”

Further information

Research / 14.03.2022
Cooperation for better medical imaging

Signing the contract (from top to bottom): Prof. Thoralf Niendorf (MDC), Prof. Dr. Georg Rose (STIMULATE Research Campus and OVGU), Prof. Heike Graßmann (MDC) and Prof. Dr. -Ing. Jens Strackeljan (OGVU) © Peter Himsel/MDC
Signing the contract (from top to bottom): Prof. Thoralf Niendorf (MDC), Prof. Dr. Georg Rose (STIMULATE Research Campus and OVGU), Prof. Heike Graßmann (MDC) and Prof. Dr. -Ing. Jens Strackeljan (OGVU) © Peter Himsel/MDC

The Max Delbrück Center for Molecular Medicine and the Otto von Guericke University Magdeburg and will cooperate in the field of medical imaging in the future. A cooperation agreement was signed on Friday, 11 March 2022 at the Research Campus in Berlin-Buch.

The STIMULATE research campus of Otto von Guericke University Magdeburg (OVGU) and the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) from Berlin want to cooperate in the future. On this behalf, a contract was signed in Berlin on 11 March 2022. The Rector of OVGU, Professor Jens Strackeljan, said after the signing: “I am very pleased that the agreed close cooperation of the MDC with the STIMULATE research campus of our university will establish a strong medical technology axis between Berlin and Magdeburg.”

“The research profiles of our two institutions are suitable for generating synergy effects and mutually optimizing resources and competencies,” added MDC Administrative Director Professor Heike Graßmann. Both institutions want to jointly develop medical technology, especially in diagnostic and interventional imaging.

The partners see the more intensive scientific cooperation as a long-term task. In addition to research, translation and teaching, both contract partners named the promotion of young scientists as an important concern.

Joint symposia and summer schools

Specifically, the aim is to use third-party funding to establish a platform for magnetic resonance imaging (MRI) together with academic and industrial partners from both sides. This aims to define the future of the technology. In addition, the two institutions want to organize joint symposia and summer schools and set up an incubator for start-ups.

The MDC and the OVGU are already involved in the “Artificial Intelligence in Digital Health (AIDHeal)” network together with Berlin and Potsdam universities. “Artificial intelligence is a technology driver for modern medical imaging. That is why we link developers and users in the AIDHeal network to increase the international visibility and competitiveness of 'Digital Healthcare, made in Germany',” said Professor Thoralf Niendorf, who heads the Experimental Ultra-High Field MR group at the MDC.

“The complementary expertise of both locations, the excellent basic research of the MDC and the transfer-oriented research combined with the start-ups that have already emerged at the STIMULATE research campus, are key to the continuous translation of solutions into society," said the spokesperson of the Magdeburg research campus, Professor Georg Rose. Medical imaging and translational application are the focus, although socio-political issues are also to be considered, which methodologically require increased interdisciplinarity.

The MDC is one of the internationally leading biomedical research centers. With the STIMULATE research campus, OVGU inhibits one of the most important international centers for image-guided minimally invasive interventions. Both institutions possess excellent expertise in imaging. 

Photo: Signing the contract (from top to bottom): Prof. Thoralf Niendorf (MDC), Prof. Dr. Georg Rose (Spokesperson of the STIMULATE Research Campus and Chair of Medical Telematics and Medical Technology, Otto von Guericke University Magdeburg), Prof. Heike Graßmann, Administrative Director (MDC) and Prof. Dr. -Ing. Jens Strackeljan (Rector of Otto von Guericke University Magdeburg). © Peter Himsel/MDC

Further information

Research / 14.03.2022
Using mRNA delivery to improve muscle strength

The human muscle stem cells fused into multinucleated myotubes following mRNA-mediated CRISPR-Cas9 gene editing. A myosin heavy chain is seen in green and the nuclei in blue. Photo: Spuler Lab
The human muscle stem cells fused into multinucleated myotubes following mRNA-mediated CRISPR-Cas9 gene editing. A myosin heavy chain is seen in green and the nuclei in blue. Photo: Spuler Lab

Mutations that lead to muscle atrophy can be repaired with the gene editor CRISPR-Cas9. A team led by ECRC researcher Helena Escobar has now introduced the tool into human muscle stem cells for the first time using mRNA, thus discovering a method suitable for therapeutic applications.

It may be only a tiny change in the genome, but this small difference can have fatal consequences: Muscular dystrophies are almost always caused by a single faulty gene. As different as the mutations are in this group of approximately 50 disorders, they all ultimately lead to a very similar outcome. “Due to the genetic defect, changes occur in muscular structure and function so that sufferers experience progressive muscle atrophy,” explains Professor Simone Spuler, head of the Myology Lab at the Experimental and Clinical Research Center (ECRC), a joint institution of the Berlin-based Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) and Charité – Universitätsmedizin Berlin. This condition can be fatal especially if the respiratory or cardiac muscles are affected.

The method has already proven successful in mice 

Muscular dystrophies are currently incurable, and that is exactly what Spuler and her team want to change. Their latest paper, which is appearing in the journal Molecular Therapy Nucleic Acids, paves the way for a clinical trial in which a therapy developed at the ECRC will be tested for the first time on patients with hereditary muscle atrophy. We have for several years been pursuing the idea of taking muscle stem cells from diseased patients, using CRISPR-Cas9 to correct the faulty genes, and then injecting the treated cells back into the muscles so that they can proliferate and form new muscle tissue,” explains Dr. Helena Escobar, a postdoctoral researcher in Spuler’s lab and along with her co-last author of the current paper.

A while back, the researchers were able to show that the method worked in mice suffering from muscle atrophy. “Yet our method had a catch,” Escobar says, explaining:. “We introduced the genetic instructions for the gene editor into the stem cells using plasmids – which are circular, double-stranded DNA molecules derived from bacteria.” But plasmids could unintentionally integrate into the genome of human cells, which is also double stranded, and then lead to undesirable effects that are difficult to assess. “That made this method unsuitable for treating patients,” Escobar says.

Targeted correction of genetic defects 

So the team set out to find a better alternative. They found it in the form of messenger RNA (mRNA), a single-stranded RNA molecule that recently gained acclaim as a key component of two Covid-19 vaccines. “In the vaccines, the mRNA molecules contain the genetic instructions for building the virus’s spike protein, which the pathogen uses to invade human cells,” explains Christian Stadelmann, a doctoral student in Spuler’s lab. Along with Silvia Di Francescantonio from the same team, he is one of the co-lead authors of the study. “In our work we use mRNA molecules that contain the building instructions for the gene-editing tool.” 

To get the mRNA into the stem cells, the researchers used a process called electroporation, which temporarily makes cell membranes more permeable to larger molecules. “With the help of mRNA containing the genetic information for a green fluorescent dye, we first demonstrated that the mRNA molecules entered almost all the stem cells,” Stadelmann explains. In the next step, the team used a deliberately altered molecule on the surface of human muscle stem cells to show that the method can be used to correct gene defects in a targeted manner.

A clinical trial is in the works 

Finally, the team tried out a tool similar to the CRISPR-Cas9 gene editor that does not cut the DNA, but only tweaks it at one spot with pinpoint accuracy. “This allows us to work with even greater precision, yet this tool is not suitable for every mutation that causes muscular dystrophy,” Stadelmann explains. In petri dish experiments, he and his team have now been able to show that the corrected muscle stem cells are just as capable as healthy cells of fusing with each other and forming young muscle fibers.  

“We are now planning to launch a first clinical trial with five to seven patients suffering from muscular dystrophy toward the end of the year,” Spuler says. The Paul-Ehrlich-Institut (PEI), Federal Institute for Vaccines and Biomedicines, which is responsible for approving the clinical trial, has been supporting the idea in an advisory meeting, she adds. Of course we cannot expect miracles, says the researcher, adding: “Sufferers who are in wheelchairs won’t just get up and start walking after the therapy. But for many patients, it is already a big step forward when a small muscle that is important for grasping or swallowing functions better again. The idea of repairing larger muscles, such as those needed for standing and walking, is already under consideration.” Yet for this to become a real-world therapy, the molecular tools would have to become so safe that they could be introduced without any reservations – not only into isolated muscle stem cells, but also directly into the degenerated muscle. 

Text: Anke Brodmerkel

Further information

Spuler Lab

Myology

A pioneer in muscle repair

Science / June 30, 2021

Literature 

Christian Stadelmann, Silvia Di Francescantonio et al. (2022): „mRNA-mediated delivery of gene editing tools to human primary muscle stem cells“. In: Molecular Therapy Nucleic Acids, DOI: 10.1016/j.omtn.2022.02.016

Photo: The researchers used mRNA to introduce the gene editor CRISPR-Cas9 into human muscle stem cells. These cells fused into multinucleated myotubes following mRNA-mediated CRISPR-Cas9 gene editing. A myosin heavy chain is seen in green and the nuclei in blue. © Spuler Lab, MDC Berlin

Research / 11.03.2022
One step closer to artificial rhino eggs

First author Dr. Vera Zywitza working in the laboratory. © Jan Zwilling, BioRescue
First author Dr. Vera Zywitza working in the laboratory. © Jan Zwilling, BioRescue

To prevent the extinction of the northern white rhino, the international consortium BioRescue is attempting to create artificial egg cells from stem cells. A team led by MDC’s Sebastian Diecke and Micha Drukker of Leiden University has now revealed in Scientific Reports that they are one step closer to achieving this goal.

Fatu and Najin are the last two northern white rhinos in the world – and they are both female. As a result, this subspecies can no longer reproduce naturally, and extinction seems inevitable. However, the BioRescue consortium is working against the clock to ensure that the northern white rhino does not disappear from our planet forever. The researchers are pursuing a two-pronged approach: First, they are developing advanced assisted reproduction techniques; second, they want to use skin cells taken from the northern white rhinoceros to create induced pluripotent stem (iPS) cells in the lab, which can eventually develop into immature egg cells, or oocytes. The team from the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), together with partners in Munich, the Netherlands and Japan, has now taken a major step towards this goal. In the journal Scientific Reports, they reveal that they have managed to obtain and conduct in-depth studies on pluripotent rhino stem cells.

“Our paper sheds new light on pluripotency – the ability of stem cells to differentiate into all cells of the body,” says lead author Dr. Vera Zywitza of the Pluripotent Stem Cells Platform at the MDC, which is led by Dr. Sebastian Diecke. “It therefore represents an important milestone on the road to artificially generated rhino oocytes.”

The BioRescue project has received €4 million in funding from the German Federal Ministry of Education and Research (BMBF). The international consortium, which includes the MDC, is led by the Leibniz Institute for Zoo and Wildlife Research (IZW) and cooperates with many more partners, including Helmholtz Zentrum München in Germany.

The fine art of cell engineering

iPS cells in a petri dish have the potential to develop into any cells of the body – including the primordial germ cells that the BioRescue scientists want to cultivate. The researchers are working closely with the lab of Professor Katsuhiko Hayashi, a Japanese stem cell researcher at Kyushu University. In 2016, Hayashi succeeded in generating egg cells from the skin of mice, artificially fertilizing these cells, and implanting them in females. The mice conceived by this method were born healthy and fertile.

Stem cell researcher Professor Micha Drukker and his teams at Helmholtz Zentrum München and at Leiden Academic Centre for Drug Research at Leiden University used a process known as episomal reprogramming to successfully produce northern white rhino iPS cells. This involved the researchers introducing foreign DNA molecules called “plasmids” into skin cells they had obtained. These plasmids contained genes to reprogram the skin cells into iPS cells. The rhino stem cells generated in this way are remarkably similar to their human equivalent. “Viewed under the microscope, they are barely distinguishable from human iPS cells,” says Drukker, adding: “They also respond very similarly to external influences.”

A promising start for germline cell cultivation

iPS cells have different states: they can be naïve – the “ground state” of pluripotency – or primed. Cells in the latter state are thought to have reached a slightly more advanced stage of embryonic development. Experiments with stem cells generated from mice show that they are particularly good at producing germline cells when converting from the primed to the naïve-like state. However, when the scientists first attempted to convert the rhino cells to a naïve-like state, the cells died. The researchers therefore introduced a gene into the rhino cells that prevents cell death – and with this, they successfully obtained naïve iPS cells. “We have characterized the cells in detail by, among other things, analyzing transcriptome data,” Zywitza explains. “The successful conversion to a naïve-like state of pluripotency is a promising starting point for generating germline cells.”

Nevertheless, Zywitza and her colleagues cannot yet move onto the next stage. “The iPS cells we have cultivated contain persistent foreign genetic material – namely, the reprogramming factors and the gene that prevents cell death,” Zywitza explains. “This means we can’t use them to make germ cells, as there is a risk these would be pathologically altered.” But these cells are still extremely useful for studying rhino stem cells in general and gaining a better understanding of their different states in specific. With their help, scientists can explore the molecular mechanisms that take place in stem cells. “For example, we can study why the gestation period of a rhinoceros is 16 months whereas that of a mouse is only 21 days, or how organs develop in different species,” the scientist explains. This teaches us a lot about evolution.”

Ovarian tissue is needed too

In the meantime, Diecke’s team has generated further iPS cells. They used RNA viruses instead of plasmids to introduce the reprogramming factors. These new iPS cells do not contain anything that does not belong there. Now the scientists are trying to produce primordial germ cells from them.

And that’s not all: primordial germ cells only mature into egg cells when they are surrounded by ovarian tissue. It is nearly impossible to obtain such tissue from living or deceased rhinos. “So we have to create not only primordial germ cells but also ovarian tissue,” Zywitza explains. The Berlin-based scientists are working closely with Hayashi to achieve this. Last year he successfully cultivated ovarian tissue from mouse stem cells.

14 embryos created so far using assisted reproduction

Meanwhile, progress is also being made with assisted reproduction. In January of this year, scientists at IZW, in collaboration with the Kenya Wildlife Service, the Wildlife Research and Training Institute, the Dvůr Králové Safari Park, and Ol Pejeta Conservancy, collected immature egg cells called oocytes from Fatu. These were matured at Avantea’s laboratories in Italy and inseminated with thawed sperm from a deceased bull. There are now a total of 14 northern white rhino embryos, which are stored in liquid nitrogen at minus 196 degrees Celsius. In the near future the embryos will be implanted into southern white rhino surrogates, with the aim of creating a healthy northern white rhino calf.

The production of 14 embryos represents a great success in reproductive biology, but this is not a large amount if the goal is to rebuild the northern white population to a self-sustaining level. “Najin and Fatu are also closely related and their genetic makeup is largely identical,” says Professor Thomas Hildebrandt of IZW, who leads the BioRescue research consortium. “Due to age and reproductive tract issues, we were unable to collect any oocytes from Najin that could be developed into embryos, so all 14 embryos are from Fatu. We therefore urgently need a complementary strategy for creating gametes – eggs and sperm – from significantly more individuals.”

Protecting the world’s species – before it’s too late

“Generating functional eggs of the northern white rhinoceros would be the crowning achievement of our research,” Diecke says. This approach could serve as a model for other endangered species. If reproduction from stem cells works, the technique could be used to revive many more threatened or already extinct species. More than 10,000 living cell cultures from more than 1,000 endangered species are stored in the Frozen Zoo at the Arnold and Mabel Beckman Center for Conservation Research in San Diego and in IZW’s biobank in Berlin. “This invaluable resource could be used to bring back species from the brink of extinction,” Diecke says. The northern white rhino would then be just the beginning – although he adds that he “would rather we never had to use our technique and did more to preserve species before it was too late.”

But for Zywitza, one thing is certain: If a northern white rhino is born someday thanks to stem cell technologies, she would love to meet it.

Text: Jana Ehrhardt-Joswig

Further information

Literature

Vera Zywitza et al. (2022): “Naïve-like pluripotency to pave the way for saving the northern white rhinoceros from extinction”, Scientific Reports, DOI: 10.1038/s41598-022-07059-w


Joint press release by MDC and Leibniz-IZW

Research / 11.03.2022
ERC-Starting Grant for exploring the effect of isotopes in Chemical Biology

Live cell imaging of native cell surface receptors (here GLP1R in red) in living cells (nucleus in green, scale bar = 5 micrometer). Author: Johannes Broichhagen and Ramona Birke
Live cell imaging of native cell surface receptors (here GLP1R in red) in living cells (nucleus in green, scale bar = 5 micrometer). Author: Johannes Broichhagen and Ramona Birke

The prestigious Starting Grant from the European Research Council (ERC) was awarded to Dr. Johannes Broichhagen from the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP).

Dr. Broichhagen will use the 1.5-million-euro grant to work on different fronts to visualize and manipulate biomolecules to fundamentally understand their localization and function. A dream of many cell biologists and imaging specialist is to image a molecule as is. And how it behaves in living cells, as it would allow the unperturbed interrogation of biological samples. This means that no genetic engineering, no singlet oxygen generation and no need to introduce additional molecules could trouble a biological sample. As such, Dr. Broichhagen envisions the use of a bio-orthogonal entity that remains “unseen” by a cell’s biology and metabolism, yet displays a signature that can be “seen” by the experimenter. In his work, he seeks to overcome this leap by introducing deuterium to small molecules in a step-by-step development. This ground-breaking approach can only be achieved with organic synthesis, which is flexible to introduce deuterium at desired positions on molecular scaffolds. Knowledge needs to be built, and as such, deuterated chromophores (i.e. fluorescent dyes and small molecule photoswitches) will be synthesized for distinctive Chemical biology disciplines, for instance in programs to elucidate receptor location and activity in endocrine and nervous tissue. Furthermore, to gain a deeper knowledge in physiological and pathological states, and to use the unique properties of a carbon-deuterium bond in imaging to allow “label-free labelling”, he aims to quickly and cleanly assess pharmacokinetics of approved drugs with not yet fully identified action mechanisms.

Title of the project: deuterON: Introducing deuterium for next generation chemical biology probes and direct imaging

About the ERC Grants: The funding program of the European Research Council (ERC) is one of the most prestigious in Europe. Starting Grants support excellent researchers beginning with their own independent research team or programme and are endowed with up to 1.5 million euros over five years.

www.leibniz-fmp.de

Research / 28.02.2022
Cholesterol-lowering drugs may slow down metastase

Many people have to take statins to lower their cholesterol levels. But statins may be able to do even more: Researchers led by Ulrike Stein of the ECRC and Robert Preißner of Charité report in Clinical and Translational Medicine that these drugs inhibit a gene that promotes cancer cell metastasis.

Cancer patients rarely die from the primary tumor but rather from the metastases – even after successful tumor surgery. This is because cancer cells sometimes spread to other parts of body early in the disease, when the tumor is still very small and may not have even been discovered yet. To do this they must break away from the extracellular matrix and migrate into neighboring lymphatic vessels or blood vessels that transport them to new tissue, where they settle and proliferate.

Understanding the molecular mechanisms of metastasis is therefore a key piece of the puzzle in the fight against cancer. More than ten years ago, Professor Ulrike Stein and her lab at the Experimental and Clinical Research Center (ECRC) were able to discover an important driver of this process in human colorectal cancer: the metastasis-associated in colon cancer 1 (MACC1) gene. The ECRC is a joint institution of the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) and Charité – Universitätsmedizin Berlin.

Drug screening identified statins

When cancer cells express MACC1, their ability to proliferate, move around the body, and invade other tissues is enhanced. “Many types of cancers spread only in patients with high MACC1 expression,” Stein explains. MACC1’s role as a key factor and biomarker of tumor growth and metastasis – not only in colorectal cancer, but in more than 20 solid tumors such as gastric, liver and breast cancer – has since been studied by many other researchers worldwide and confirmed in more than 300 publications. Now together with Dr. Robert Preißner of Charité, Stein has discovered what could disrupt metastatic progression in such cases: Statins, which are prescribed as cholesterol-lowering drugs, inhibit MACC1 expression in tumor cells. The scientists are presenting their findings in the journal Clinical and Translational Medicine.

In their search for MACC1 inhibitors, the researchers conducted high-throughput drug screening with colleagues at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany. They independently hit upon statins. They tested this discovery on various tumor cell lines, with favorable results: All seven drugs tested reduced MACC1 expression in the cells but to varying degrees. The scientists then administered the cholesterol inhibitors to genetically modified mice with increased MACC1 expression. This almost completely suppressed the formation of tumors and metastases in the animals. “What is particularly remarkable is that the benefits continued in the animals even after we reduced the animal dose to a human equivalent dose,” Stein says.

Statins have one big advantage: they are already approved

Robert Preißner and scientists at the University of Virginia also examined data from a total of 300,000 patients who had been prescribed statins. This analysis found a correlation: “Patients taking statins had only half the incidence of cancer compared to the general population,” Preißner explains.

Stein advises against taking statins as a preventive measure without consulting a doctor and having their lipid levels checked, so as to ensure no serious side effects occur.

“We are still at the very beginning,” the scientist stresses. “Cell lines and mice are not human beings, so we cannot directly transfer the results.” The experimental studies and retrospective data analysis will now be followed up by a clinical trial, she says. Only after that will it be possible to say with certainty whether statins actually prevent or reduce metastasis in patients with high MACC1 expression.

Source: Press Release MDC
Cholesterol-lowering drugs may slow down metastase

Research / 28.02.2022
Always toward the arteries

Blood vessels of a zebrafish embryo: expression of the Wiskott-Aldrich gene is reduced in the right image. The actin filaments in the cell cytoskeleton are shown in black, nuclei of endothelial cells in red. (© Andre Angelo Sousa Rosa/Gerhardt Lab, MDC)
Blood vessels of a zebrafish embryo: expression of the Wiskott-Aldrich gene is reduced in the right image. The actin filaments in the cell cytoskeleton are shown in black, nuclei of endothelial cells in red. (© Andre Angelo Sousa Rosa/Gerhardt Lab, MDC)

Until now, it was unknown how a new blood vessel obtains the suitable diameter. A team led by MDC researcher Holger Gerhardt has published a paper in the journal Development outlining how targeted migration of newly formed cells from the veins toward the arteries is crucial in this process.

Stretching some 150,000 kilometers, human blood vessels form a widely branching network, which supplies even remote parts of the body with oxygen and nutrients. The more vessels leading away from the heart branch out, the finer they become. While the main artery in the body, the aorta, has a diameter of around three centimeters, the tiniest capillaries are just a few microns in diameter.

The situation is similar on the way back to the heart. The diameter of tiny venules, which transport oxygen-poor blood, is in the two- to three-digit micron range. But the two vena cavae that flow into the heart have a diameter of two centimeter.

Understanding malformations of the blood vessels

“It was previously unknown how a newly formed vessel obtains the suitable diameter and continually maintains this throughout its entire length,” says Professor Holger Gerhardt, leader of the Integrative Vascular Biology Lab the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) in Berlin. Together with researchers from the German Centre for Cardiovascular Research (DZHK) in Berlin, the Berlin Institute of Health (BIH) and the University of Edinburgh in Scotland, Gerhardt and his team have been investigating this question.

“Our research can contribute to a better understanding of congenital vascular malformations – such as the development of shunts in which arteries and veins are directly connected, which means that the tissue can no longer be adequately supplied with fresh blood through the capillaries,” Gerhardt explains. His study, which recently appeared in the scientific journal Development, was funded by the DZHK, the German Federal Ministry of Education and Research (BMBF), the European Research Council (ERC) and the Leducq Foundation. The lead authors of the publication are the developmental biologist Dr. André Rosa and the mathematician Dr. Wolfgang Giese, both postdocs in Gerhardt’s lab.

Migration against the bloodstream

“In experiments with transparent zebrafish larvae, we were able to observe how arteries and veins initially form,” Gerhardt reports. His team focused on the endothelium, the inner lining of blood vessels, to understand how vessels sprout and connect. “This involved following each individual endothelial cell as it migrated through the organism,” the researcher says. The scientists then analyzed numerous live recordings on a computer using mathematical models.

The number of cell divisions determines the diameter of the veins. In arteries, on the other hand, the diameter is determined by the targeted migration of cells from the veins. “So the cells actively migrate against the flow of blood into the forming arteries,” Gerhardt explains. “If they don’t do this, the veins become too thick and the arteries too thin – and shunts are also formed and remain in place.”

A protein regulates migration

In the next step, the researchers looked into whether cell migration from veins into arteries is controlled by a specific gene. “We first examined the genetic material that regulates the actin cytoskeleton, which is involved in all cell movements in the organism,” Gerhardt recounts. “Surprisingly, we saw that the gene for a protein called WASp is extremely active in endothelial cells.”

The abbreviation WASp stands for “Wiskott-Aldrich syndrome protein,” which is essential for the function of the cytoskeleton. If it is defective, it can cause a hereditary immune disorder. “Until now, it had been thought that the WASp gene was expressed only in white blood cells,” says Gerhardt. “It did not seem to play a major role in endothelial cells.”

However, this assumption turned out to be false. “After we specifically switched off the WASp gene in some zebrafish larvae, the targeted migration of endothelial cells toward the arteries did not occur and shunts became more frequent,” Gerhardt reports. This observation is particularly interesting because people with an altered WASp gene sometimes suffer from recurrent aneurysms. An aneurysm is a balloon-like bulge in the wall of blood vessels, usually occurring in arteries. If it ruptures, it can result in a life-threatening loss of blood.

Research using human tissue

Now Gerhardt and his colleagues would like to verify the extent to which their observations can be transferred to humans. “We want to find out whether the mechanism we have discovered plays a role in the development of diseases and, if so, to what extent this can be influenced,” Gerhardt says. His research not only focuses on the rare Wiskott-Aldrich syndrome. It is also conceivable that an altered WASp gene could lead to pulmonary hypertension, which occurs much more frequently.

Text: Anke Brodmerkel

Figure: Blood vessels of a zebrafish embryo: expression of the Wiskott-Aldrich gene is reduced in the right image. The actin filaments in the cell cytoskeleton are shown in black, nuclei of endothelial cells in red. (© Andre Angelo Sousa Rosa/Gerhardt Lab, MDC)

Further information

Literature

André Rosa, Wolfgang Giese et al. (2022): „WASp controls oriented migration of endothelial cells to achieve functional vascular patterning“, Development, DOI: 10.1242/dev.200195

Research / 21.02.2022
What the gut reveals about the heart

Drugs can affect the gut microbiota in different ways. © Isabel Romero Calvo/EMBL
Drugs can affect the gut microbiota in different ways. © Isabel Romero Calvo/EMBL

Changes in the gut microbiome can ultimately lead to cardiovascular disease. Yet some of the alterations appear to normalize in chronic conditions, a team led by ECRC researcher Sofia Forslund reports in Nature Medicine. This finding may have clinical implications.

The bacteria of the human gut have a major impact on health. To date, however, scientists have only a rudimentary understanding of the complicated relationships between the gut microbiome and disease development. The Swedish bioinformatician Dr. Sofia Forslund, who heads the Host-Microbiome Factors in Cardiovascular Disease Lab at the Experimental and Clinical Research Center (ECRC), has once again succeeded in identifying changes in the complex interplay of intestinal microbiota that apparently play a decisive role in the development of major common diseases. The ECRC is a joint institution of the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) and Charité – Universitätsmedizin Berlin.

 

Back in December, Forslund published a study as lead author in the journal Nature in which she and her colleagues analyzed data from 2,173 European patients to find out how the microbiome and cardiometabolic diseases – such as heart disease and diabetes – influence each other and what role prescribed drugs play in this.

The microbiome is involved from the start

In her current paper in the journal Nature Medicine, Forslund and an international team of 62 other researchers describe several important alterations in the gut microbiome that play a role in cardiovascular disease development, focusing in particular on coronary heart disease (CHD). In this disease the blood vessels that supply oxygen to the heart muscle are constricted. CHD is the most frequent cause of death in Western countries. Forslund is one the of six lead authors of the paper, which may open up new avenues for preventing heart disease.

For the study, the researchers recruited 1,241 middle-aged Europeans, both healthy individuals and patients with CHD at three distinct clinical stages – acute coronary syndrome, chronic CHD, and CHD with heart failure. Also recruited were patients without CHD but with metabolic diseases such as obesity or type 2 diabetes. Other institutions collaborating on the study included the German Centre for Cardiovascular Research (DZHK) in Berlin, the European Molecular Biology Laboratory (EMBL) in Heidelberg, and the Weizmann Institute of Science in Rehovot, Israel.

The scientists analyzed the gut metagenome and the blood and urine metabolome in all subjects. The metagenome contains the genomic information of all the microorganisms that inhabit the gut, while the metabolome comprises all the molecules involved in metabolism. “When taking lifestyle factors and medication effects into account, we have found that about three-quarters of the microbiome and metabolome characteristics that distinguish people with CHD from healthy individuals are also present in people with metabolic disease,” Forslund says. “This suggests that the microbiome and metabolome are altered long before the apparent onset of cardiovascular disease, even in the early stages of metabolic disease.” That in turn, she says, strongly suggests that the microbiome is involved in the early pathogenesis of heart disease.

Some characteristics return to normal

In a further step in the research, Forslund’s team analyzed microbiome and metabolome characteristics that are specific to CHD and the three clinical stages being studied – in order to facilitate accurate diagnosis in the future. “We also wanted to find out to what extent these signatures were associated with a change in medication,” Forslund reports. “What came as a surprise in all our analyses was the observation that some anomalies we find in acute disease seem to normalize in chronic conditions.” She says she plans to examine these differences in greater detail: “Eliminating them could help stabilize acutely ill patients.”

In addition, Forslund says, the results show that caution is needed in future clinical trials. “Many of the signatures we found are not specific to cardiovascular disease,” she says. That is something that must be addressed in further studies of patients, she adds. Forslund also recognizes the limitations of her current work: “As this is a cross-sectional study, we can’t determine causality but only associations.”

Further insights into the human heart

It now remains to be seen whether longitudinal data will confirm the results. “Such data will be provided, for example, by the BeLOVE (Berlin Long-term Observation of Vascular Events) study, for which we are recruiting some 10,000 patients with cardiovascular disease,” says Forslund. The researcher anticipates that the first findings from the study, in which the MDC, Charité and the Berlin Institute of Health (BIH) are involved, will be available in a few years. Forslund is also looking forward to data from another study. Together with colleagues, she is currently analyzing the microbiome of heart failure patients whose heart’s pumping capacity is limited.

The ECRC researcher was also involved in another paper published simultaneously in Nature Medicine. In this publication, the authors profiled the blood microbiome and metabolome of 199 patients with acute coronary syndrome for abnormalities. Among other things they found that the affected individuals, who were treated in two large Israeli hospitals, had significantly lower levels of a previously unknown bacterial species from the Clostridiaceae family compared to people without the life-threatening cardiovascular condition.

Text: Anke Brodmerkel

Press release at the website of the MDC
What the gut reveals about the heart

 

Research / 11.02.2022
ERC Proof of Concept Grant for Gaetano Gargiulo

© David Ausserhofer, MDC
© David Ausserhofer, MDC

High-throughput methods that help search for new cancer drugs often rely on oversimplified models. For example, they do not account for the most common cell states found in patients with cancer. MDC researcher Gaetano Gargiulo has now received an ERC Proof of Concept Grant to seek a solution to this problem.

Cancer cells deceive the body in insidious ways. Not only do they change their DNA and thus become more diverse, they can also change states over and over again. “If you want to tackle cancer cells with precise therapies, you have to take into account all their heterogeneity and factor in possible evasive maneuvers,” says Dr. Gaetano Gargiulo, head of the Molecular Oncology Lab at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC). It is becoming increasingly clear that cell states are an essential part of this process. He and his colleagues have invented a technology that can visualize and document the transitions from one cell state to another.

The cells of many solid tumors, including common cancers like those of the lung, breast, colon and pancreas, take advantage of a cellular program that occurs in embryonic development: epithelial-mesenchymal transition (EMT). When epithelial tumor cells transition into the mesenchymal state, they can travel through the body more easily and respond to anti-cancer therapies differently. Using their new technology, Gargiulo and his team were able to show, for example, that immune cells can become collaborators in this process. They help glioblastoma cells in the brain transition to a mesenchymal state and thus become resistant to chemotherapy. The team has also followed these cell state changes in lung cancer. “And they are hardly a one-way street,” Gargiulo says.

The invention of the molecular reporters that visualize the transition was part of a project that the European Research Council (ERC) is already funding with a Starting Grant. Gargiulo and his team quickly realized that the technology was not only relevant to their own research questions, but also could make the search for new drugs against cancer more effective. The ERC shares this view and is now funding the first steps toward commercialization of the discovery with a Proof of Concept (PoC) Grant of €150,000. Gargiulo is one of 166 researchers from all over Europe who is receiving PoC funding this year, paving the way for them to translate their findings into broadly applied solutions.

Searching more efficiently for new cancer drugs

Garguilo’s project aims to improve the high-throughput methods that scientists and the pharmaceutical industry use to search for new cancer drugs. Established cell lines are the standard models for testing large compound libraries in one screening. “However, this approach is currently oversimplified, as information on cell states is neither obtained nor accounted for in the process,” Gargiulo says. “Yet cell states have a profound impact on whether therapeutics can be effective or not. And there is consensus that in the future a combination of different agents will be employed to prevent possible evasive maneuvers.” With the help of the PoC Grant, he and his colleagues now intend to develop a toolbox that makes molecular reporters available for frequently used cell lines. They also want to specify the culture media in such a way that they purposefully push the cells into one state or another.

“As scientists, we can develop a prototype,” Gargiulo says, “but that’s only one step toward broad implementation.” Intellectual property expertise and a strategy that promotes discovery value creation, he says, are also essential – for example in collaboration with the MDC’s technology transfer team. “The ERC grant gives us time to focus on these steps. It’s an important boost.” He is convinced it will be pay off. After all, shortcomings in drug development currently eat up billions of euros and small optimizations might have a significant impact on the economy and society – and on the countless patients who need effective therapies.

Further information

economic development, Innovation / 09.02.2022
Eckert & Ziegler to Supply Telix with Lutetium-177 for Clinical Trials

Eckert & Ziegler (ISIN DE0005659700, TecDAX) has executed with Telix Pharmaceuticals Limited (ASX:TLX, Telix) a comprehensive global supply agreement for Eckert & Ziegler’s therapeutic radioisotope Lutetium-177 (non-carrier-added 177Lu). The radiopharmaceutical will be used to advance Telix’s portfolio of Molecularly Targeted Radiation (MTR) investigational products.

EZAG will immediately commence supply of n.c.a. 177Lu for use in clinical trials of Telix’s therapeutic candidates TLX591 (177Lu-rosopatamab for advanced prostate cancer) and TLX250 (177Lu-girentuximab for kidney cancer).

Lutetium-177 is used in precision oncology for targeted radionuclide therapy. The radioisotope Lutetium-177, is linked to tumor specific drugs which then incorporates the radiating element of the radioisotope into the tumor cells, while largely sparing healthy tissue.

"The agreement underlines our outstanding expertise in delivering isotopes to the pharmaceutical industry. With our production facilities in Europe, Asia and in North America, we are excellently positioned to meet the increasing demand for this isotope and related development and manufacturing services," explained Dr. Harald Hasselmann, Executive Director and responsible for the Medical segment of Eckert & Ziegler. “Our recently concluded joint venture with Atom Mines LLC provides us with excellent access to the scarce and indispensable precursor ytterbium-176, enabling us to supply lutetium-177 n.c.a. in highest purity and reliably to pharmaceutical customers worldwide.”

Dr. Gabriel Liberatore, Telix Group Chief Operating Officer continued, “We are pleased to have established this agreement with EZAG, a premier supplier of high-quality medical radioisotopes, who are now part of our global network of lutetium suppliers. We are committed to working with global partners with a reputation for delivering the highest quality isotopes, and a demonstrated commitment to environmentally sustainable production technologies. Telix’s relationship with EZAG is a multi-isotope partnership and we are delighted to include 177Lu access as part of the supply chain.”

Radiotherapeutic agents that are coupled with Lutetium-177 prior to injection are currently under late-stage clinical development for several types of cancer.

About Eckert & Ziegler.
Eckert & Ziegler Strahlen- und Medizintechnik AG with more than 900 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 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, Switzerland 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)

Source: Press Release EZAG
Eckert & Ziegler to Supply Telix with Lutetium-177 for Clinical Trials

www.ezag.de

Research / 03.02.2022
Solving puzzles of the chloride ion channel ASOR

(c) FMP
(c) FMP

The chloride ion channel ASOR is found in almost all our cells. But apart from its involvement in cell death, not much is known about its physiological role. Two years ago, researchers of the FMP and MDC led by Prof. Thomas Jentsch were able to identify the gene encoding this acid-sensitive ion channel. Now, in collaboration with Prof. Long (New York), they have gained astonishing insight about its structure and activation mechanisms. The findings, now published in Science Advances, are another step on the way to solving the puzzle of ASOR.

Ion channels have vital functions: They ensure that ions such as chloride, potassium or sodium can flow in and out of our cells. Thereby they regulate the electrolyte content of cells and their environment and can generate electrical signals. Ion channels are also very important for the function of intracellular organelles. ASOR is a pH sensitive chloride channel that is present both in outer and inner membranes of cells.

Until now, little has been known about the Acid-Sensitive Outwardly Rectifying Anion Channel - ASOR for short. In 2019, the team of Prof. Thomas Jentsch from the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) and Max Delbrück Center for Molecular Medicine (MDC) in Berlin identified the gene for the acid-sensitive ion channel, in parallel with another group in the USA. Long before, it was known that this channel only opens when the extracellular environment becomes very acidic. This is unusual, because such a low pH normally only occurs when cells die - for example, in case of stroke or heart attack.

To date, it is unclear why virtually all human and animal cells possess this ion channel. Recent data suggest that ASOR plays an important role in intracellular vesicles, whose pH is acidic enough to activate ASOR. However, the mechanism of this activation, and the structure of the chloride-conducting pore were unknown. Knowledge of these properties is, however, a prerequisite for designing pharmaceuticals that may affect ASOR. In close collaboration with structural biologists in New York, the Berlin researchers have now gained important new insights: For the first time, the structure of the open channel was shown and a novel activation mechanism was identified.

Structure of the open channel described
Using cryo-electron microscopy, the collaborating team led by Professor Steve Long at the Memorial Sloan Kettering Cancer Institute in New York, obtained high-resolution structures of the channel at different pH values. Models for the molecular mechanisms underlying ASOR’s function were derived from a comparison of these structures. They were tested by the Berlin team using replacements of single amino acids and subsequent electrophysiological analysis. "What we found is quite unusual for an ion channel", says postdoctoral researcher Maya Polovitskaya, one of the study's first authors. "Changes in pH lead to contraction of the channel's extracellular domain, which thereby pulls on membrane-spanning helical segments of the channel protein. Unlike other channels, where opening of the pore involves only relatively small changes in the position of a single or a few amino acids, we see a dramatic change in the membrane-spanning segment of ASOR. This process, which we call transmembrane metamorphosis, results in the formation of a pore through which chloride flows. This remodeling is strikingly different from the opening mechanism of other known channels."

Acid leads to channel metamorphosis via electrical forces
By comparing the channel structures at neutral and acidic pH, the researchers also tracked down the underlying activation mechanism. For each subunit of the channel, which is composed of three identical proteins, there are three pairs of negatively charged amino acids in the extracellular domain. They normally repel each other electrically. At acidic pH, i.e., a high concentration of H+ (protons), these positively charged particles intercalate between the negative side chains of the amino acid pairs and 'stick' them together. This results in the contraction of the extracellular part described above and the formation of the membrane pore. This mechanism explains the strong pH dependence of ASOR.

The sodium channel ASIC, known for decades, is also opened by acidic pH. However, the mechanism of pH sensitivity and the iris-like opening of ASIC’s pore are fundamentally different from ASOR. "In our work, we have discovered new mechanisms and laid a foundation for the development of ASOR-influencing compounds", says Polovitskaya.

The question remains: what is ASOR actually good for? Some time ago, a group from the USA showed that the ion channel plays a fatal role in stroke. Knock-out mice in which ASOR was switched off survived the stroke with less permanent damage than their counterparts with a functioning channel.

Cell death may not be the only purpose of ASOR
"ASOR definitely plays a role in acid-induced cell death, but a role in intracellular processes, for example in the transport of vesicles, is now coming to the fore", says research group leader Prof. Thomas Jentsch. He has already discovered a number of ion channels, described their biological functions and showed that some of them are mutated in human disease. The researcher is confident that he will also be able to solve the mystery of ASOR. "We already have evidence that inhibiting the channel could mitigate brain cell death in stroke. But being basic researchers, we naturally also want to understand the biological function in healthy organisms", Jentsch says. "Much of our effort is directed towards solving this exciting question."

Source:
Chongyuan Wang, Maya M. Polovitskaya, Bryce D. Delgado, Thomas J. Jentsch, Stephen B. Long. Gating choreography and mechanism of the human proton-activated chloride channel ASOR. Science Advances, Vol 8, Issue 5, DOI: 10.1126/sciadv.abm3942

Press release on the website of the FMP:
Solving puzzles of the chloride ion channel ASOR

Research, Innovation, Patient care, Education / 02.02.2022
Campus Berlin-Buch promotes "Jugend forscht"

© Jugend forscht
© Jugend forscht

Young talents from the fields of mathematics, computer science, natural sciences and technology (MINT) will start in February in Berlin at the nationwide competition for young scientists "Jugend forscht". This year's motto is: "Ingenious by chance?".

The Buch Campus is one of the four locations of "Jugend forscht" in Berlin. The Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), the Leibniz Research Institute for Molecular Pharmacology (FMP), Campus Berlin-Buch GmbH and - associated - the Experimental and Clinical Research Center (ECRC) of MDC and Charité - Universitätsmedizin Berlin are hosting the competition as sponsors.

A total of 38 projects by students between the ages of 10 and 18 were assigned to the Campus Buch. The sponsoring institutions design a program for the regional competition - from the introductory event to the design of the presentations and their evaluation by the jury to the award ceremony.

"The competition is exciting every time," says Dr. Ulrich Scheller, managing director of Campus Berlin-Buch GmbH. "Whether 'accidentally ingenious' or simply enthusiastic about implementing their own ideas - 'Jugend forscht' is a very good incentive to try out the natural sciences and technology and to come into contact with research institutions or companies."

Text: CBB

Further information

economic development / 01.02.2022
Glycotope to spin-out its Service Business to the newly formed FyoniBio GmbH

Glycotope GmbH, a biotechnology company developing antibodies against proteins carrying tumor-specific carbohydrate structures, and CantonBio Deutschland GmbH, a subsidiary of Canton Biologics Co. Ltd., a leading Chinese CDMO, today announced the successful completion of CantonBio’s acquisition of Glycotope’s service business under the newly formed FyoniBio GmbH.

The spin-out completes Glycotope’s refocus solely towards drug discovery and development, utilizing its proprietary technology platform to develop uniquely tumor-specific monoclonal antibodies. FyoniBio, now as part of Canton Biologics Group, will continue the contract development service business and offer a broad range of ISO-9001 compliant services from cell line development to clinical bioanalysis.

Henner Kollenberg, Glycotope’s Chief Executive Officer, said “We look forward to collaborating with FyoniBio for our development needs, while Glycotope’s renewed focus solely on drug discovery and development sharpens our profile as a platform company for tumor targeting antibodies with unique specificity.”

Dr. Lars Stöckl, Managing Director of FyoniBio said “We are also looking forward to continuing the service business with a great team of long-term colleagues and long-standing existing partners as well as potential new collaborators.”

Dr. Hans Baumeister, Managing Director of FyoniBio added; “We are so happy to be able to offer extended one-stop service packages from clone and cell line development all the way to GMP manufacturing. Our portfolio in clinical bioassay services performed under GCLP quality regulations is surely an add-on for the CDMO service offered by FyoniBio and Canton Biologics.”

Dr. Xiao Shen, Founder and Chief Executive Officer of Canton Biologics said, “The acquisition of FyoniBio not only supports the international growth strategy of Canton Biologics, more importantly, through FyoniBio, Canton Biologics can significantly extend our technology platforms and service scope to better support international clients in Europe and worldwide.”

About Glycotope
Glycotope is a biotechnology company utilizing a proprietary technology platform to develop uniquely tumor-specific monoclonal antibodies. Glycotope antibodies target specific tumor-associated carbohydrate structures or protein/carbohydrate combined glyco-epitopes (GlycoTargets). Glycotope has to date discovered in excess of 150 GlycoTargets with antibodies against several of these targets currently under development.

Based on their superior tumor-specificity, Glycotope antibodies are suitable for development in an array of different modes of action including naked antibodies, bispecifics, antibody-drug-conjugates, cellular therapies or fusion-proteins.

Currently six clinical and pre-clinical programs based on this technology are under development by Glycotope or its licensing partners. Visit www.glycotope.com.

About FyoniBio
FyoniBio is a newly formed contract development and clinical lab company continuing the service business of Glycotope on the biotech campus Berlin Buch. FyoniBio is offering 20 years of experience in developing biopharmaceuticals to customers. FyoniBio is an ISO 9001 certified company and operates in part under GCLP. Comprehensive one-stop shop services, from clone development to RCB for CHO and GEX cell lines, process development ready to transfer to the GMP facility of your choice, cutting edge know-how in glycobiology (analytics and cell biology), bioassay development for a wide range of proteins. Excellent know-how in clinical PK, biomarker and immunogenicity analysis of clinical samples under good clinical and laboratory practice (GCLP). Visit www.fyonibio.com.

About Canton Biologics
Canton Biologics Co., Ltd. is a private-funded science-driven high-tech enterprise located in Canton Greater Bay Area. It is in process of international-leading cell line development, upstream, downstream process development, formulation development, physicochemical analysis and bioanalysis method development technology platforms in its R&D centre, as well as fed-batch and perfusion cGMP manufacturing in 50-2000L SUBs under the most stringent regulatory requirement in its commercial manufacturing site. Since the establishment in 2016, Canton Biologics has provided biopharmaceutical and biotech companies with high quality one-stop CMC services covering a broad range of biomacromolecule drugs including monoclonal (mono- and multi-specific) antibodies, recombinant and fusion proteins, probiotic bacteria, vaccines and recombinant viruses for cell and gene therapy. Visit www.cantonbio.com.

Quelle: GLYCOTOPE GmbH
Glycotope to spin-out its Service Business to the newly formed FyoniBio GmbH

Research, Innovation / 21.01.2022
Combination is key – new treatments for lung and colon cancer?

Researchers from the Experimental Pharmacology and Oncology (EPO) in Berlin-Buch in cooperation with academic partners identified new experimental approaches to treat therapy resistant cancer. Patients with advanced colon cancer have limited treatment options as tumors frequently metastasizes to the peritoneum or the liver. Together with the Charite, Alacris, the Max-Plack-Institute for Molecular Genetics in Berlin and the University of Graz, scientists have identified genetic instability and mutations in the mitogen-activated protein kinase pathway (MAPK) as common markers for therapy resistance in experimental colon cancer models.

Evaluation of new therapy combinations, targeting specific pathways revealed strong tumor growth inhibition in those otherwise resistant colon cancers. The study was recently published by Marlen Keil and colleagues (1) in Cancers and is demonstrating, that molecular profiling allows identification of colon cancer subgroups for personalized combination treatments. Genetically stable colon cancers with mutations in the MAPK pathway (KRAS and BRAF) have shown responses to the combination of drugs inhibiting EGFR (cetuximab), MEK (trametinib), and BRAF (regorafenib), providing a strong hypothesis for further clinical evaluation. In addition we have seen that PI3K, mTOR and RET inhibition by everolimus or regorafenib seems to be additive with EGFR inhibition (cetuximab) in selected colon cancers with those activated pathways.

A second study is addressing lung cancer without targetable oncogenic mutations, still a major challenge for oncologists. Lung tumors can be conceived as an organ constituted of different cell types with distinct biologic functions, building a Cellular Tumorigenic Network. Next to the neoplastic cells, originating from critical genetic alterations, non-neoplastic cells such as cancer associated fibroblasts, endothelial cells and immune cells comprise a heterogenic tumor microenvironment. The simultaneous inhibition of signaling within the Cellular Tumorigenic Network and suppression of cellular interdependency by targeting critical paracrine signaling axes is intended to inhibit tumor cell proliferation and thus to
overcome drug resistances. Bioinformatics analysis of gene expression profiles provides evidence of a relationship between the expression of the paracrine signaling pathway members and common drug resistances.

Based on this hypothesis, Stefan Langhammer (2) together with scientists from the University of Kiel and EPO compiled a low-dose targeted drug regimen combining drugs inhibiting tumor, endothelial and immune cell as well as cancer associated fibroblasts function by blocking VEGFR and HGFR (cabozantinib), SDF1α and CXCR4 (plerixafor), the EGFR pathway (afatinib), and COX2 (etoricoxib). For experimental validation of this hypothesis, highly resistant patient derived lung cancer xenograft (PDX) models have been subjected to treatment with the proposed drug combination regimen. All 16 PDX tumors were completely growth suppressed by this drug regimen, leading to an Objective Response Rate of 81% and a Clinical Benefit Rate of 100% with an excellent safety profile. These results strongly encourage the further validation of this cabozantinib, afatinib, plerixafor and etoricoxib combination therapy in preclinical and clinical studies for advanced stage lung cancer patients without current therapeutic options.

(1) Keil et al. Modeling of Personalized Treatments in Colon Cancer Based on Preclinical Genomic and Drug Sensitivity Data. Cancers (2021)
https://www.mdpi.com/2072-6694/13/23/6018

(2) Guergen et al. Breaking the crosstalk of the Cellular Tumorigenic Network by low-dose combination therapy in lung cancer patient-derived xenografts. Commun Biol 5, 59 (2022)
https://www.nature.com/articles/s42003-022-03016-5

Innovation / 10.01.2022
Eckert & Ziegler Signs Exclusive Supply Agreement for Ytterbium-176

10.01.2022 / Insider information pursuant to Article 17 MAR

Eckert & Ziegler Radiopharma GmbH (EZR), the radiopharmaceutical production arm of Eckert & Ziegler, has signed a joint venture and exclusive long-term supply agreements for Ytterbium-176 with Atom Mines LLC, an innovative producer of enriched Ytterbium isotopes and a subsidiary of the non-profit Pointsman Foundation, both based in Austin, Texas. Cancer therapies based on Lutetium-177 are proving highly effective, yet the world supply of the indispensable precursor, Ytterbium-176, has previously been measured in grams per year. A new technology partially financed by EZR and developed by Atom Mines now promises to overcome this bottleneck: first samples delivered met the relevant quality criteria, in particular isotope purity. This opens the way for EZR to make Lutetium-177 available in large quantities to pharmaceutical companies worldwide to treat hundreds of thousands of patients per year.

While shown to be highly effective in clinical trials, regulatory approvals previously limited Lutetium-177 based radiotherapeutics to rare cancer types such as neuroendocrine tumours. Recently, however, the FDA and other regulatory bodies extended approvals for Lutetium-177 based radiotherapeutics to prostate cancer, the second leading cause of cancer death. This has raised supply chain concerns among pharmaceutical producers, in particular about the scarce supply of Ytterbium-176.

“We are excited about the achievements of the team at Atom Mines and the potential of their isotope separation technology”, commented Lutz Helmke, COO of EZR. “They have closed an important gap in the supply chain for Lutetium-177 nca which will enable EZR to strengthen its position as a partner of choice for global radiopharmaceutical companies such as Novartis, Bayer, or Telix.”

About Eckert & Ziegler
Eckert & Ziegler Strahlen- und Medizintechnik AG with approx. 900 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.
 

Source: Press Release EZAG
Eckert & Ziegler Signs Exclusive Supply Agreement for Ytterbium-176

Innovation / 05.01.2022
T-knife Therapeutics Appoints Ronald Krasnow, J.D., as General Counsel

T-knife Therapeutics, Inc., a biopharmaceutical company dedicated to developing novel therapeutics to fight cancer, today announced the appointment of Ronald Krasnow, J.D., who brings over thirty years of legal counsel and executive management experience to T-knife.

“I am pleased to welcome Ron to the senior leadership team at T-knife,” stated Thomas M. Soloway, Chief Executive Officer of T-knife. “Ron is a seasoned executive who has led the legal, compliance and business operations functions at several innovative biotech companies, and additionally has specialized expertise in patent law. As a rapidly growing organization with multiple pipeline programs, his contributions will be instrumental as we pursue our mission of developing best-in-class T-cell receptor (TCR) therapies to transform patient outcomes.”

Mr. Krasnow was most recently the Chief Operating Officer of Arch Oncology, a company dedicated to antibody therapies for the treatment of cancer. Previously, he was General Counsel, Secretary and Chief Compliance Officer at Menlo Therapeutics. Prior to Menlo, he served as Senior Vice President, General Counsel and Secretary of Relypsa, Inc. At Relypsa, he helped the company grow from start-up, through IPO, commercialization and acquisition as it invented, developed and marketed Veltassa, the first new drug to treat hyperkalemia approved by the FDA in more than 50 years. Earlier in his career, he focused on intellectual property and was at Symyx Technologies, Inc. where he spent 10 years in various positions, including Senior Vice President of Intellectual Property. Prior to Symyx, he was an attorney at Fish & Neave representing clients in complex patent litigation and interferences. He has also been a patent examiner at the U.S. Patent and Trademark Office. He holds a B.S. in Materials and Metallurgical Engineering from The University of Michigan and a J.D. from The George Washington University Law School. He is admitted to practice in California, New York and the U.S. Patent and Trademark Office.

Mr. Krasnow added, “I am excited by the cutting-edge science being deployed at T-knife to generate differentiated treatments for cancer patients. Their HuTCR platform has been successful in the identification of novel TCR engineered T cell therapies, and I look forward to building upon this great momentum.”

About T-knife Therapeutics

T-knife Therapeutics is a biopharmaceutical company dedicated to developing novel therapeutics to fight cancer, initially focused on T cell receptor (TCR) engineered T cell therapies (TCR-Ts), a modality that holds the potential to generate transformative responses in patients with solid tumors. The Company’s unique approach leverages its proprietary HuTCR mouse platform, a next-generation T cell receptor and epitope discovery engine that produces fully human, tumor-specific TCRs, naturally selected in vivo for optimal affinity and high specificity.

T-knife is advancing a portfolio of TCR-T product candidates against targets with high unmet medical need, including cancer testis antigens, oncoviral antigens and commonly shared tumor-driving 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 – Universitätsmedizin Berlin. For additional information, please visit the company’s website at www.t-knife.com.

Contact

T-knife Therapeutics, Inc.

Camille Landis
Chief Business Officer / Chief Financial Officer
media@t-knife.com

Quelle: T-knife Therapeutics, Inc.
T-knife Therapeutics Appoints Ronald Krasnow, J.D., as General Counsel

Innovation / 04.01.2022
Eckert & Ziegler Acquires Argentinian SPECT Specialist

Eckert & Ziegler has acquired 100% of the shares of Argentinian nuclear medicine specialist Tecnonuclear S. A., a manufacturer of Technetium-99 generators and a portfolio of related biomolecules. These so-called “cold kits” function as vectors for the in-vivo delivery of Technetium-99 to more specific biological targets such as receptors and transporters. In tandem with the generators these generic tracers are commonly also referred to as SPECT diagnostics. Worldwide they represent the most widely used class of nuclear medicine products for the detection of cancer and cardio-vascular abnormalities at all.

Based in Buenos Aires, Tecnonuclear employs a staff of 60 and in 2021 booked revenues of about 10 million USD. Its products have already been distributed in the past by Eckert & Ziegler in Brazil, where they are sold, together with the generators, as consumables for single-photon emission computerized tomography (as the acronym SPECT is spelled out). Even though Tecnonuclear has managed to keep a substantial share of the value creation for SPECT biomolecules in-house, the company’s products, up until now, have not been sold outside Latin America.

The purchase price was primarily based on Tecnonuclear’s earnings power and completely paid out of Eckert & Ziegler’s cash flow. No third-party financing was involved in the transaction.

“Together with Eckert & Ziegler’s global network of productions sites, it’s financial resources and expertise in the production and marketing of radioisotopes, Tecnonuclear is ideally positioned to serve as an entry ticket into the global SPECT market”, comments Frank Yeager, the member of the Group Executive Committee at Eckert & Ziegler responsible for the SPECT business. “Our plan is to bring the technology developed in Argentina to patients anywhere in the world”.

“The acquisition allows us also to extend critical healthcare in Brazil, in line with recent government actions there, and throughout South America”, adds Claudia Goulart, CEO of Eckert & Ziegler’s Latin American operations. “This will make it possible to support the regional healthcare establishments in world class research, development and patient care”.

Currently about 25 million patients per year benefit from SPECT-diagnostics, bringing the global market to a volume of about 1.7 billion USD. With the advent of new proprietary SPECT tracers demand is projected to expand dynamically, surpassing a volume of about 2.7 billion USD in 2027. Except for a small sales volume in Brazil, Eckert & Ziegler currently has not been active in the SPECT segment.

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.
 

Source: Press Release EZAG
Eckert & Ziegler Acquires Argentinian SPECT Specialist

Research / 04.12.2021
How to fill a heart

Artificial heart tissue pulled onto plastic rods to measure its elasticity (Photo: M. Gotthardt, MDC)
Artificial heart tissue pulled onto plastic rods to measure its elasticity (Photo: M. Gotthardt, MDC)

Heart failure with preserved ejection fraction was previously considered largely untreatable. An MDC team led by Professor Michael Gotthardt has now succeeded for the first time in improving cardiac function with the help of a synthetic nucleic acid, as the researchers report in the journal Science Translational Medicine.

Patients with heart failure often have shortness of breath and become fatigued quickly. They frequently suffer from water retention, heart palpitations, and dizziness. The condition can be triggered by a combination of elevated blood pressure, diabetes, and kidney disease, or by acute events such as heart attacks or infections. As people age the number of adverse factors increase, so heart failure primarily affects older people, especially women.

Although the symptoms are similar, there are various causes. In one form of the condition the pumping function of the heart is impaired. This can however be improved with widely available medication. In the other form, the heart pumps with adequate force, but the chambers of the heart – the ventricles – fail to fill properly because the ventricular walls become thickened or stiff. There is currently no effective therapy for this form of heart failure. Together with colleagues from Heidelberg University and the California-based company Ionis Pharmaceuticals a team led by Professor Michael Gotthardt of the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) has now developed a therapeutic agent to improve the treatment of heart failure with preserved ejection fraction. The scientists have described their new therapeutic approach in the journal Science Translational Medicine.

The giant protein titin influences heart elasticity

The mechanics of the heart depend on an elastic giant protein called titin. It is produced by heart muscle cells in distinct variants or isoforms that differ in their flexibility. While very elastic titin proteins predominate in infants, later when growth and remodeling are completed, stiffer titin isoforms are produced to increase pumping efficiency. In heart failure with preserved ejection fraction, thickened heart walls, intercalated connective tissue, and stiffer titin filaments may lead to impaired filling of the ventricles.

Heart muscle cells are virtually unable to renew themselves in adults. Yet the constant pumping activity of the heart muscle puts such severe strain on titin that the worn-out proteins must be broken down and replaced every three to four days. “The mechanical properties of titin proteins are difficult to adjust,” says Gotthardt. “But we can now intervene in the process preceding protein synthesis – that is alternative splicing.” Alternative splicing is a clever trick that nature has devised to create a variety of similar proteins based on a single gene – including the different forms of titin. This process is controlled by splicing factors. “One of these, the master regulator RBM20, is a suitable target that we can address therapeutically,” explains Gotthardt.

Antisense agent deactivates RBM20

RBM20 determines the elastic, contractile, and electrical properties of the heart chambers. That it is indeed the decisive factor was shown in preliminary experiments with mice that, due to a deletion, can produce only half as much RBM20 as normal mice: In the deficient mice, there was a shift to more elastic titin isoforms. Together with the Ionis researchers, the scientists now began looking for a way to influence RBM20. “We were surprised at how easily this could be done,” says Gotthardt – namely with antisense oligonucleotides (ASOs). These are short chains of single-stranded nucleic acids that are synthetically produced. They bind specifically to the complementary RNA sequence, the blueprint of the targeted protein, thereby blocking its synthesis.

Dr. Michael Radke, a lead author of the study, first successfully tested the ASOs in mice with stiffer heart walls. His colleague Victor Badillo Lisakowski then grew heart muscle cells derived from human stem cells into artificial heart tissue. The tiny 3D structures can be stimulated to contract and relax when they encounter resistance, enabling them to mimic the pumping action of the heart. This artificial heart tissue also showed what effect the treatment had: The researchers were able to demonstrate that the ASO molecules actually penetrate the cells and trigger the desired response. “These tests on artificial heart tissue were an important step, because the primary sequences for titin are not identical in mice and humans,” says Radke.

A weekly injection?

For the first time, antisense oligonucleotides have been successfully used to therapeutically influence alternative splicing in cardiac disease. The Ionis researchers were able to stabilize the sensitive molecule in such a way that it reaches the striated muscles in the mouse model and is not already degraded in the blood, liver, or eliminated by the kidneys. Most of it winds up in the heart, with some entering the skeletal muscle. “In the mouse model, however, we observed that it has no disruptive effect if increased amounts of elastic titin are formed in skeletal muscle,” stresses Radke.

Heart failure is a chronic disease that requires long-term treatment. “So we treated our mice over a longer period of time and were able to see lasting treatment effects,” says Gotthardt. The therapeutic approach still needs some work, he says, adding: “An improvement over a weekly injection, which many patients are already familiar with from insulin or heparin, would be oral administration.”

Text: Catarina Pietschmann

Literature

Michael H. Radke et al. (2021): „Therapeutic inhibition of RBM20 improves diastolic function in a murine heart failure model und human engineered heart tissue“. Science Translational Medicine, DOI: 10.1126/scitranslmed.abe8952

Source: Press Release MDC
How to fill a heart

Research, Innovation, Patient care / 30.11.2021
Eckert & Ziegler Partners with University Health Network and CanProbe to Advance PENTIXAFOR Imaging Diagnostic Tool for Wider Application

Eckert & Ziegler Group is pleased to announce their partnership today with the Canadian Molecular Imaging Probe Consortium (CanProbe), a leader in the advancement and commercialization of novel radiopharmaceuticals to better serve patients and with the University Health Network (UHN), Canada’s largest health research organization affiliated with the University of Toronto. The partnership involves clinical research to further advance PentixaPharm’s Ga-68 radiodiagnostic tracer PENTIXAFOR in its detection of different tumour entities and other diseases.

The collaboration includes robust clinical exploration of the tracer in various applications and is set to include lymphoma, gynecological malignancies and lung cancer, as well as inflammatory conditions, all with the intent to further investigate the diagnostic potential of PENTIXAFOR and is set to include clinical trials with up to 300 doses administered. 

Developed by PentixaPharm, PENTIXAFOR is an innovative imaging agent targeting the chemokine-4 receptor (CXCR4) for the diagnosis of cancer patients with various haemato-oncological and solid tumour indications. The Ga-68-based PET radiodiagnostic is expected to significantly improve the treatment of patients suffering from these diseases.

Eckert & Ziegler (ISIN DE0005659700, TecDAX) and its subsidiary, PentixaPharm GmbH, are working with CanProbe and UHN to provide PENTIXAFOR to patients in Toronto. The intent is to provide further support toward the approval of PENTIXAFOR as a diagnostic agent for a portfolio of different indications. In the spring of 2021, Eckert & Ziegler already received permission from the European Medicines Agency (EMA) to launch directly into a Phase III clinical trial, enabling the company to save a number of time-consuming evaluation steps. Clinical trials are scheduled to begin next year and include about 500 patients worldwide.

"Given the great potential of PENTIXAFOR, a number of physicians worldwide have decided to test the radiodiagnostic on their own initiative. The data collected in this way will support our approval of PENTIXAFOR, commented Dr. Hakim Bouterfa, co-founder and CEO of PentixaPharm GmbH.

"The great interest in PENTIXAFOR from nuclear physicians, oncologists and haematologists confirms our strategy to push the clinical development of the Ga-68 based radiodiagnostic," explains Dr. Andreas Eckert, founder and CEO of Eckert & Ziegler AG.

"We are pleased to be working with PENTIXAFOR, as it is an imaging agent that potentially provides much clearer diagnostic images than can be achieved with conventional methods. We are hopeful that this will enable more targeted therapy options for patients,” comments Dr. Bruno Paquin, President of CanProbe. “We are delighted to see this partnership emerging between PentixaPharm, CanProbe, and UHN”, adds Luke Brzozowski, Senior Director, Techna and Diagnostics Innovation, University Health Network. “We are looking forward to seeing the results of the investigator-initiated studies at UHN with the tracer produced by CanProbe.”

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.

About CanProbe
CanProbe is a joint venture between the Centre for Probe Development and Commercialization (CPDC) and University Health Network (UHN) to create a Canadian Centre of Excellence for the development, translation, utilization and commercialization of radiopharmaceuticals. CanProbe leverages the strengths of its partners and their affiliates. www.canprobe.ca

About UHN
University Health Network consists of Toronto General and Toronto Western Hospitals, the Prin​cess Margaret Cancer Centre, Toronto Rehabilitation Institute, and The Michener Institute of Education at UHN. The scope of research and complexity of cases at University Health Network has made it a national and international source for discovery, education, and patient care. It has the largest hospital-based research program in Canada, with major research in arthritis, cardiology, transplantation, neurosciences, oncology, surgical innovation, infectious diseases, genomic medicine, and rehabilitation medicine. University Health Network is a research hospital affiliated with the University of Toronto. www.uhn.ca

Source: Press Release EZAG

Research / 19.11.2021
Genome folding in the mouse brain

The ultracryomicrotome can produce about 200 nm thick slices of brain tissues (Foto: Felix Petermann/MDC)
The ultracryomicrotome can produce about 200 nm thick slices of brain tissues (Foto: Felix Petermann/MDC)

A team led by MDC researcher Ana Pombo has deciphered the 3D structure of the genome in three cell types of the mouse brain. They not only discovered specific folding patterns but also found that very long genes almost completely lose their compact folded structure when most at work, as they report in “Nature”.

Warren Winick-Ng is working at the ultracryomicrotome, which can produce about 200 nm thick slices of brain tissues. The Pombo Lab processes these sclices for Genome Architecture Mapping. Photo: Felix Petermann, MDC

What happens in the brain when we learn something new? What happens when we develop an addiction or a neurological disease? Which genes spring into action in the brain cells at such moments? And how is the whole process regulated in the cell nucleus? These sorts of questions have been driving Professor Ana Pombo’s work for many years. The molecular biologist is the head of the Epigenetic Regulation and Chromatin Architecture 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). The current study by Pombo and her team, published in the journal “Nature”, has brought the scientists closer to answering to such questions.

3D maps of the genome

“After the human genome was decoded, it has become clear that only a very small part of the DNA actually contains the instructions for making proteins,” Pombo says. The other much larger part, she says, was initially considered superfluous and often dubbed ‘junk DNA’. “Yet it turns out that these mysterious regions of the genome contain the crucial information that regulates the activity of genes by direct spatial contacts with them or by influencing their position,” the researcher explains.

To learn more about these tiny switches that turn genes ‘on’ and ‘off’, Pombo and her team developed a technique called genome architecture mapping, or GAM for short, which they described in “Nature” in 2017. The technique creates 3D maps of the entire genome and uses statistical calculations to determine which sections of the genome prefer to connect with each other – in other words, the locations of the switches that regulate each gene.

Investigations performed directly in the cells

For their current study, led by Dr Warren Winick-Ng, they applied the GAM technique in combination with a procedure called immunoselection. They labelled three different cell types from the mouse brain to specifically assess their 3D chromatin structure. The cells investigated included two types of neurons and a specific type of glial cells that support and insulate the long projections of neurons.

The researchers also compared the spatial chromatin structure in these three very specialized cell types with that in embryonic stem cells, the latter which have yet to take on a specific cell lineage. “A major advantage of combining immunoselection with the GAM technique is that we can study all cells in their native tissue environment without having to remove them from their tissue context,” Winick-Ng explains.

Like the buds of a flower

“It was very exciting for us to discover that the folding of the DNA strands and the contacts between the individual genome elements, both on a large and small scale, are each highly specific in the different mouse brain cells,” lead co-author Dr Alexander Kukalev recounts. The researchers found particularly characteristic folding patterns in genes that are only transcribed and translated into proteins in one of the cell types studied. “We also came across contacts between genomic segments that are located really far apart in the chromosome,” Pombo reports. Together with colleagues from Ohio University’s Bioinformatics Lab, they searched for patterns in the contacting regions.

She says: “We discovered a small set of genomic ‘word pairs’ that appear within the neuron-specific contacts, bringing us closer to understanding the underlying molecular mechanisms, which we plan to study next.”

But what surprised the Pombo team most was the observation in all three cell types that very long genes, which can give rise to many different proteins, almost completely lose their compact folded structure during the transcription process. “They blossom like a flower bud,” is how Pombo describes the phenomenon. This has not been seen before using sequencing-based approaches, she says, adding that completely different genetic material “blossomed” depending on the brain cell type. Together with Professor Mario Nicodemi, Einstein-BIH Visiting Fellow hosted at the Pombo lab, they used polymer modelling to visualize the remarkable events. “Our discoveries are relevant because many of these long neuronal genes are associated with neurodevelopmental and neurodegeneration diseases like epilepsy or autism spectrum disorder,” says lead co-author Izabela Harabula.

Understanding ALS better

Genetic neurological diseases also stem from changes in the sequence of the genome itself, which can affect either protein-expressing genes or, more often, the genetic elements that regulate their expression. “It is very difficult to understand what these variations actually mean and how they ultimately lead to disease, because they often occur in the non-coding, ‘dark matter’ regions of the genome, which is actually the vast majority of the whole genome,” Pombo says. That is another reason that Pombo and Winick-Ng are excited about using their newly developed methods to examine brain tissue from deceased patients with amyotrophic lateral sclerosis (ALS), which they have received from Berlin’s Charité research hospital, in collaboration with Professor Frank Heppner and Dr. Helena Radbruch. This research is being made possible by collaborative funding from the NeuroCure Cluster of Excellence.

“Now that we have established our methods in mice, we can begin large-scale mapping of the 3D genome in human samples,” Winick-Ng says. Since each ALS patient has numerous variations in their genome sequence, they need to analyze tissue from multiple patients. “That’s the only way,” the researcher says, “we can understand the relationship between genetic variations that play a key role in the disease and the many changes in 3D chromatin structure we are likely to identify.”

Text: Anke Brodmerkel

Photo: Warren Winick-Ng is working at the ultracryomicrotome, which can produce about 200 nm thick slices of brain tissues. The Pombo Lab processes these sclices for Genome Architecture Mapping. Photo: Felix Petermann, MDC

Source: Press Release MDC
Genome folding in the mouse brain