News

Research / 16.09.2022
Inhibitor of lipid kinase PI3KC2α identified as potential new treatment of thrombosis

Visualization Barth van Ross
Visualization Barth van Ross

 The lipid kinase PI3KC2α is a potential pharmacological target for the treatment of thrombosis and, possibly, cancer. Researchers from the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) have now identified a potent inhibitor of its activity that serves as a lead for further drug development.

Thrombosis including venous thrombosis and pulmonary embolism with an annual incidence of about 1 in 1,000 adults is a major threat for human health, in particular at old age. To counteract blood clotting, patients take blood thinning medication, which, however, often display severe side-effects such as bleeding (hemorrhage). The lipid kinase PI3KC2a has been found to potently modulate thrombosis by regulating the function of blood platelets that are at the heart of initiating the blood clotting mechanism e.g. in response to high blood pressure or atherosclerosis. PI3KC2a, thus, is a powerful target for the development of novel anti-thrombotic drugs. However, so far no specific inhibitor of PI3KC2a has been described.

Dr. Wen-Ting Lo from the research group of Prof. Volker Haucke in close collaboration with medicinal chemist Dr. Marc Nazaré and his team, researchers from Toulouse, and the Screening Unit of the FMP (led by Dr. Jens Peter von Kries) now has developed and characterized the first PI3KC2a inhibitors. As a result of extensive chemical optimization studies the researchers succeeded to tweak the selectivity of the inhibitors over the entire kinome, in particular against all other lipid kinases. One of these compounds termed PITCOIN3 displays particularly striking selectivity for PI3KC2a and is shown to potently impair platelet membrane remodeling and thrombus formation.

"This breakthrough development has only been possible because of our earlier structural studies on PI3KC2a", comments Dr. Lo, the first author of the study just published in Nature Chemical Biology. Dr. Nazaré adds “that the unexpected non-classical binding mode of the PITCOIN inhibitors reveals a promising new blueprint for the development of related drug leads. The PITCOINs may also be important tools to help other researchers to probe and uncover unknown functions of PI3KC2a”.

"The antithrombotic effect of the PITCOIN inhibitors counteracts thrombosis via effects on the internal membrane structure of platelets, not by blocking their activation, thereby opening an improved therapeutic window" highlights Prof. Haucke.

The reported findings could open new possibilities for the treatment of thrombosis and cancer, as demonstrated by the ability of PITCOINs to interfere with the migration of breast cancer cells in vitro.

www.fmp-berlin.de

Research / 14.09.2022
Dense and permeable: molecular organization of tight junctions decoded

Nanoscale Meshwork formed by segragating Claudin 2 (yellow) and Claudin 10a (mangenta) was visualized by STED microscopy with 20nm pixel size (Picture: FMP)
Nanoscale Meshwork formed by segragating Claudin 2 (yellow) and Claudin 10a (mangenta) was visualized by STED microscopy with 20nm pixel size (Picture: FMP)

They seal epithelial cells and, under certain conditions, allow the passage of ions and water: Tight junctions form a paracellular barrier in tissues and their dysfunction is associated with diseases ranging from pulmonary edema to inflammatory and meatbolic disorders. Although their molecular components have been known since the 1990s, it is not apparent how the 26 proteins called claudins are organized. Scientists from the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) have now gained deep insights into the structure of tight junctions, using super-resolution stimulated emission depletion (STED) microscopy. It is the first time that the basic mechanism underlying all epithelial barrier properties has been described. The results of the study have been published in the renowned journal “Nature Communications”.

Tight junctions (TJ) are normally excellent at enabling the passage of necessary ions or molecules, while forming a dense barrier to prevent unwanted bacteria and their toxins from entering the body. These paracellular barriers, which can simultaneously be selective ion and water channels, are found wherever epithelial cells or endothelial cells meet, i.e. where different tissues are connected to each other or when the lumen of an organ needs to be sealed from the blood stream.

The existence of tight junctions was discovered some 60 years ago, and their main molecular components have been known for 30 years: 26 membrane proteins called claudins. Depending on the cell, claudins are organized in various constellations to form semi-permeable meshworks up to several hundred nanometers wide. Usually, multiple claudins come together, but some barriers consist of just one or two structural proteins.But the question is, how are claudins organized so as to create different barrier properties depending on the cell or tissue in question? And, to what extent do claudins depend on each other in the process? Until now, these questions have remained unanswered because it was impossible to see through the structure of strands, which are only about ten nanometers thick. Now scientists from the FMP have succeeded in doing just that using STED microscopy.

“This type of super-resolution microscopy and an excellent team of cell biologists, computer scientists and physiologists have helped us to shed light on the molecular architecture of tight junctions,” remarked Dr Martin Lehmann, head of the Cellular Imaging Group last author of the study. “We have now been able for the first time to describe the mechanism underlying the main epithelial barrier properties.”

Using STED to resolve single meshworks

Normally, the resolution of fluorescence microscopes is limited to about 250 nanometers. Using STED microscopy, 50 nanometers or less are possible. This literally gave the researchers greater insight. “With standard fluorescence microscopy, we would never have penetrated the dense organization of the tight junction, but STED has enabled us to resolve the individual meshes of the network. As a result, we are now able to determine the exact position of proteins, as well as to see whether claudins intermix or separate, and how they segregate,” states Hannes Gonschior, the first author of the study, who conducted his PhD thesis on the topic at the FMP. “This nanoscale organization was previously unknown.”

First, the studies were carried out at the cellular level, and then in intestinal and kidney tissue of mice. Striking images reproduced the fluorescently labeled proteins in different colors, showing where which proteins are located and how they chain together to form a colorful zipper.

Three findings from the study, now published in Nature Communications, are of particular note:

First: Claudins seal intercellular spaces for ions and small molecules – much like a zipper. These seals are selectively ion-permeable, depending on the tissue and composition of the tight junction.
Second: One in two claudins are unable to polymerize into strands. They are reliant on other team members to form and “functionalize” a tight junction.
Third: Claudins interact with each other in five organization principles. This means that there are five different ways, in which they can intermix or segregate.

Creation of model for drug discovery

The fact that FMP researchers have been able to determine the nanoscale organization of tight junctions for the first time is a major success for basic research. But medicine can also benefit from the breakthrough. This is because mutations in claudins play a role in a number of hereditary diseases, the most obvious one being the HELIX syndrome – a rare condition causing reduced sweat production. A mutation in claudin 10b is the culprit, causing hypohidrosis, and lacrimal and salivary gland defects, as well as impaired calcium and magnesium regulation in the kidney. The team of researchers had also experimented with this disease mutant.

“Our research is still a long way from having clinical relevance,” stated biophysicist, Martin Lehmann, assessing their findings. “But at least now we understand how these meshworks are structured. This is the first step, which will allow us to search for small molecules that open or close these barriers.”

Cell biologist Hannes Gonschior added: “We have found a simplified model for drug discovery and, more generally, conducted research into the paracellular passage of ions. It is very likely that our findings will enable us to understand previously unexplained clinical phenotypes and symptoms – with a defect in one of these particular paracellular barriers.”

Publication

Gonschior H, Schmied C, van der Veen RM, Eichhorst J, Himmerkus N, Piontek J, Günzel D, Bleich M, Furuse M, Haucke V, Lehmann M. Nanoscale segregation of channel and barrier claudins enables paracellular in flux Nat Commun 13, 4985 (2022) doi.org/10.1038/s41467-022-32533-4

www.fmp-berlin.de

Research, Innovation, Patient care / 05.09.2022
Million euro support for MyoPax

Picture: Eric Metzler, Scientist of the MyoPax GmbH
Picture: Eric Metzler, Scientist of the MyoPax GmbH

MyoPax, a new spin-off of the Max Delbrück Center and Charité, receives a 1.3 million euros loan to jump-start its entrepreneurial activities. The start-up develops regenerative therapies for previously incurable muscle diseases using its innovative muscle stem cell technology.

The BioInnovation Institute Foundation (BII) in Copenhagen, Denmark, announced that it will be supporting three international start-up companies from Germany, the UK, and Finland. The ventures are strategically aligned with the incubator’s focus, developing ground-breaking scientific initiatives across the therapeutics and health tech space.

MyoPax: Website

MyoPax is one of the three life science spin-offs. It builds on cutting-edge technologies developed by scientists at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (Max Delbrück Center) and the Charité – Universitätsmedizin Berlin. MyoPax was founded by the medical doctor Verena Schöwel-Wolf and Professor Simone Spuler, who leads the muscle research group and the Outpatient Clinic for Muscle Disorders at the Experimental and Clinical Research Center (ECRC), a joint institution established by the Max Delbrück Center and Charité on the campus in Berlin Buch. Now, the start-up has three employees and is taking its first steps on an international level.

Repair muscle function

MyoPax’ mission is to develop advanced regenerative therapies to fight the devastating consequences of muscle diseases. Their pioneering technology combines cell and gene therapy to repair muscle function.

The spin-off is based in Berlin and Copenhagen and originates from the translational ecosystem of the Max Delbrück Center, the Charité and the Berlin Institute of Health at Charité (BIH). In the lead-up to spin-off launch, both the Max Delbrück Center and the BIH have closely supported MyoPax. To make the leap from the lab to clinical use possible, the Max Delbrück Center facilitated the development of the project in the ERDF-funded Pharma Incubator with its programs PreGoBio and SPOT. The BIH accelerated the spin-off activity via its Spark program. Furthermore, the German Federal Ministry of Education and Research (BMBF) and the Helmholtz Validation Fund (HVF), provided optimal support for the first-in-human clinical trials at Charité with around five million euros to proof safety and efficacy of the investigational drugs developed with the new technology

Guided to a competitive international level

Like the two other companies, MyoPax will now be funded with a risk-free convertible loan of 1.3 million euros and is going to be part of the BII’s community of life science start-ups. In collaboration with the BII team and its network of experts, the three companies will be guided to a competitive international level, receiving support in the roll out of detailed development plans concerning drug development, good manufacturing practice and regulatory strategy, ahead of a Seed or Series A financing round.

Thomas Sommer, Scientific Director of the Max Delbrück Center (interim) said: "We are very pleased for MyoPax to receive this support. Based on the research at Max Delbrück Center and ECRC, important new therapeutic approaches are being advanced here. Muscle diseases are common and have multiple causes. Unfortunately, the prospect of finding a cure is so far low. Stem cell technologies could help alleviate this."

Verena Schöwel, CEO of MyoPax, added: “We thank BII for placing their trust in MyoPax. We are looking forward to a fruitful collaboration. With operational locations in Berlin and Copenhagen, we are integrated in two excellent ecosystems to develop MyoPax and achieve our mission of translating cutting-edge science into regenerative therapies for muscle diseases.”

The two other ventures

Sevenless Therapeutics: Using state-of-the-art mathematical methodology, this next generation biotech company has identified a novel target in pain signaling, defined the properties required for success and validated these predictions with data. Enabled by this insight, their highly experienced drug discovery team will efficiently deliver a safe and effective drug candidate for treating pain. This discovery will make a significant difference to the many patients suffering from inadequately treated chronic pain.

VEIL.AI: A company that brings the quality of anonymized health data to a new level with next-generation anonymization technology creating extremely high-quality subject-level anonymized and synthetic data. It enables better use of GDPR-free data for life science and diagnostics companies, hospitals and health data hubs.

Text: BII / MDC

 

Further information

Spuler Lab
Myology

 

MAX DELBRÜCK CENTER

The Max Delbrück Center for Molecular Medicine in the Helmholtz Association (Max Delbrück Center) is one of the world’s leading biomedical research institutions. Max Delbrück, a Berlin native, was a Nobel laureate and one of the founders of molecular biology. At the locations in Berlin-Buch and Mitte, researchers from some 70 countries analyze the human system – investigating the biological foundations of life from its most elementary building blocks to systems-wide mechanisms. By understanding what regulates or disrupts the dynamic equilibrium in a cell, an organ, or the entire body, we can prevent diseases, diagnose them earlier, and stop their progression with tailored therapies. Patients should benefit as soon as possible from basic research discoveries. The Max Delbrück Center therefore supports spin-off creation and participates in collaborative networks. It works in close partnership with Charité – Universitätsmedizin Berlin in the jointly run Experimental and Clinical Research Center (ECRC), the Berlin Institute of Health (BIH) at Charité, and the German Center for Cardiovascular Research (DZHK). Founded in 1992, the Max Delbrück Center today employs 1,600 people and is funded 90 percent by the German federal government and 10 percent by the State of Berlin.

www.mdc-berlin.de

 

THE BIOINNOVATION INSTITUTE FOUNDATION

The BioInnovation Institute Foundation (BII) is an international commercial foundation with a non-profit objective supported by the Novo Nordisk Foundation. BII operates an incubator to accelerate world-class life science innovation. Our vision is to support world-class life science innovation that drives development of new solutions by early life science start-ups for the benefit of people and society. With continued positive development, The Novo Nordisk Foundation can provide up to EUR 470 million (3,5 mia. DKK) to BII over ten years. The BII has supported 62 start-ups with EUR 50 million in funding. The BII’s start-ups have in total raised EUR 207 million from local and international investors. Its diverse team brings venture capital, pharma and business expertise together to help early-stage companies accelerate to the next level. Recent company successes include Adcendo, Stipe Therapeutics, Twelve Bio, Octarine Bio, and Cirqle Biomedical

Research, Innovation, Patient care / 02.09.2022
With patience and a green thumb

Blumenrabatten auf dem Campus Berlin-Buch (Foto: Campus Berlin-Buch GmbH)
Blumenrabatten auf dem Campus Berlin-Buch (Foto: Campus Berlin-Buch GmbH)

Viola Ehrig is the green-thumbed gardener who works hard to ensure it’s not only science and innovation that flourish at the Berlin-Buch campus, but trees and flowers as well. She and her colleague Steve Kossack provide stimulating surroundings for everyone at the science campus, including employees of the MDC.

When she hears the crows kicking up a fuss at 4 a.m., Viola Ehrig knows the raccoon must be coming home. “I don’t yet know where it lives, but there’s certainly one hanging out around here,” she says. The gardener has worked for Campus Berlin-Buch GmbH since 2013; she and her colleague Steve Kossack are responsible for the green areas here on the campus.

In the summertime, Ehrig and Kossack’s working day begins as early as three or four o’clock in the morning. They load spades, shovels, rakes, hoses, and more onto their truck and then head out to where they are needed. The flowerbeds and trees must be watered in the early hours of the morning as there isn’t sufficient water pressure later in the day. And on hot days the moisture would immediately evaporate. It takes around two to three hours to give all the plants a drink. “A single tree needs as much as 120 liters,” says Ehrig.

Trees instead of graves

With grounds totaling 32 hectares, the Berlin-Buch campus recalls the expansive parkland of a manor house. Although a place of science, the campus is also an oasis on the edge of one of Europe’s biggest cities. Paths wind their way through the numerous green spaces between the research and administrative buildings. There are numerous trees and flowers, and the occasional sculpture. At one time, this site was intended to be a cemetery. Berlin’s Director of Public Gardens from 1910 to 1924, the landscape architect Albert Brodersen, planned to establish the “Buch-Karow Municipal Central Cemetery” here. The gatehouse, a service building (today’s Building A15, the Life Science Learning Laboratory), and a chapel had already been constructed when the discovery was made that the site’s water table was too high to bury bodies. So in 1925 a tree nursery opened here instead. Two Doric columns can still be seen where the chapel once stood, before it was demolished in the 1950s to make way for Walter-Friedrich-Haus (Building C27), and remnants of the tree nursery include the campus woodland and individual trees of unusual species for these parts – black locust, Canadian hemlock, cedar, and Jerusalem thorn.

Ehrig is acquainted with every single one. She knows when which trees were felled and when others were planted; where the deer graze at night; and where the two swarms of goldfinches that swoop across the campus like to spend their time – the answer is on the pile of chippings between the bike workshop and the gardeners’ office. Next to Building D23, which belongs to medical technology company Eckert & Ziegler, a large species of thistle is blooming. “Last year it was on the other side of the road,” says Ehrig. “Now it has spread over here. And of course we’ll leave it to grow.” The bushy purple flowers are a good food source for birds and insects. And thistles cope well in dry conditions.

A feast for the eyes – and the bees

Thistle do nicely! The prickly beauties perfectly fulfill the requirements of appropriate campus plants. These shouldn’t just be nice to look at; they should also help provide a good home for insects and other creatures. And they should be able to cope with increasingly warm summers. Outside Building D85 (Arnold-Graffi-Haus), the headquarters of Campus Berlin-Buch GmbH, and Building D82 (Karl-Lohmann-Haus), Ehrig and Kossack have laid out borders that are appealing to humans and insects alike. Here, day lilies bloom alongside phlox, lavender, sage, coneflowers, and hollyhocks. The colorful, fragrant flowers attract bumblebees, hoverflies, and butterflies as well as wild bees – and probably the campus’s very own honeybees, too! The hives outside the Life Science Learning Laboratory are home to two bee colonies. During school vacations, children can attend special “Bee Days” at the lab and learn all about the busy lives of bees and their crucial role in nature – as well as harvesting their own honey.

Our six-legged friends can also enjoy a veritable cornucopia outside Building D79 (Erwin-Negelein-Haus). Students at Eberswalde University for Sustainable Development planted a wildflower meadow here that includes wild strawberries, wild carrots, cornflowers, wild basil, motherwort, lesser burnet, and greater yellow-rattle. The seeds for the plants came from the Wildsamen-Insel in Schorfheide, a heath north of Berlin and west of Eberswalde. The meadow project is slated to last for five years, with ongoing scientific observation and analysis. The students are observing how the various plants reproduce and spread. “Our ideas of beauty must be redefined,” says Claudia Lühr, head of Campus Berlin-Buch’s facility management team. Carefully laid-out lawns and symmetrical rosebeds should now be consigned to the past. However, we don’t want to do without lawns entirely, as they are the perfect place for campus employees to relax and unwind. “Special events like barbecues or even just lunch breaks require mown surfaces,” says Lühr. “But we have to carefully consider where we can let nature take its course and where we intervene.”

Replenishing felled trees

During the 40 years of the German Democratic Republic, little work was invested in the campus woodland. It might sound good to let nature run wild, but it actually caused problems. “The trees are too close together,” says Ehrig. This is a remnant of the old tree nursery. Because springtime is getting warmer, the trees are sprouting leaves earlier in the year, which ultimately weakens them. After decades of neglect, many of the woodland trees are suffering from fungal infections and white rot. And oak processionary caterpillars are causing problems for the older oaks. “Sometimes you have to fell a tree or two,” says Ehrig.

Pankow’s environmental authorities regularly inspect the woods to ensure that the chainsaws aren’t employed too hastily. Dr. Christina Quensel, Managing Director of Campus Berlin-Buch GmbH, tells us that all landscaping work is carried out in close consultation with Eberswalde University for Sustainable Development and the Pankow Environment and Nature Conservation Office. “We have to get the office’s permission before a single tree can be felled, and for each one chopped down a new one has to be planted.”

“When we want to redesign an area of the grounds, we first present the plans to the campus management team,” Quensel continues. “Then a vote is taken involving representatives of every organization.” When some trees by Building B54, one of the guesthouses, were cut down because they were rotten with age and represented a danger, the group decided that a wetland biotope should be established in their place. Rainwater from the guesthouse roof and the road had always had a habit of gathering there. And so the depression in the ground was hollowed out further and lined with gravel so that the water wouldn’t seep away in the sandy soil. A small pond formed, which Ehrig and Kossack planted with bulrushes, yellow irises, and moneywort. Beside it they laid out a wildflower meadow, which is now home to cherry and pear trees as well as some rhododendron bushes.

Patience, the gardener’s greatest virtue

The poplars outside Building C32 (Max-Delbrück-Haus) also had to be felled after they began dropping deadwood and the roots were found to have infiltrated pipes and cable ducts. They, too, have to be replaced – preferably with trees from the “future trees list” drawn up by GALK, the association of German park managers. GALK currently recommends 65 tree species that are particularly resistant to drought, heat, frost, and pests. One species on the list is the catalpa; some of these were planted outside the campus cafeteria three years ago. Others are Juneberry, sweetgum, and mulberry. These are set to flank the BerlinBioCube once it is built. Tulip trees are another “tree of the future.” One is now growing alongside three trumpet trees. “In ten years or so it will have a dense crown full of tulip-shaped blossoms,” enthuses Ehrig. “It’s awesome. And all we need is a little patience.”

Patience will also be required when it comes to the princess tree that is growing in the courtyard of Building D9. When it reaches six to ten years old, in the spring it will sprout enchanting violet-blue blossoms that grow in upright clusters, rather like flowering horse-chestnut trees, and emit an intoxicating scent reminiscent of vanilla. The walls of the building protect the tree, providing good conditions for its growth. “Berlin’s continental climate is actually a little too cold for her,” says Ehrig, as if speaking of a dear friend. She has plenty to say about – and to – all her leafy friends here. When she whispers words of encouragement to them, it’s as if the plants perk up before our very eyes.

One person’s weeds are another’s heroes

Sadly, no amount of encouraging whispers will work for the plants by the artwork outside the Berlin Ultrahigh Field Facility (Building B88). Here, under a canopy of conifers, are narrow flowerbeds lined with metal edging, where mint and caraway are slowly wasting away. They are part of a sculpture by artist Ulrike Mohr, which stands outside the MDC’s Building 89 (Max-Rubner-Haus). The sculpture represents the molecular structure of carvone, a chemical found naturally in many essential oils, most abundantly in caraway and spearmint. “It’s a great idea,” says Ehrig. “But unfortunately mint and caraway have little chance of thriving in the shade of conifers.” What’s more, the plants regularly disappear from the beds. “Some people must be digging them up,” she says, shaking her head in disbelief. 

What’s her favourite plant? She can’t answer that question; there are too many. “I love orderly chaos,” says Ehrig. She’s particularly fond of unassuming wild plants, the quiet heroes in a patch of garden. They help perennials to grow by casting shade and keeping the soil moist for longer. But now it’s time for Ehrig to leave the meadow outside Building C84, where a red squirrel is scampering merrily across the grass, and head back to the gardeners’ office. She has to draw up plans for tomorrow, which once again begins at dawn, just before the deer retreat into the undergrowth.

Text: Jana Ehrhardt-Joswig 

Source: MDC
With patience and a green thumb

 

Research / 01.09.2022
How new structures evolve

Mammals possess a novel gene that controls a novel structure in nerve cells. Researchers at the Max Delbrück Center and the Milner Centre for Evolution have discovered it and describe it in the journal „Molecular Biology and Evolution”.

Evolution is often portrayed as a “tinkering” process, one that makes use of slight modifications to pre-existing capabilities.  So how do organisms evolve brand new structures?

A new study by Dr. Zsuzsanna Izsvák from the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (Max Delbrück Center) and Professor Laurence Hurst from the Milner Centre for Evolution at University of Bath (UK) found evidence that evolution of a new gene underpins the evolution of a new structure found in nerve cells. They describe this unusual gene called piggyBac Transposable Element-derived 1, or PGBD1, in the journal “Molecular Biology and Evolution”.

“Jumping genes” cause mutations

PGBD1 is one of five related PGBD genes that shows a distinct resemblance to the piggyBac element first identified in insects – hence the name piggyBac Transposable Element-derived. The PiggyBac elements are “jumping genes”, also called transposons. They are able to copy themselves and to move from one location in the genome to another, sometimes introducing mutations or changing functions. PiggyBac transposons arrived into our species by horizontal transfer – similar to how some viruses can integrate their genome into our DNA. However, while the piggyBac transposons have lost their ability to jump around in our DNA over time, five piggyBac Transposable Element-derived genes (PGBD1-5) have been fixed in humans. “We aimed at finding out what potentially useful function the PGBD genes might have,” says Zsuzsanna Izsvák. “For this study, we focused on PGBD1.”

Amongst the five PGBD genes PGBD1 is unique in that it has also incorporated parts of other genes, resulting in a protein that has extra parts that are able to bind other proteins and to bind DNA. PGBD1 is thus a novel gene that is part human gene fragment, part inactive jumping gene.

PGBD1 regulates nerve cells and their “protein traps

PGBD1 is found only in mammals. It is particularly active in cells that become neurons. The researchers first investigated, where PGBD1 protein binds to DNA, observing that it glues itself in and around genes associated with nerve development. They found PGBD1 controls nerve cell development by blocking genes expressed in mature nerve cells while keeping those genes associated with being pre-nerve cells activated. Reducing the level of PGBD1 in pre-nerve cells caused them to start developing as nerve cells.

One of the genes that PGBD1 protein binds especially attracted their interest. NEAT1 is a strange gene that codes for an RNA which, unusually, doesn’t then go on to make a protein. Instead, this product, a non-coding RNA, makes the backbone of a physical structure, the paraspeckles. These are tiny structures in the nuclei of some of our cells that act like traps for some RNAs and proteins. The researchers found that in pre-nerve cells PGBD1 protein binds to the NEAT1 gene and stops it from working.  However, when PGBD1 levels go down, NEAT1 RNA levels go up, paraspeckles form and cells become mature nerve cells. PGBD1 thus has evolved to be a key regulator of presence or absence of paraspeckles, and thus the regulator of nerve cell development.

Evolution is not random tinkering

What, however, is most intriguing is that paraspeckles are, like PGBD1, also mammal-specific. PGBD1 is then a rare example of a new gene that has evolved to regulate a new structure, albeit a rather small one. Zsuzsanna Izsvák, co-senior author from Max Delbrück Center,  says: “This is a really unusual and serendipitous discovery. We have known that duplication of pre-existing genes can underpin the evolution of novelty, but this is a rare example of evolution doing more than just tinkering. This is a novel gene to control a novel structure.” The exciting question now is whether it also plays a role in adult neurons.

Co-senior author Professor Laurence Hurst of the Milner Centre for Evolution at the University of Bath adds: “We have worked out how paraspeckles are controlled, now we just need to work out how the paraspeckle itself evolved. This might be a much harder task as non-coding RNAs like NEAT1 tend to be fast evolving and therefore hard to trace over evolutionary time.”

This coupling between NEAT1 and PGBD1 may also be involved in schizophrenia. While NEAT1 has been previously associated with this neurological disease, the team identified some mutations in PGBD1 that they could show were also common in patients with schizophrenia – one of these mutations changes the protein of PGBD1 while others may control its level. First author Dr Tamas Raskó, at the time of the study a postdoctoral researcher in the group of Zsuzsanna Izsvák: “It is surely more than coincidence that both genes are involved in schizophrenia.  It is very unusual to find a mutation that changes a protein that is coupled to this disease.  The effects of this mutation must be a priority for further studies.”

Source: Joint press release of the Max Delbrück Center and the University of Bath
How new structures evolve

 

Research, Innovation, Patient care / 17.08.2022
Made in Berlin - Senator of Economics Schwarz visits Campus Buch

Dr. Ulrich Scheller, Senator of Economics Stephan Schwarz, Michael Biel and Dr. Christina Quensel in front of the Start-up Center BerlinBioCube (Photo: Peter Himsel)
Dr. Ulrich Scheller, Senator of Economics Stephan Schwarz, Michael Biel and Dr. Christina Quensel in front of the Start-up Center BerlinBioCube (Photo: Peter Himsel)

Berlin's Senator for Economics Stephan Schwarz joined State Secretary Michael Biel on August 17, 2022 to learn about the economic development of the Berlin Buch Science and Biotech Campus. During his tour, he also spoke with researchers from the MDC and ECRC about their spin-off projects.

Berlin-Buch is one of the eleven “Zukunftsorte” in Berlin with a high potential and space for innovation. On the biomedical research campus, excellent scientists from all over the world are working on the medicine of the future. In the BiotechPark Berlin-Buch, spin-offs from campus research institutions demonstrate how science can be turned into business.

As part of the "Made in Berlin" company tour, Stephan Schwarz, Senator for Economics, Energy and Public Enterprises of the State of Berlin, visited successful companies at the BiotechPark together with State Secretary Michael Biel on August 17, 2022 and learned about promising spin-off projects of research teams at the Max Delbrück Center for Molecular Medicine (MDC).

Close network for health

For decades, research and healing, invention and therapy have been combined at the health location Berlin-Buch. Here, established companies work alongside start-ups in the life sciences, and teams of doctors and researchers work hand in hand. Internationally renowned research institutions such as the 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 initial spin-offs in the early 1990s, the campus is now one of the largest biotech parks in Europe. With a clear focus on biomedicine, it covers the entire value chain from discovery and development to the production of marketable innovations and has outstanding growth potential.

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. "Quite decisive for the economic success of our campus is the close connection between basic and clinical research, state-of-the-art technology platforms and the goal of bringing biomedical findings into application," said Dr. Christina Quensel, managing director of the campus' operating company.

A visible sign of the ongoing growth is the construction of the BerlinBioCube, a new incubator center in the BiotechPark. The "BerlinBioCube" will open in 2023 and offer 8,000 square meters of state-of-the-art laboratory and office space for start-ups in biotechnology, medical technology and related fields. When it is completed next year, around 30 startups will be able to begin operations and create up to 400 jobs. Dr. Ulrich Scheller, managing director of Campus Berlin-Buch GmbH, and Dr. Quensel informed the visitors about plans for the expansion of the campus, the extension of the BiotechPark to approximately 9 hectares in the immediate vicinity, in order to enable the expansion of local companies and additional settlement of biotech companies.

Made in Berlin - Made in Buch

The program included a visit to the laboratories of T-knife, a spin-off of the MDC together with the Charité. T-knife, whose technology for novel immunotherapies against cancer is based on decades of basic research at MDC, is one of the most successful start-ups in the biotech scene. The young company is able to modify the patient's T-cells so that they can identify cancer cells as invaders. T-knife's goal is to cure cancers with the help of genetically modified immune cells. In 2021, T-knife raised $110 million from international investors.

The second stop led to emp Biotech GmbH. The company was founded in 1993 and was among the first in the BiotechPark. Strongly grown, emp Biotech is now a leading manufacturer of reagents for oligonucleotide synthesis, fine chemicals and chromatography materials – products for the early phase of research and development up to large-scale production in the pharmaceutical and biotechnology industries.

MDC Board of Directors: we support spin-offs

At the Max Delbrück Center, Scientific Director Professor Thomas Sommer (acting) and researchers PD Dr. Uta Elisabeth Höpken and Dr. med. Verena Schöwel-Wolf presented two promising spin-off projects. Uta Höpken's research group is using designer immune cells to develop a cellular immunotherapy that can combat leukemias and lymphomas more specifically. The start-up project MyoPax of the MDC-Charité team of Prof. Simone Spuler, presented by Dr. Schöwel-Wolf, uses its innovative muscle stem cell technology to develop regenerative therapies for previously incurable muscle diseases.  "At the MDC, we systematically support such innovative projects and spin-offs. We want to bring our research to patients quickly and in this sense encourage an entrepreneurship culture," said Thomas Sommer.

Finally, Economics Senator Schwarz and State Secretary Biel visited Eckert & Ziegler Strahlen- und Medizintechnik AG, which also has its origins on campus and is now one of the largest suppliers of isotope technology components for nuclear medicine and radiation therapy with more than 900 employees. The company offers services for radiopharmaceuticals at its worldwide locations, from early development to commercialization, and is listed on the SDAX of the German Stock Exchange.

In conclusion, Senator Stephan Schwarz said, "I am fascinated to have this biotechnology and life science location in Berlin. It is certainly one of the drivers of economic development."

Innovation / 11.08.2022
Eckert & Ziegler with Successful First Half of 2022

11.08.2022 / Eckert & Ziegler Strahlen- und Medizintechnik AG (ISIN DE0005659700, SDAX) increased sales by 19% to EUR 106.8 million in the first half of the year. At EUR 15.4 million, net income was down on the same period of the previous year, in which the sale and associated deconsolidation of the tumor irradiation device division generated exceptional income of approximately EUR 9.4 million. Adjusted for this one-off effect, consolidated net income attributable to EZAG shareholders increased by around 20% year-on-year from EUR 12.8 million to EUR 15.4 million. Higher sales of industrial products and radiopharmaceuticals as well as favorable exchange rates contributed to this growth in earnings.

The Isotope Products segment generated sales of EUR 68.2 million, an increase of EUR 17.9 million (36%) compared with the first six months of 2021. Almost all main product groups contributed to this good performance, in particular the industrial components and recycling business. Around EUR 4.7 million of the increase was due to the acquisition of the Argentine company Tecnonuclear SA. EUR 3.7 million was due to a favorable US dollar exchange rate.

In the first half of the year, revenue in the Medical segment was at the previous year's level of EUR 41.7 million. However, considering the loss of sales of EUR 1.1 million due to the deconsolidation of the tumor irradiation device business, the level of sales increased slightly compared to the previous year.

The results for the first half of the year are in line with the expectations of the Management Board. For the financial year 2022, the Management Board expects sales of around EUR 200 million and net income of around EUR 27 million. This forecast is subject to the assumption that 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/euz222e.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 SDAX index of Deutsche Börse.
 

Source: Press Release EZAG
Eckert & Ziegler with Successful First Half of 2022

Research / 24.07.2022
Strengthening the immune response to blood cancer

Armin Rehm and Uta Höpken want to improve our immune defenses against cancer. They have recently shown in human cells what was previously only possible in mouse models. Their findings, published in Molecular Therapy, have raised the chances of a highly effective immunotherapy being developed for blood cancer.

For patients with lymphoma, multiple myeloma, or certain types of leukemia, treatment with chimeric antigen receptor T cells (CAR T cells) is sometimes the last chance of overcoming the cancer. The treatment involves taking T cells from the patient’s blood and adding artificial receptors – the CARs – to them in the lab. As the guards of our immune system, T cells are on permanent patrol in our blood vessels and tissues, where they hunt down foreign structures. Equipped with CARs, T cells can also detect very specific surface structures on cancer cells. Once the CAR T cells are returned to the patient by infusion, they circulate in the body as a kind of living drug that can bind to very specific tumor cells and destroy them.

The engineered immune cells remain in the body permanently and multiply. If the cancer flares up again, they’ll go back into action. That’s the theory, at least. But in practice, many patients still relapse. This is because the tumor cells can outwit the CAR T cells by producing more of the protein EBAG9 – and by causing the T cells to produce more of it, too. In T cells, EBAG9 inhibits the release of cytotoxic enzymes, which slows the desired immune response.

A month earlier, a team led by last authors Dr. Armin Rehm and Dr. Uta Höpken from the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) showed in the journal JCI Insight that shutting down the EBAG9 gene in mice led to a sustained increase in the immune response to cancer. The mice also developed more T memory cells. These cells are part of our immunological memory, which allows our immune system to respond better to a cancer antigen after encountering it previously.

Now the researchers have also shown these key findings in vitro, in human CAR T cells. Writing in Molecular Therapy, the team says that this is the decisive step on the road to therapeutic use. “Shutting down EBAG9 allows the body to eradicate tumor cells earlier and more radically. As well as achieving longer-lasting therapeutic success, this could also create a real chance of cure,” says Rehm.

Releasing the brake for immunotherapy

As soon as the EBAG9 gene was discovered, researchers recognized that it played an important role in cancer. But it took a long time to identify what that role actually was. When the MDC team started working on it in 2009, they found that mice without the gene dealt with bacterial and viral infections much better than mice with the gene, and that they formed more T memory cells, which are of particular interest in tumor biology.

Then in 2015, lead author Dr. Anthea Wirges succeeded in curbing synthesis of the EBAG9 protein using microRNA. For the latest study, she used microRNA to cultivate “EBAG9-silenced” CAR T cells with different human leukemia or lymphoma cells. Just like in the mouse model, the silencing reduced tumor growth much more. Relapses also only developed much later.

“Releasing the EBAG9 brake allows the genetically engineered T cells to release more cytotoxic substances. However, they don’t cause the strong cytokine storm that is typically a side effect of CAR therapy,” says Wirges. In fact, the risk is minimized because fewer cells are used. “Switching off the immune brake works across the board. We can do it with every CAR T cell that we produce – regardless of which type of blood cancer it targets.

Clinical studies are the next step

However, the first-line therapy for blood cancer will remain chemotherapy combined with conventional antibody therapy, as many patients respond very well to this. “CAR therapy only comes into play if the cancer returns. It’s very expensive because it’s an individual cellular product for a single person,” says Höpken. And a single treatment with that product can save a life.

The EBAG9 work shows how important perseverance and patience are for researchers. Wirges was motivated by the prospect of her work having a real chance of clinical application. Rehm adds: “Projects like this allow you to get to grips with a technique in basic research and then apply everything in translational research – right up to toxicological screening for the regulatory processes.” Their project has now reached this last stage: The researchers will present their concept to the Paul Ehrlich Institute, Germany’s biologics approval agency, in November.

Thanks to their findings from animal models and the in vitro experiments using human cells, the team now knows that releasing the EBAG9 brake is highly effective and doesn’t cause any more side effects than conventional CAR T therapy. “We now need bold clinicians and a partner for financing the clinical studies,” says Rehm. If everything goes well, the therapy using EBAG9-silenced CAR T cells could be available to patients in as little as two years’ time.

Text: Catarina Pietschmann

Source: Press Release MDC
Strengthening the immune response to blood cancer

economic development / 21.07.2022
Eckert & Ziegler Affiliate Receives Further NIAID Funding for Clinical Development

Myelo Therapeutics GmbH, an Affiliate of Eckert & Ziegler Strahlen- und Medizintechnik AG (ISIN DE0005659700, SDAX), has announced that the U.S. National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, extended their contract to advance the development of the new chemical entity Myelo001 to mitigate the acute radiation syndrome. The extension into year three of the three-year contract provides additional $ 2 million USD to Myelo Therapeutics to develop clinical-stage Myelo001 as an oral formulation MCM for the treatment of Hematopoietic Acute Radiation Syndrome (H-ARS). Initially awarded in April 2020, the total contract is valued at up to $ 6.5 million USD over three years, extending until March 2023.

About Acute Radiation Syndrome: ARS, also known as radiation toxicity or radiation sickness, is an acute illness that presents after exposure of large portions of the body to high levels of radiation, like those that might be experienced during a radiological or nuclear incident or attack. The primary manifestation of ARS is the depletion of hematopoietic stem and progenitor cells, constituting one of the major causes of mortality.

About Myelo001: Myelo001 is a clinical-stage, adjuvant cancer therapy for the treatment of chemotherapy- and radiotherapy-induced myelosuppression. It is delivered as an oral tablet formulation and can be stored at room temperature. Preclinical and clinical studies have shown that Myelo001 has prophylactic and therapeutic efficacy in reducing hematopoietic symptoms caused by radiation and chemotherapy. In irradiated mice and rabbits, Myelo001 reduced the nadir and accelerated the recovery of neutrophils, lymphocytes, thrombocytes, and erythrocytes. In mice, treatment 24 hours post-total body irradiation resulted in increased survival, faster bone marrow recovery, and reduced body weight loss. Moreover, Myelo001 treatment prior to and after chemotherapy led to the accelerated recovery of blood cells in human subjects. Comprehensive chronic toxicology and safety studies, as well as clinical studies, have confirmed Myelo001’s excellent safety profile.

About Eckert & Ziegler: Eckert & Ziegler Strahlen- und Medizintechnik AG with its 900 employees, is a leading global specialist for isotope-related applications in nuclear medicine, industry, and radiation therapy. The company offers a broad range of services and products along the radioactive value chain, from early development work to contract manufacturing and distribution. Eckert & Ziegler shares (ISIN DE0005659700) are listed in the SDAX index of Deutsche Börse.

About Myelo Therapeutics: Myelo Therapeutics GmbH is a clinical-stage pharmaceutical company focused on developing medical countermeasures (MCM) and therapies for cancer supportive care in areas of high unmet medical needs, among them Radiation-Induced Myelosuppression (RIM), Acute Radiation Syndrome (ARS), and Chemotherapy-Induced Myelosuppression (CIM).

Quelle: Press Release EZAG
Eckert & Ziegler Affiliate Receives Further NIAID Funding for Clinical Development

Innovation / 20.07.2022
Eckert & Ziegler and PRECIRIX Sign Agreement on Priority Supply of the Therapeutic Radioisotope Actinium-225 (Ac-225)

Eckert & Ziegler (ISIN DE0005659700, SDAX) and the Belgian biotech company PRECIRIX NV (PRECIRIX) have signed an agreement for the supply of Actinium-225. This gives PRECIRIX priority access to Eckert & Ziegler's high-purity, non-carrier-added Actinium-225, which is used for the labeling of trial drugs in radionuclide therapy.

"Until now, clinical research and commercial use of Actinium-225 has been limited by the shortage of this radioisotope. We are therefore pleased to collaborate with PRECIRIX and to be able to supply radiopharmaceutical manufacturers with this promising therapeutic radioisotope," said Dr. Lutz Helmke, member of the Executive Board and Chief Operating Officer for the Medical Segment. "Thanks to our cooperation with the Nuclear Physics Institute of the Czech Academy of Sciences (UJF), the first radiochemical-grade production of Actinium-225 is planned for the end of 2023. We expect to subsequently submit a Drug Master File to the FDA (USA) to produce Actinium-225 in cGMP quality.

"Precirix is developing novel precision radiopharmaceuticals using single-domain antibodies to address the high unmet need in the treatment of solid tumors. We aim to unlock the value of both alpha and beta-emitting radionuclides in our broad pipeline of product candidates." explained Ruth Devenyns, Chief Executive Officer of Precirix. "We are particularly pleased to have an experienced radioisotope specialist like Eckert & Ziegler at our side to support our ambitious development plans."

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

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 SDAX index of Deutsche Börse.
Contributing to saving lives.

About Precirix

Precirix is a private, clinical-stage biopharmaceutical company founded in 2014 as a spin-off from the VUB, dedicated to extending and improving the lives of cancer patients by designing and developing precision radiopharmaceuticals, using camelid single-domain antibodies labeled with radioisotopes. The company has a broad pipeline with one product candidate in a Phase I/II clinical trial and two in advanced preclinical stage. Research on multiple isotopes, linker technology and combination therapies further expand the platform. Precirix’ technology also allows for a theranostic approach, where patients can be selected using a low dose/imaging version of the product, followed by a therapeutic dose for treatment.

www.ezag.com

Research / 14.07.2022
Unchartered territory in the human genome

Uncharted territories in the human genome. Bild: Karen Arnott/EMBL-EBI
Uncharted territories in the human genome. Bild: Karen Arnott/EMBL-EBI

An international consortium brings together 7,200 segments of the human genome that are virtually unexplored and presents a roadmap for integrating them into genome databases in “Nature Biotechnology”. They could hold information about what sets humans apart from other animals.

When researchers working on the Human Genome Project completely mapped the genetic blueprint of humans in 2001, they were surprised to find only around 20,000 genes that produce proteins. Could it be that humans have only about twice as many genes as a common fly? Scientists had expected considerably more.

Now, researchers from 20 institutions worldwide bring together more than 7,200 unrecognized gene segments that potentially code for new proteins. For the first time, the study makes use of a new technology to find possible proteins in humans – looking in detail at the protein-producing machinery in cells. The new study suggests the gene discovery efforts of the Human Genome Project were just the beginning, and the research consortium aims to encourage the scientific community to integrate the data into the major human genome databases.

The study recently published story in “Nature Biotechnology”, was co-led by Dr. Jorge Ruiz Orera from Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) in Germany, Dr. Sebastiaan van Heesch from the Princess Máxima Center for pediatric oncology in the Netherlands, Dr. Jonathan Mudge from the European Molecular Biology Laboratory – European Bioinformatics Institute (EMBL-EBI) in the United Kingdom, and Dr. John Prensner from the Broad Institute of MIT and Harvard in the United States.

New gene sequences remained out of reach

In the past few years, thousands of frequently very small open reading frames (ORFs) have been discovered in the human genome. These are spans of DNA sequence that may contain instructions for building proteins. Several authors of the current study have previously found ORFs and described them in scientific journals: Van Heesch, together with MDC-Professors Norbert Hübner and Uwe Ohler described new mini-proteins in the human heart and reported on them in “Cell in 2019; Prensner also published on ORFs in “Nature Biotechnology” in 2021. Yet none of these previously virtually unexplored segments were included afterwards in reference databases. Other sequences were reported in journals such as “Science” or “Nature Chemical Biology”, but remained largely out of reach for most members of the scientific community – despite evidence that they produce RNA molecules that subsequently bind to ribosomes, the cell’s protein factories.

Traditionally, protein-coding regions in genes have been identified by comparing DNA sequences from multiple species: the most important coding regions have been preserved during animal evolution. But this method has a drawback: coding regions that are relatively young, i.e., that arose during the evolution of primates, fall through the cracks and are therefore missing from the databases.

So now the task is to integrate the largely ignored ORFs into the largest reference databases, because researchers have so far had to specifically search for them in the literature if they wanted to study them.

As a first step, the international research team collected information on sequences that had been discovered using ribosome profiling – a technique that determines which part of the messenger RNA (mRNA) the ribosome interacts with. They then assembled the data into a standardized catalogue. This was no small feat, as data obtained in a wide variety of ways from different laboratories cannot simply be combined.

Once this was accomplished, the international consortium labored over central questions that define our very notion of the human genome: What is a gene? What is a protein? Do we need flexible notions of whether ribosomes always produce a protein or rather some other cellular output?

The group now calls for the human genome databases used by scientists worldwide to be revised. Ensembl-GENCODE are configuring this ORF catalog as a component of their reference annotation database. The approach will be supported by many others like UniProt, HGNC, PeptideAtlas and HUPO.

ORFs likely play a role in common diseases

Dr. Sebastiaan van Heesch, group leader at the Princess Máxima Center for pediatric oncology, says: “Our research marks a huge step forward in understanding the genetic make-up and complete number of proteins in humans. It’s tremendously exciting to enable the research community with our new catalog. It’s too soon to say whether all of the unexplored sections of DNA truly represent proteins, but we can clearly see that something unexplored is happening across the human genome and that the world should be paying attention.”

“For too long, the scientific community has been mostly left in the dark about these ORFs,” says Jonathan Mudge of the EMBL-EBI. “We’re very proud that our work will be able to let researchers across the world start to study them. This is the point at which they enter the mainstream of genomic and medical science – an effort which we expect to have wide-ranging ripple effects.”

“It is especially remarkable that most of these 7,200 ORFs are exclusive to primates and might represent evolutionary innovations unique to our species,” reports Jorge Ruiz-Orera, an evolutionary biologist working in Hübner’s lab at the MDC. “This shows how these elements can provide important hints of what makes us humans.”

So, what’s next? John Prensner, Broad Institute of MIT and Harvard, says: “These ORFs almost certainly will be contributing factors to many human traits and diseases, both rare diseases and common ones such as cancer. The challenge is now to figure out which ones have which roles in which diseases.”

About the Princess Máxima Center for pediatric oncology
When a child is seriously ill from cancer, only one thing matters: a cure. That is why in the Princess Máxima Center for pediatric oncology, we work together with passion, pushing the boundaries to improve survival and quality of life for children with cancer. Now, and in the long term. Because children have their entire lives ahead of them.The Princess Máxima Center for pediatric oncology is no ordinary hospital but a research hospital, the biggest childhood cancer center in Europe. Here, more than 400 scientists and 900 healthcare professionals work closely with Dutch and international hospitals to find new treatments and new perspectives for a cure. In this way, we offer children today the very best care, and take important steps toward improving survival for the children who are not yet cured.

About EMBL-EBI
The European Bioinformatics Institute (EMBL-EBI) is a global leader in the storage, analysis and dissemination of large biological datasets. We help scientists realise the potential of big data by enhancing their ability to exploit complex information to make discoveries that benefit humankind. We are at the forefront of computational biology research, with work spanning sequence analysis methods, multi-dimensional statistical analysis and data-driven biological discovery, from plant biology to mammalian development and disease. We are part of EMBL and are located on the Wellcome Genome Campus, one of the world’s largest concentrations of scientific and technical expertise in genomics.

Source: Joint press release by MDC, Prinses Máxima Centrum & EMBL-EBI
Unchartered territory in the human genome

www.mdc-berlin.de

Innovation / 12.07.2022
LegoChem Biosciences and Glycotope Announce Research Collaboration and License Agreement for an Antibody for use as Antibody Drug Conjugate

Seoul, South Korea, and Berlin, Germany - (July 12, 2022)

LegoChem Biosciences Inc. (LCB) and Glycotope GmbH (Glycotope) have signed a Research Collaboration and License Agreement to develop an antibody drug conjugate (ADC) by combining LCB's proprietary ADC technology with one of Glycotope's investigational tumor targeting antibodies.
Under the terms of the agreement LCB has the right to exercise its option for worldwide exclusive rights to develop and commercialize the selected antibody as ADC, upon successful completion of a feasibility study. If LCB exercises these rights, Glycotope will receive an upfront payment as well as development and sales milestone payments plus royalties. Specific financial terms have not been disclosed.

“Through this collaboration, once the candidate ADC is discovered and nominated, Glycotope and LCB plan to advance this very innovative program to clinical stage as a competitive cancer therapy,” said Dr. Yong-Zu Kim, CEO & President of LCB. “We are very pleased that companies with innovative antibody platforms, such as Glycotope have recognized the advantages of LCB’s linker-payload technology, which has been proven to be plasma stable as well as cancer-selectively activated.”

"This exciting collaboration with LegoChem further underlines the value of Glycotope’s unique technology platform and strengthens our leading position in the development of highly specific glyco-epitope targeting antibodies," added Henner Kollenberg, CEO, Glycotope.
“Our antibodies are designed to deliver increased tumor selectivity. Combining these with LCB’s ADC technology platform offers the opportunity to develop ADCs with potential to perform beyond today’s best standard of care,” said Patrik Kehler, CSO, Glycotope.

ADCs are a type of targeted cancer medicine that deliver cytotoxic chemotherapy ("payload") to cancer cells via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells. LCB's ADC platform technologies overcome the existing limitations of ADCs by imparting a trinity of improved properties, (1) site-specific stable bioconjugation (2) cancer selective linker activation and (3) cancer-selective activation of potent payload, all of which in a significantly broader Therapeutic Window.

Glycotope’s antibodies target specific tumor-associated carbohydrate structures or protein/carbohydrate combined glyco-epitopes (GlycoTargets). Targeting these specific antigens enables broad indication range, long-term treatment potential and reduced on-target/off tumor toxicity, key elements of highly potent therapies. Based on this unrivalled tumor-specificity, Glycotope’s antibodies are highly suitable for a multi-function platform approach with independent modes of action to provide a tailored therapy format for as many patients as possible. Contact Information: LegoChem Biosciences

About LegoChem Biosciences
LegoChem Biosciences (LCB, KOSDAQ: 141080) is a clinical-stage biopharmaceutical company focusing on the development of next-generation novel therapeutics utilizing its proprietary medicinal drug discovery technology LegoChemistry and ADC platform technology ConjuAll Since its foundation in 2006, LCB has focused on the research and development of Antibody-Drug-Conjugates (ADCs), antibiotics, anti-fibrotic and anticancer therapeutics based on proprietary platform technologies.

About Glycotope
Glycotope is a biotechnology company utilizing a proprietary technology platform to develop uniquely tumor-specific monoclonal antibodies. We combine expertise in glycobiology and antibody development to advance first-in-class therapeutics for oncology. Our antibodies target specific tumor-associated carbohydrate structures or protein/carbohydrate combined glyco-
epitopes (GlycoTargets). Based on their superior tumor-specificity, our 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. Glycotope has to date discovered more than 200 GlycoTargets with antibodies against several of these targets currently under development. Visit http://www.glycotope.com/.

www.glycotope.com

Innovation / 06.07.2022
Eckert & Ziegler Becomes Contract Manufacturer for Clinical Development Candidates Based on Lutetium-177 and Actinium-225

Eckert & Ziegler (ISIN DE0005659700, SDAX) has signed an agreement with the U.S. pharmaceutical company Ratio Therapeutics Inc. for the joint development and manufacture of innovative radiopharmaceutical products based on Lu-177 and Ac-225. The agreement covers the development of a validated manufacturing process as well as the GMP-compliant production of clinical investigational products. Ratio Therapeutics will use the newly built GMP suites at the Eckert & Ziegler production site near Boston, MA, USA, from July 2022 for this purpose.

"The growing interest in radiopharmaceuticals is creating a huge demand for expertise in the development and manufacture of investigational products. Due to the need to reduce costs, the pharmaceutical industry has initiated a paradigm shift in recent years - from a vertically integrated business model to a more cost-efficient supplier network. With our new GMP suites and our many years of know-how, we support the pharmaceutical industry in bringing their radiopharmaceuticals to market more quickly," explains Dr. Lutz Helmke, Executive Director and Chief Operating Officer at Eckert & Ziegler for the Medical segment.

“With Eckert & Ziegler, we have an established partner with best-in-class radiopharmaceutical manufacturing capabilities for medical and scientific use,” commented Dr. Matthias Friebe, Chief Technology Officer at Ratio Therapeutics. “Their expertise in radiopharmaceutical manufacturing will ensure high-quality products and robust manufacturing and logistics expertise for our upcoming clinical programs as we rapidly move toward the submission of our first investigational new drug (IND) application.”

The Eckert & Ziegler radiopharmaceutical production facility in Boston, MA, USA, has state-of-the-art hot cells for alpha, beta and gamma emitters, radiosynthesis, quality control and other equipment for production under GMP conditions. The rentable clean room suites are optimized for carrying out processes for the production of radiopharmaceuticals.

With the GMP facility, Eckert & Ziegler offers both regional and global pharmaceutical companies a one-stop service for a variety of radiopharmaceutical services under GMP and cGMP conditions. These include complete early development services including process development and scale-up, CMC manufacturing and packaging, product release and stability programs. As a radiopharmaceutical contract manufacturer, Eckert & Ziegler is able to produce small batches for Phase I, II and III clinical studies and large commercially applicable batch sizes.

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 SDAX index of Deutsche Börse.
Contributing to saving lives.

About Ratio Therapeutics.

Ratio Therapeutics Inc. is a Boston-based pharmaceutical company with the mission to accelerate the development of next-generation precision radiopharmaceuticals for solid tumors and, thus, transform oncology treatment paradigms. Ratio’s fully integrated proprietary R&D platforms, Trillium™ and Macropa™, enable the imaging, discovery and advancement of novel radiopharmaceuticals that have first/best-in-class delivery, safety and efficacy properties. The tunable nature of the company’s platforms allows the generation in an efficient and timely manner of numerous novel radiopharmaceuticals for a broad range of high unmet need in solid tumors. Please visit www.ratiotx.com for more information and follow us on Twitter and LinkedIn.

www.ezag.com

Research / 23.06.2022
A fine-tuned gene editor

Van Trung Chu working in the lab. © Felix Petermann, MDC
Van Trung Chu working in the lab. © Felix Petermann, MDC

The molecular tool CRISPR-Cas9 can be used to treat inherited blood disorders, but this may cause unintended genetic alterations. A team led by MDC researchers Klaus Rajewsky and Van Trung Chu has now presented an approach in “Science Advances” that minimizes such adverse consequences.

Hopes are high for the therapeutic potential of the CRISPR-Cas9 gene-editing tool. These “molecular scissors” can be used to very precisely cut out and repair gene mutations that are responsible for hereditary diseases. But despite the precision with which the tool is able to locate its target in the genome, its work is not yet completely error-free.

Sometimes, cuts are made at sites that are very similar to the target sequence, but are located in entirely different regions of the DNA. These mistakes, which scientists refer to as “off-target mutations,” can have unexpected consequences. And even if CRISPR-Cas9 makes its cut at the correct site, errors can occur when the cut is repaired – a phenomenon known as “on-target mutations”.

Spacing out the cuts

“These errors mainly occur because, in the classic method, both strands of the DNA molecule are cut at once,” explains Professor Klaus Rajewsky, head of the Immune Regulation and Cancer Lab at the Berlin Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC). Together with other researchers from the MDC and the Humboldt-Universität zu Berlin, the scientist has now presented a new, refined approach in the journal “Science Advances” that has been dubbed “spacer-nick”. This method employs a modified pair of molecular scissors, known as nickases, that make nicks on opposite strands of the DNA at two different points.

But the greater precision with which this gene-editing duo is able to detect and repair faulty genes is largely down to a spacer that the team has built into the tool. “We use this spacer to ensure that the two nicks are made 200 to 350 base pairs apart and that double-strand breaks in the DNA are avoided,” explains Dr. Van Trung Chu, a scientist in the Rajewsky Lab and co-last author of the paper, along with Rajewsky himself. “Our experiments with hematopoietic stem cells and T cells have shown that this is the optimal distance for minimizing both on-target and off-target mutations,” says Chu. “Any shorter, and we risk cutting through the entire DNA molecule – despite the use of two separate scissors.” 

Two other MDC teams – Professor Kathrin de la Rosa’s Cancer & Immunology / Immune Mechanisms and Human Antibodies Lab, and Dr. Ralf Kühn’s Genome Editing & Disease Models Lab, of which Chu is also a member – also made important contributions to the paper, especially in terms of detecting off-target mutations. “Spacer-nick is therefore also a good example of the successful collaboration between researchers working in the different labs at the MDC,” says Rajewsky.

Effective and almost error-free

The scientists can even quantify the superiority of their fine-tuned genetic scissors and offset double nicks: “With the classic CRISPR-Cas9 method, on-target mutations occur in more than 40 percent of interventions,” reports Chu. “The spacer-nick system can bring this down to under two percent.” The success with off-target mutations, Chu explains, cannot be determined quite as easily and accurately: “All we can really say is that they occur relatively frequently when the classic genetic scissors are used, but have been a rare, if not non-existent, occurrence in our approach.” What remains unclear for now is the exact mechanism by which the genetic material is repaired following the spacer-nick cuts. “It doesn’t seem to happen via the well-known – and error-prone – NHEJ pathway,” says Chu.

In terms of effectiveness, spacer-nick is on par with the conventional tool: “With both methods, we are able to successfully repair between 20 and 50 percent of the treated cells,” says Chu. That is probably enough, he explains, to cure patients with an inherited blood disorder that stems from only a single altered gene. Examples of such disorders include beta thalassemia, which involves the faulty synthesis of the red blood pigment hemoglobin, or severe congenital neutropenia, which is characterized by a significantly reduced number of granulocytes – a type of white blood cell – and is associated with a severely weakened immune defense.

Fixing stem cells 

Chu and Rajewsky hope that other researchers will take up their idea and test spacer-nick – first in animal models and then soon on the first human patients. Chu explains that the principle behind the therapy is simple: Blood-forming stem cells are taken from people with a monogenic inherited disorder using established methods. Spacer-nick then repairs the faulty genes directly in the cell culture. Once the genetic scissors have done their work, the repaired stem cells are administered back into the patient – where they produce new and, most importantly, healthy blood cells.

Text: Anke Brodmerkel

Source: Press Release MDC
A fine-tuned gene editor

Research / 21.06.2022
What makes blood vessels grow?

© AG Potente
© AG Potente

Blood vessels must adapt their growth to the nutrients available in their surroundings so that they can keep organs adequately supplied. A team led by Michael Potente has identified two proteins that are important for this process and published their findings in Nature Metabolism.

Blood vessels run throughout the human body and ensure that our organs get all the nutrients and oxygen they need. If these finely woven networks stop working as they should, we risk developing diseases. While age-related cardiovascular conditions frequently cause vessels to atrophy, malignant tumors are characterized by excessive growth of misrouted vessels. Wet macular degeneration is also associated with the sprouting of new blood vessels in the wrong place. At its worst, the condition can cause blindness.

A door-opener for nutrients

“To help us develop targeted therapies for these kinds of disease, we want to find out how exactly the growth of new blood vessels – a process called angiogenesis – is regulated within the body,” says Potente, who is Professor for Translational Vascular Biomedicine at the Berlin Institute of Health at Charité (BIH) and a guest researcher at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC). His Angiogenesis & Metabolism Laboratory is part of the Berlin Center for Translational Vascular Biomedicine, an interdisciplinary facility that is a joint focus area of the BIH, Charité – Universitätsmedizin Berlin, and the MDC.

Potente and his international team have now made some important progress: Writing in Nature Metabolism, the researchers report that two proteins named YAP and TAZ play a crucial role in allowing vessels to sprout, even under challenging metabolic conditions. The proteins are part of the Hippo signaling pathway, which regulates organ growth and size in almost all living things. “If these two molecules are active in the cells of the vessels’ inner wall – the endothelium – they read genes that lead to increased growth of certain surface transporters,” says Potente. “These allow the vessel cells to absorb more nutrients that are important for growth and cell division.” YAP and TAZ, which both function in a similar way, therefore act as a kind of door-opener.

“This increased absorption of nutrients leads to the activation of another protein, called mTOR,” says Potente. mTOR is an important control point in the cells that triggers growth and cell division. “This allows new blood vessel networks to expand,” he explains. However, the team does not yet know which signals regulate the activity of YAP and TAZ in endothelial cells.

Insights from mouse retinas

The study’s lead author is Dr. Yu Ting Ong from the Max Planck Institute for Heart and Lung Research in Bad Nauheim in western Germany. Before moving to Berlin, Potente led a lab there. Also involved in the report was Professor Holger Gerhardt, head of the Integrative Vascular Biology Laboratory at the MDC, who works next door to Potente in the Käthe Beutler Building in Berlin-Buch. “Together, we’ve discovered a mechanism that enables blood vessels to align their growth closely to the situation in their surroundings,” says Gerhardt. “The mechanism stops endothelial cells from dividing if the metabolic resources needed for the process aren’t there.”

The findings are based on mouse experiments. The mouse retina is an ideal model for studying blood vessel development. “Using genetically modified mouse lines, we showed how endothelial cells that don’t produce YAP and TAZ almost never divide,” says Potente. “This inhibited vessel growth in the mice.” The TAZ protein plays an especially important role in this process, while YAP is the decisive factor in most other types of cell.

Important molecular machinery

“Because new blood vessels frequently form in tissues with a poor blood supply, endothelial cells must be able to grow in the most challenging metabolic conditions,” says Potente. “That’s why it’s so important for these cells to have molecular machinery that recognizes and reacts to subtle changes in the extracellular milieu.”

Together with their teams, Potente and Gerhardt now want to study how much the mechanism – which they described during tissue development – is also involved in regeneration and repair processes that rely heavily on blood vessels. “We’re primarily interested in finding out whether and, if relevant, how malfunctions in that signaling pathway can cause vascular diseases in humans,” says Potente.

Text: Anke Brodmerkel

Further information

Photo: Growing blood vessel network in mouse retina made visible by immunofluorescence staining and confocal microscopy. Shown are the cells of the inner vessel wall - the endothelial cells (turquoise/white), which migrate into the surrounding tissue to form new connections. © AG Potente

Source: Joint press release by the Max Delbrück Center for Molecular Medicine and the Berlin Institute of Health at Charité
What makes blood vessels grow?

 

Research / 17.06.2022
Maike Sander named to lead the Max Delbrück Center

Prof. Dr. Maike Sander (Foto: Peter Himsel/MDC)
Prof. Dr. Maike Sander (Foto: Peter Himsel/MDC)

Maike Sander has been selected to direct the Max Delbrück Center for Molecular Medicine (MDC). The Supervisory Board appointed the diabetes researcher and professor of pediatrics and cellular and molecular medicine as the Scientific Director and Chair of the Board on June 16, 2022.

On November 1, 2022, Prof. Maike Sander will take the reins as Scientific Director and Chair of the Board of the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC). The Supervisory Board of the MDC formally appointed her to the post on Thursday, June 16, 2022. The MDC, which is celebrating its 30th anniversary this year, is one of five Health Centers in the Helmholtz Association of German Research Centers. The internationally renowned researcher and experienced science manager Maike Sander will be succeeding Prof. Thomas Sommer, who has directed the MDC on an interim basis since 2019. That will make Sander the first woman to head one of the Helmholtz Health Centers.

“The MDC has distinguished itself as an internationally renowned center for highly innovative biomedical research,” says Maike Sander. “Work at the MDC lays the foundation for better medicine of the future. The MDC provides on outstanding environment for research and attracts talent from around the globe. I had the opportunity to experience this first-hand as a visiting professor at the MDC. As Scientific Director, my goal will be to further strengthen the MDC’s role as a leading biomedical research center and to deepen partnerships with other institutions in Berlin and beyond, so that our discoveries can be rapidly turned into medical innovations.” Sander emphasizes that “medical innovation needs strong basic science, clinical science and industry partners – components that are all part of the vibrant Berlin biomedical ecosystem,” she points out. “The Berlin region is developing into a flourishing biotech pharma hub and I see the MDC as a principal driver of innovation in this landscape. I very much look forward to working with all stakeholders across Berlin.”

Novel therapeutic approaches for diabetes

Maike Sander’s research focuses on identifying novel therapeutic approaches for diabetes. To this end, Sander studies the molecular mechanisms that underlie the formation and function of the different cell types in the pancreas, in particular the insulin-producing beta cells. Her goal is to identify strategies for replacing beta cells in diabetes using beta cells derived from human pluripotent stem cells. 

Since 2012, Sander has served as the Director of the Pediatric Diabetes Research Center at the University of California, San Diego (UC San Diego), where she is also a Professor in the Departments of Pediatrics and Cellular & Molecular Medicine. In Berlin, Maike Sander will be appointed as Professor at the Charité – Universitätsmedizin.

German Research Minister: An outstanding scientist with international experience

“Maike Sander is an outstanding scientist with a track record of innovation in biomedical research,” says Bettina Stark-Watzinger, Germany’s Federal Minister of Education and Research. “I am delighted we have been able to bring her back to Germany after many years in the United States and to win her as the new Scientific Director of the Max Delbrück Center. It demonstrates the attractiveness of Berlin as a hub for biomedical research. As a scientist and administrator, Prof. Sander is the perfect match for the MDC with its mission to improve human health through transformative biomedical research. Also, having a female leader is an important signal. Prof. Sander’s appointment represents a significant gain for German research.”

Berlin’s Senator for Higher Education and Research, Health, Long-Term Care and Gender Equality, Ulrike Gote, says: “In Prof. Maike Sander, the Max Delbrück Center has gained an internationally renowned scientist as its new Scientific Director. I warmly welcome her to the science and healthcare metropolis Berlin. Prof. Sander’s expertise and experience provide the ideal background for future development of the MDC and for increasing the international visibility of the vibrant life sciences community at the MDC and in Berlin. As the senator in charge of higher education, research, and gender equality, I am delighted to see a woman at the helm of a Helmholtz Health Center.”

Wiestler: The Helmholtz Association stands to benefit tremendously

“I got to know Maike Sander as an expert in diabetes and stem cells when she was a visiting professor at the MDC,” says Otmar D. Wiestler, President of the Helmholtz Association. “With her high scientific standing and international experience, she is the ideal person to determine the future direction of the MDC as Scientific Director and Chair of the Board. With Prof. Sander we are gaining an excellent scientist whose expertise will be of tremendous benefit to the Helmholtz Association. A critical focus area is the development of precision medicine approaches. The MDC is at the forefront of advancing research in this important area. I look forward to working with Prof. Sander and to a vivid exchange of ideas.”

About Maike Sander

Maike Sander, a native of Göttingen, is 54 years old. After graduating with a medical degree from the University of Heidelberg Medical School in 1994, she conducted research at the University of California, San Francisco. Before moving to UC San Diego in 2008, she held faculty positions at Hamburg Medical School and the University of California, Irvine. An expert on insulin-producing pancreatic beta cells, she has nearly 30 years of experience in medicine and diabetes research.  

Sander is an elected member of the German National Academy of Sciences Leopoldina, the Association of American Physicians, and the American Society of Clinical Investigation. In addition, she is a member of two NIH consortia: The Human Islet Research Network and the NIH Impact of Genomic Variation on Function Consortium, which seeks to define basic mechanisms of gene regulation. 
 
She is a recipient of the Grodsky Award of the Juvenile Diabetes Research Foundation, the 2022 Albert Renold Prize of the European Association for the Study of Diabetes, and the Alexander von Humboldt Foundation Research Award. Since 2019, Sander has been an Einstein Visiting Fellow at the Berlin Institute of Health at Charité (BIH).

Source: Press Release MDC
Maike Sander named to lead the Max Delbrück Center

Research / 16.06.2022
Cancer Grand Challenge: Solving the mystery of DNA rings

Circular DNA: fluorescently labeled ecDNA (green) in tumor cell nuclei (blue). © AG Henssen, MDC
Circular DNA: fluorescently labeled ecDNA (green) in tumor cell nuclei (blue). © AG Henssen, MDC

Pediatric oncologist Anton Henssen and a group of researchers from the US and the UK have won funding for a Cancer Grand Challenge. The international team will receive almost €24 million to research the role that ring-shaped strands of DNA play in the development of cancer, and how to fight them.

In 2014, Professor Anton Henssen discovered something unusual in the cells of pediatric cancer patients: small rings of DNA, which meant that part of the genetic information was no longer packaged in the chromosomes as normal. It was very clear that the rings disturbed the rest of the genome so much that the children’s cells began to mutate.

Once he had made the discovery, Henssen (36) couldn’t stop thinking about it. A researcher and physician, Henssen has been leading the Emmy Noether Research Group “Genomic Instability in Pediatric Cancer” at the Experimental and Clinical Research Center (ECRC), a joint institution of Charité – Universitätsmedizin Berlin and the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), since 2019.

The role of the rings

“When I began getting interested in the circular DNA and its role in the development of cancer, I was pretty much on my own,” says Henssen, who in addition to his research work also treats young cancer patients at the Department of Pediatric Oncology and Hematology at Charité. The field is now attracting more scientific interest, he says.

Henssen and his project, CancerCirculome, have been receiving support for roughly two years now, thanks to a Starting Grant from the European Research Council. The funding initiative Cancer Grand Challenges, which was founded in 2020 by the two largest funders of cancer research worldwide (Cancer Research UK and the National Cancer Institute, part of the National Institutes of Health in the US), is also aware of the possibly underestimated role of the tiny DNA rings. It chose the topic of extrachromosomal DNA, or ecDNA for short, as one of the nine challenges in its latest funding round.

Cancer Grand Challenges currently supports more than 700 researchers and advocates across 10 countries, representing 11 teams are supported to take on 10 of the toughest challenges in cancer research. On 16 June, 4 new teams were announced.

Berlin team to get £1 million

“When I saw that, I knew I wanted to participate in the challenge,” says Henssen, who on June 1 began a Mildred Scheel Professorship funded by German Cancer Aid at Charité. He explains that just a handful of groups are working on ecDNA worldwide. Now the team he is part of – which brings together researchers from the US, the UK, and Germany and is led by Professor Paul Mischel of Stanford Medicine in California – has won funding from Cancer Grand Challenges for its project entitled eDyNAmiC (extrachromosomal DNA in Cancer). The team will receive £20 million over the next five years. Roughly one million of that will be available to Henssen and his team in Berlin.

Henssen says scientists now know that nearly a third of all childhood and adult tumors have DNA rings in their cells and that these tumors are almost always highly aggressive: “Now we want to find out what exactly makes the rings so dangerous, how they form, and how we can slow them down – so that we can develop more effective therapies.” Biologists and physicians aren’t the only ones tackling this challenge; mathematicians and computer scientists are also involved.

The prospect of brand-new therapies

Henssen and his Berlin team, which also includes researchers from the Berlin Institute of Health at Charité (BIH), plan to start by looking at the structure of the rings in more detail to find out how their DNA is packaged in histones and other proteins, and how their gene expression is regulated. “It’s possible that changes in gene expression mean the rings help the tumors become resistant to existing therapies,” says Henssen.

It’s not surprising that Henssen is delighted to see his once “niche” topic garnering such attention and support: “It’s the best thing that could have happened, as far as I’m concerned.” He now hopes that it won’t be too long before he can help his young patients – who have their whole lives ahead of them – with a novel therapy that attacks the rings and cause the fatal tumors to disappear.

Text: Anke Brodmerkel

Further information

The DNA artist – a portrait of Anton Henssen

Department of Pediatric Oncology and Hematology at Charité

Anton Henssen honored with Berlin science award

Anton Henssen receives ERC Starting Grant

Source: Joint press release by Charité – Universitätsmedizin Berlin and the Max Delbrück Center for Molecular Medicine
Cancer Grand Challenge: Solving the mystery of DNA rings

Research / 10.06.2022
AI identifies cancer cells

National Cancer Institute / NIH
National Cancer Institute / NIH

How do cancer cells differ from healthy cells? A new machine learning algorithm called “ikarus” knows the answer, reports a team led by MDC bioinformatician Altuna Akalin in the journal Genome Biology. The AI program has found a gene signature characteristic of tumors.

When it comes to identifying patterns in mountains of data, human beings are no match for artificial intelligence (AI). In particular, a branch of AI called machine learning is often used to find regularities in data sets – be it for stock market analysis, image and speech recognition, or the classification of cells. To reliably distinguish cancer cells from healthy cells, a team led by Dr. Altuna Akalin, head of the Bioinformatics and Omics Data Science Platform at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), has now developed a machine learning program called “ikarus.” The program found a pattern in tumor cells that is common to different types of cancer, consisting of a characteristic combination of genes. According to the team’s paper in the journal Genome Biology, the algorithm also detected types of genes in the pattern that had never been clearly linked to cancer before.

Machine learning essentially means that an algorithm uses training data to learn how to answer certain questions on its own. It does so by searching for patterns in the data that help it to solve problems. After the training phase, the system can generalize from what it has learned in order to evaluate unknown data. “It was a major challenge to get suitable training data where experts had already distinguished clearly between ‘healthy’ and ‘cancerous’ cells,” relates Jan Dohmen, the first author of the paper.

A surprisingly high success rate

In addition, single-cell sequencing data sets are often noisy. That means the information they contain about the molecular characteristics of individual cells is not very precise – perhaps because a different number of genes is detected in each cell, or because the samples are not always processed the same way. As Dohmen and his colleague Dr. Vedran Franke, co-head of the study, reports, they sifted through countless publications and contacted quite a few research groups in order to get adequate data sets. The team ultimately used data from lung and colorectal cancer cells to train the algorithm before applying it to data sets of other kinds of tumors.

In the training phase, ikarus had to find a list of characteristic genes which it then used to categorize the cells. “We tried out and refined various approaches,” Dohmen says. It was time-consuming work, as all three scientists relate. “The key was for ikarus to ultimately use two lists: one for cancer genes and one for genes from other cells,” Franke explains. After the learning phase, the algorithm was able to reliably distinguish between healthy and tumor cells in other types of cancer as well, such as in tissue samples from liver cancer or neuroblastoma patients. Its success rate tended to be extraordinarily high, which surprised even the research group. “We didn’t expect there to be a common signature that so precisely defined the tumor cells of different kinds of cancer,” Akalin says. “But we still can’t say if the method works for all kinds of cancer,” Dohmen adds. To turn ikarus into a reliable tool for cancer diagnosis, the researchers now want to test it on additional kinds of tumors.

AI as a fully automated diagnostic tool

The project aims to go far beyond the classification of “healthy” versus “cancerous” cells. In initial tests, ikarus already demonstrated that the method can also distinguish other types (and certain subtypes) of cells from tumor cells. “We want to make the approach more comprehensive,” Akalin says, “developing it further so that it can distinguish between all possible cell types in a biopsy.”

In hospitals, pathologists tend only to examine tissue samples of tumors under the microscope in order to identify the various cell types. It is laborious, time-consuming work. With ikarus, this step could one day become a fully automated process. Furthermore, Akalin notes, the data could be used to draw conclusions about the tumor’s immediate environment. And that could help doctors to choose the best therapy. For the makeup of the cancerous tissue and the microenvironment often indicates whether a certain treatment or medication will be effective or not. Moreover, AI may also be useful in developing new medications. “Ikarus lets us identify genes that are potential drivers of cancer,” Akalin says. Novel therapeutic agents could then be used to target these molecular structures.

Home-office collaboration

A remarkable aspect of the publication is that it was prepared entirely during the COVID pandemic. All those involved were not at their usual desks at the Berlin Institute for Medical Systems Biology (BIMSB), which is part of the MDC. Instead, they were in home offices and only communicated with one another digitally. In Franke’s view, therefore, “The project shows that a digital structure can be created to facilitate scientific work under these conditions.”

Text: Janosch Degg

 

Source: Press Release MDC
AI identifies cancer cells

Research / 09.06.2022
Immunotherapy may get a boost

Photo: Rita Elena Serda, NIH
Photo: Rita Elena Serda, NIH

T cells are usually very good at eliminating diseased cells. But they seem to fail when it comes to tumor cells. MDC researchers have recently discovered what inhibits this immune function. In JCI Insight, they describe how they can release the brake and boost the immune response against cancer.

T cells are the immune system’s SWAT team. Their job is to constantly patrol the blood, lymphatic system, tissues, and organs. If they come across cells that are contaminated with or damaged by pathogens, they eliminate them. They can also recognize and destroy cancer cells. The problem, though, is that the tumor cells find ways of escaping this line of defense. Researchers around the world are working to prevent these evasive maneuvers and harness T cells for targeted immunotherapies against cancer.

The labs led by Dr. Armin Rehm and Dr. Uta Höpken at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) in Berlin have now identified a mechanism that tumor cells use to dodge the body’s immune response. “In many cases, tumor cells read the EBAG9 gene especially often. The cells then produce a protein that protects them. But EBAG9 also influences the cells of the immune system because T cells produce it too. In T cells, EBAG9 inhibits the secretion of enzymes that act as poison to kill tumor cells,” says Rehm. Writing in the journal JCI Insight, the researchers describe how they released this brake in mice: “We shut down the EBAG9 gene,” says co-lead author Dr. Anthea Wirges, who works in Rehm’s research group. “This meant we could stop EBAG9 being produced in the T cells and strengthen the immune response to cancer for the long term.”

EBAG9 disarms immune cells

Scientists already know that cancer cells can outwit immune cells. This knowledge led to the development of checkpoint inhibitors, a type of immunotherapy that is already in clinical use. Checkpoint inhibitors make it hard for the cancer cells to trick T cells into thinking they’re harmless. “But EBAG9 gives cancer cells another line of defense against our immune system,“ says Rehm. “It disarms the immune cells and stops them from secreting substances that would harm the cancer cells.”

Rehm and Höpken have long suspected that EBAG9 inhibits T cells. In 2009, Rehm’s ream developed a mouse model in which the researchers switched off the EBAG9 gene. “The mice’s immune system worked better without EBAG9 and they were able fight infections much more effectively,” says Rehm. Höpken’s team then crossed the EBAG9-free mice with another genetically modified mouse model that spontaneously developed leukemia. “We observed these doubly modified mice over a long period of time,” says Höpken. “Their tumors developed much more slowly than in the mice with EBAG9.”

Cancer and infections trigger different immune responses

Wirges checked the effects of the EBAG9 gene on the T cells using single-cell RNA sequencing and bioinformatic methods. As well as confirming that EBAG9 inhibits the T cell response, the data also showed that the immune response to cancer differs from the one triggered by infections.

“Knowledge about how the immune system develops a ‘memory’ comes from infection models. It can’t be transferred 1:1 to tumors,” says Rehm. T cells recognize diseased or infected cells by the signaling molecules on their surface. When they detect these harmful structures, they differentiate into cytotoxic T cells and memory T cells. The cytotoxic T cells secrete proteins that punch holes in the target cell’s membrane so that they can penetrate it and kill it by poisoning. Infected tissue also produces inflammatory signaling molecules, such as cytokines, that summon more T cells and cause them to mature into memory T cells. The memory cells record the immune response so that the immune system doesn’t have to start from scratch every time the T cells detect a disease.

The idea: Create CAR T cells without an immune brake

Tumors don’t cause inflammation in their early stages. Previously, scientists assumed that this was because T cells can’t identify tumor cells very well. “Because they’re produced by the body, tumor cells have very few surface molecules that are identifiable as foreign,” says Höpken. But it seems as if these minimal differences are enough for the T cells to spot the tumor cells: When the researchers switched off EBAG9, the reaction was astonishing. “The uninhibited T cells eliminate tumor cells very early and very radically,” notes Rehm. This also creates lasting protection against tumor cells. “The stronger the initial T cell reaction, the better the subsequent T cell memory,” says Rehm.

“Based on these findings, we now want to develop CAR T cells without EBAG9 as an immunotherapy for leukemia,“ says Wirges. CAR stands for chimeric antigen receptor – an artificial receptor that detects tumor cells and is integrated into the patient’s own T cells. When patients have a CAR T-cell infusion, it equips their body with cells capable of fighting the cancer. The MDC researchers expect the CAR T cells to be even more effective without EBAG9. Although it will be a while before the cells reach the clinical trial stage, it could well be worth the wait: “We aren’t just hoping that this therapy will result in more efficient treatments for leukemia and lymphoma. We’re hoping that it will cure them,” says Rehm.

Text: Jana Ehrhardt-Joswig

Further information

AG Höpken, Microenvironmental Regulation in Autoimmunity and Cancer
AG Rehm, Translational Tumorimmunology

Literature

Armin Rehm et al. (2022): “EBAG9 controls CD8 + T cell memory formation responding to tumor challenge in mice.” JCI Insight, DOI: 10.1172/jci.insight.155534

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 / 03.05.2022
FMP & LMU spin-off Tubulis closes €60 million Series B financing to accelerate its ADC Pipeline

Great relief after the contract was signed: Ingo Lehrke, Christian Hackenberger, Marc-André Kasper, Dominik Schumacher and Jonas Helma-Smets (Foto: Tubulis)
Great relief after the contract was signed: Ingo Lehrke, Christian Hackenberger, Marc-André Kasper, Dominik Schumacher and Jonas Helma-Smets (Foto: Tubulis)

The company Tubulis announced today the closing of a Series B financing round totaling €60 million to advance the development of a novel class of highly stable and efficient antibody drug conjugates (ADCs) for treating cancer, and to expand its breadth of platform technologies.

Tubulis has a set of proprietary technologies for producing novel and particularly stable antibody drug conjugates (ADCs). Their portfolio enables the company to link a wide range of drugs to an antibody specific to the relevant indication by way of stable coupling (conjugation). One positive aspect of this is that adverse side effects in healthy tissue can be minimized, since biophysical properties of the ADC are optimized and the drug is prevented from separating from the antibody prematurely, a common side effect from current compounds on the market. In addition, the company’s proprietary technologies offer the potential to generate previously inaccessible protein-drug combinations, enabling a broader therapeutic window.

“Our research group is very proud to be part of Tubulis’ success story. Together with Prof. Heinrich Leonhardt’s group at LMU München, we have developed new methods to generate the novel ADCs that form the scientific basis that Tubulis uses. Closing the Series B round is a big step forward and the proceeds will enable the company to deliver the true therapeutic potential of ADCs through further innovation of novel payload classes and identification of new cancer targets.” remarks Professor Dr. Christian Hackenberger, Head of Chemical Biology at the FMP and Leibniz-Humboldt Professor at the Humboldt-Universität zu Berlin and co-founder of Tubulis.

 “This funding emphasizes that Tubulis is uniquely positioned to consolidate the findings of the last 20 years in the ADC field and translate this understanding into meaningful therapeutic benefits for patients. We have reached an important inflection point in the development of our platform technologies as well as our pipeline of highly novel protein-drug conjugates and we are now focused on unlocking new avenues in the treatment of solid tumors bringing safe and effective ADCs to patients,” said Dominik Schumacher, PhD, CEO and co-founder of Tubulis. “With this capital in place, we will execute on our growth strategy, including important focus areas for our pipeline and for how we can apply our proprietary technologies, biologic insights and new mechanisms of action to enable the true therapeutic value inherent in targeted therapeutics.”

In conjunction with the round, Sofia Ioannidou, PhD, Partner at Andera Partners, Thomas Hanke, PhD, EVP, Head of Academic Partnerships at Evotec as well as Jan Van den Bossche, Partner at Fund+ will join Tubulis’ Board of Directors consisting of Sebastian Pünzeler, PhD, Principal at coparion, Dominik Schumacher, PhD, CEO of Tubulis and Christian Grøndahl, MD, DVM, PhD, MBA, the Chairman of the Board. In addition, Valentin Piëch, PhD, Partner at BioMedPartners will take over the board seat from Michael Wacker, PhD, General Partner at BioMedPartners.

Tubulis was founded as a spin-off of the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) in Berlin and the Ludwig-Maximilians-Universität (LMU) München in 2019.

Press release at the website of the FMP

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.

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